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Sample records for bisphosphonate zoledronic acid

  1. The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation

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    Xie, Fan; Li, Pengcheng; Gong, Jianhua; Zhang, Jiahong; Ma, Jingping

    2015-01-01

    Aberrant activation of oncoproteins such as members of the Ras family is common in human lung cancers. The proper function of Ras largely depends on a post-translational modification termed prenylation. Bisphosphonates have been shown to inhibit prenylation in cancer cells. In this study, we show that zoledronic acid, a third generation bisphosphonate, is effective in targeting lung cancer cells. This is achieved by the induction of apoptosis and inhibition of proliferation, through suppressing the activation of downstream Ras and EGFR signalling by zoledronic acid. The combination of zoledronic acid and paclitaxel or cisplatin (commonly used chemotherapeutic drugs for lung cancer) augmented the activity of either drug alone in in vitro lung cancer cellular system and in vivo lung xenograft mouse model. Importantly, zoledronic acid inhibits protein prenylation as shown by the increased levels of unprenylated Ras and Rap1A. In addition, the effects of zoledronic acid were reversed in the presence of geranylgeraniol and farnesol, further confirming that mechanism of zoledroinc acid's action in lung cancer cells is through prenylation inhibition. Since zoledronic acid is already available for clinic use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of lung cancer. - Highlights: • Zoledronic acid (ZA) is effectively against lung cancer cells in vitro and in vivo. • ZA acts on lung cancer cells through inhibition of protein prenylation. • ZA suppresses global downstream phosphorylation of Ras signalling. • ZA enhances the effects of chemotherapeutic drugs in lung cancer cells.

  2. The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation

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    Xie, Fan [Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China); Li, Pengcheng [Department of Oncology, Wuhan Union Hospital Affiliated to Huazhong University of Science and Technology, Wuhan (China); Gong, Jianhua; Zhang, Jiahong [Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China); Ma, Jingping, E-mail: mjpjzhospital@hotmail.com [Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China)

    2015-11-27

    Aberrant activation of oncoproteins such as members of the Ras family is common in human lung cancers. The proper function of Ras largely depends on a post-translational modification termed prenylation. Bisphosphonates have been shown to inhibit prenylation in cancer cells. In this study, we show that zoledronic acid, a third generation bisphosphonate, is effective in targeting lung cancer cells. This is achieved by the induction of apoptosis and inhibition of proliferation, through suppressing the activation of downstream Ras and EGFR signalling by zoledronic acid. The combination of zoledronic acid and paclitaxel or cisplatin (commonly used chemotherapeutic drugs for lung cancer) augmented the activity of either drug alone in in vitro lung cancer cellular system and in vivo lung xenograft mouse model. Importantly, zoledronic acid inhibits protein prenylation as shown by the increased levels of unprenylated Ras and Rap1A. In addition, the effects of zoledronic acid were reversed in the presence of geranylgeraniol and farnesol, further confirming that mechanism of zoledroinc acid's action in lung cancer cells is through prenylation inhibition. Since zoledronic acid is already available for clinic use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of lung cancer. - Highlights: • Zoledronic acid (ZA) is effectively against lung cancer cells in vitro and in vivo. • ZA acts on lung cancer cells through inhibition of protein prenylation. • ZA suppresses global downstream phosphorylation of Ras signalling. • ZA enhances the effects of chemotherapeutic drugs in lung cancer cells.

  3. Safety and tolerability of zoledronic acid and other bisphosphonates in osteoporosis management

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    Luca Dalle Carbonare

    2010-08-01

    Full Text Available Luca Dalle Carbonare, Mirko Zanatta, Adriano Gasparetto, Maria Teresa ValentiClinic of Internal Medicine D, Department of Medicine, University of Verona, ItalyAbstract: Bisphosphonates (BPs are widely used in the treatment of postmenopausal ­osteoporosis and other metabolic bone diseases. They bind strongly to bone matrix and reduce bone loss through inhibition of osteoclast activity. They are classified as nitrogen- and non-nitrogen-containing bisphosphonates (NBPs and NNBPs, respectively. The former inhibit farnesyl diphosphate synthase while the latter induce the production of toxic analogs of adenosine triphosphate. These mechanisms of action are associated with different antifracture efficacy, and NBPs show the most powerful action. Moreover, recent evidence indicates that NBPs can also stimulate osteoblast activity and differentiation. Several randomized control trials have demonstrated that NBPs significantly improve bone mineral density, suppress bone turnover, and reduce the incidence of both vertebral and nonvertebral fragility fractures. Although they are generally considered safe, some side effects are reported (esophagitis, acute phase reaction, hypocalcemia, uveitis, and compliance with therapy is often inadequate. In particular, gastrointestinal discomfort is frequent with the older daily oral administrations and is responsible for a high proportion of discontinuation. The most recent weekly and monthly formulations, and in particular the yearly infusion of zoledronate, significantly improve persistence with treatment, and optimize clinical, densitometric, and antifracture outcomes.Keywords: bisphosphonates, osteoporosis, safety, tolerability, zoledronic acid

  4. Symptomatic Hypocalcemia Associated with Zoledronic Acid Treatment for Osteoporosis: A Case Report

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    Abdulmohsen H. Al Elq

    2013-03-01

    Full Text Available Intravenous bisphosphonates are widely used in the management of solid tumors, metastatic bone disease, metabolic bone diseases and hypercalcemia of malignancies. Recently, yearly intravenous injections of zoledronic acid, one of the potent nitrogen-containing bisphosphonates, have also been approved for the prevention and treatment of osteoporosis. Although infrequently observed, asymptomatic hypocalcemia mainly due to intravenous bisphosphonates has been documented. Here we report a female patient who exhibited profound symptomatic hypocalcemia after receiving intravenous zoledronic acid as treatment of postmenopausal osteoporosis. The patient was not assessed for calcium status prior to the intravenous bisphosphonate therapy, and she was later found to have severe vitamin D deficiency. To our knowledge, this is the first patient with symptomatic hypocalcemia to be reported after zoledronic acid was approved for the management of osteoporosis. We highlight the importance of evaluating calcium and vitamin D levels before initiating intravenous bisphosphonate treatment, particularly in the presence of widespread vitamin D deficiency and the likelihood of future increases in the prescription of intravenous bisphosphonates.

  5. Bilateral retrobulbar optic neuropathy as the only sign of zoledronic acid toxicity.

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    Lavado, Félix Manco; Prieto, Marta Para; Osorio, María Rosalba Ramoa; Gálvez, María Isabel López; Leal, Lucía Manzanas

    2017-10-01

    Bisphosphonates may rarely cause ocular adverse effects and retrobulbar optic neuropathy (RON) secondary to zoledronic acid is very rare. A 67-year-old man was referred because of progressive and painless decrease vision in the left eye. He had been treated with 7 cycles of zoledronic acid infusions because of metastatic prostate cancer. On examination, VA was 20/20 in the right eye (OD) and 20/50 in the left eye (OS). The optic nerve was unremarkable OU. Pattern visual evoked potentials (pVEP) and electroretinography were performed with the result of VEP responses abolished in OS, and the VEP waveform within the normal range amplitude and delayed peak latencies in OD. Due to the high suspicion of bilateral RON secondary to zoledronic acid, we decided to discontinue the treatment. Two months later, VA was 20/20 OD and hand motions OS, with relative afferent pupillary defect and a pallor of the optic disc in OS. The diagnosis of bilateral RON secondary to zoledronic acid infusions was confirmed, and it was only partially reversible. Zoledronic acid is a potent new generation bisphosphonate increasingly used in oncologic patients and it is usually well tolerated. Optic nerve toxicity is not a side effect recognised by either the Food and Drug Administration or the drug manufacturers, and to our knowledge, this is the first case of zoledronic acid-related bilateral RON with late onset. In conclusion, patients treated with bisphosphonates should be informed about the possibility of ocular side-effects, and ophthalmologists should be consider discontinuing the drug. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Once-yearly zoledronic acid in the prevention of osteoporotic bone fractures in postmenopausal women

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    Irene Lambrinoudaki

    2008-09-01

    Full Text Available Irene Lambrinoudaki, Sophia Vlachou, Fotini Galapi, Dimitra Papadimitriou, K Papadias2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieio Hospital, GreeceAbstract: Zoledronic acid is a nitrogen-containing, third-generation bisphosphonate that has recently been approved for the treatment of postmenopausal osteoporosis as an annual intravenous infusion. Zoledronic acid is an antiresorptive agent which has a high affinity for mineralized bone and especially for sites of high bone turnover. Zoledronic acid is excreted by the kidney without further metabolism. Zoledronic acid administered as a 5 mg intravenous infusion annually increases bone mineral density in the lumbar spine and femoral neck by 6.7% and 5.1% respectively and reduces the incidence of new vertebral and hip fractures by 70% and 41% respectively in postmenopausal women with osteoporosis. Most common side effects are post-dose fever, flu-like symptoms, myalgia, arthralgia, and headache which usually occur in the first 3 days after infusion and are self-limited. Rare adverse effects include renal dysfunction, hypocalcemia, atrial fibrillation, and osteonecrosis of the jaw.Keywords: zoledronic acid, postmenopausal osteoporosis, bisphosphonate

  7. Zoledronic acid in metastatic chondrosarcoma and advanced sacrum chordoma: two case reports

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    Capasso Elena

    2009-01-01

    Full Text Available Abstract Introduction Chondrosarcomas and chordomas are usually chemoresistant bone tumors and may have a poor prognosis when advanced. They are usually associated with worsening pain difficult to control. Patients and Methods Zoledronic acid was used in a 63-year-old man with metastatic chondrosarcoma and in a 66-year-old woman with a diagnosis of sacrum chordoma both reporting severe pain related to tumor. Results In the first case, zoledronic acid was able to maintain pain control despite disease progression following chemotherapy, in the other case, zoledronic acid only produced significant clinical benefit. Conclusion Control of pain associated with bone tumors such as chondrosarcoma and chondroma may significantly improve from use of zoledronic acid, independently from tumor response to other treatments. Evaluation on larger series are needed to confirm the clinical effect of this bisphosphonate on such tumors.

  8. Use of Zoledronic Acid in Paediatric Craniofacial Fibrous Dysplasia

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    Chiara Di Pede

    2016-01-01

    Full Text Available We describe a case of a paediatric patient affected by mandibular fibrous dysplasia (FD with severe and chronic pain who was successfully treated with zoledronic acid (ZOL: a third-generation bisphosphonate. Further research is needed to assess its safety and efficacy as a treatment option for FD in the paediatric population.

  9. Orthodontic tooth movement and root resorption in ovariectomized rats treated by systemic administration of zoledronic acid.

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    Sirisoontorn, Irin; Hotokezaka, Hitoshi; Hashimoto, Megumi; Gonzales, Carmen; Luppanapornlarp, Suwannee; Darendeliler, M Ali; Yoshida, Noriaki

    2012-05-01

    The effect of zoledronic acid, a potent and novel bisphosphonate, on tooth movement and orthodontically induced root resorption in osteoporotic animals systemically treated with zoledronic acid as similarly used in postmenopausal patients has not been elucidated. Therefore, this study was undertaken. Fifteen 10-week-old female Wistar rats were divided into 3 groups: ovariectomy, ovariectomy + zoledronic acid, and control. Only the ovariectomy and ovariectomy + zoledronic acid groups underwent ovariectomies. Two weeks after the ovariectomy, zoledronic acid was administered only to the ovariectomy + zoledronic acid group. Four weeks after the ovariectomy, 25-g nickel-titanium closed-coil springs were applied to observe tooth movement and orthodontically induced root resorption. There were significant differences in the amounts of tooth movement and orthodontically induced root resorption between the ovariectomy and the control groups, and also between the ovariectomy and the ovariectomy + zoledronic acid groups. There was no statistically significant difference in tooth movement and orthodontically induced root resorption between the ovariectomy + zoledronic acid and the control groups. Zoledronic acid inhibited significantly more tooth movement and significantly reduced the severity of orthodontically induced root resorption in the ovariectomized rats. The ovariectomy + zoledronic acid group showed almost the same results as did the control group in both tooth movement and orthodontically induced root resorption. Zoledronic acid inhibits excessive orthodontic tooth movement and also reduces the risk of severe orthodontically induced root resorption in ovariectomized rats. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  10. Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project

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    F. Bertoldo

    2011-06-01

    Full Text Available Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Despite evidence supporting the anti-fracture efficacy of aminobisphosphonates approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within the first year. Poor compliance is associated with negative outcomes, including increased fracture risk. Tolerability and safety are among the causes of poor compliance. Intravenous bisphosphonates avoids the gastrointestinal intolerance and the complex dosing instruction of the oral route ensuring full compliance which may provide improved efficacy. However, there are some concerns regarding potent intravenous bisphosphonates as zoledronic acid with respect to tolerability, mainly the acute phase response and to safety, mainly a theoretical risk of over suppression of bone turnover, renal toxicity and osteonecrosis of the jaw. In the HORIZON study, 152 patients on active treatment (82 or placebo (70 underwent to a bone biopsy after double tetracycline labeling. Bone biopsies (iliac crest were obtained at the final visit at month 36, 1 year after the last infusion. The biopsies were analyzed by histomorphometry on bone sections and by micro-CT (μCT analysis. 143 biopsies (76 zoledronic acid, 67 placebo had at least one μCT parameter measured and 111 were available for quantitative histomorphometry (59 zoledronic acid, 52 placebo. Micro-CT analysis of bone structure revealed higher trabecular bone volume (BV/TV, decreased trabecular separation (Tb.Sp, and a strong trend towards improvement in connectivity density in biopsies obtained from patients treated with zoledronic acid, indicating preservation of trabecular bone structure with respect to placebo. Histomorphometric analysis obtained from patients treated with zoledronic acid exhibited reduction of bone turnover, as suggested by decreased activation frequency (Ac.F by 63%, mineralizing surface (MS

  11. In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover.

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    De Colli, Marianna; Tortorella, Paolo; Marconi, Guya Diletta; Agamennone, Mariangela; Campestre, Cristina; Tauro, Marilena; Cataldi, Amelia; Zara, Susi

    2016-11-01

    Bisphosphonates (BPs) are drugs clinically used in resorptive diseases. It was already proved that some clinically relevant BPs can inhibit a class of enzymes called matrix metalloproteinases (MMPs), required during tissue remodelling. Combining the arylsulfonamide function with the bisphosphonic group, several compounds were synthesized to obtain selective inhibitors of MMPs. The aim of the present study was to compare the effect of zoledronic acid (ZA), the most potent bisphosphonate available as therapy, with new sulfonamide containing BPs in an in vitro model of human gingival fibroblasts (HGFs). Western blot was used to measure procollagen I, β1 integrin MMP-8 and MMP-9, phase contrast and MTT for cell viability; L-lactate-dehydrogenase (LDH) measurement was performed for toxicity evaluation and ELISA for prostaglandin E 2 (PGE 2 ) secretion assessment. When compared with ZA, the treatment with the newly synthesized compounds shows increasing viability, procollagen I expression and decreased expression of β1 integrin in HGFs. Higher levels of released LDH, PGE 2 and MMP-9 expression are recorded in ZA-treated HGFs. Increased levels of MMP-8 are recorded in newly synthesized compounds-treated samples. These findings allowed to conclude that new tested BPs did not affect HGFs viability and adhesion, did not induce cellular toxicity, were not responsible for inflammatory event induction and could preserve the physiological matrix turnover. It could be hypothesized that the new molecules were better tolerated by soft tissues, resulting in lesser side effects.

  12. Zoledronic Acid Treatment in Primary Bone Marrow Edema Syndrome.

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    Flores-Robles, Bryan Josué; Sanz-Sanz, Jesus; Sanabria-Sanchinel, Adel Abel; Huntley-Pascual, Dixie; Andréu Sánchez, José Luis; Campos Esteban, José; Blanco, Ricardo; Merino-Argumanez, Carolina; Espinosa-Malpartida, Maria; Ramos-Giráldez, Maria Consuleo; Godoy-Tundidor, Hildegarde; Jiménez-Palop, Maria Mercedes; Barbadillo Mateos, Carmen; Villa-Alcázar, Luis Fernando; Isasi, Carlos Maria; Mulero, Juan Bartolome

    2017-03-01

    Primary bone marrow edema syndrome (BMES) is characterized by the combination of joint pain and distinctive magnetic resonance imaging changes. It has been suggested that the use of bisphosphonate drugs reduce symptom severity. Our objective was to review cases of patients diagnosed with BMES in the last 7 years who had been treated with zoledronic acid. Access to a pharmaceutical database was gained in order to obtain a list of zoledronic acid prescriptions. Based on clinical and MRI criteria for BMES, patients were selected. Baseline pain intensity was evaluated on a scale of 0 to 3 and was also assessed after 3 and 12 months. Functional recovery was evaluated by noting if a patient had returned to carrying out his or her normal daily activities. Out of 633 patients, 17 cases of BMES were identified (8 men), with a median age of 54 ± 14.1 years. The most frequently affected joint was the ankle (9), followed by the hip. Sixteen patients presented with moderate to severe pain initially. Of those patients, 13 had no pain after 12 months. Zoledronic acid is a option in the management of BMES, since 75% of patients treated with it presented with a complete response.

  13. Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid.

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    Meckel, M; Bergmann, R; Miederer, M; Roesch, F

    2017-01-01

    Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68 Ga-labelled analogues, endoradiotheraphy with 177 Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTA PAM and DOTA ZOL (MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68 Ga and the β - emitting nuclide 177 Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [ 18 F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats. The new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68 Ga and >98 % with 177 Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [ 68 Ga]DOTA ZOL (SUV Femur  = 5.4 ± 0.6) followed by [ 18 F]NaF (SUV Femur  = 4.8 ± 0.2), [ 68 Ga]DOTA PAM (SUV Femur  = 4.5 ± 0.2) and [ 68 Ga]BPAPD (SUV Femur  = 3.2 ± 0.3). [ 177 Lu]DOTA ZOL showed a similar distribution as the diagnostic 68 Ga complex. The 68 Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [ 68 Ga]DOTA ZOL , which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177 Lu. The therapeutic compound [ 177 Lu]DOTA ZOL showed a high target-to-background ratio. SPECT experiments showed concordance

  14. Zoledronic Acid Injection

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    Zoledronic acid (Reclast) is used to prevent or treat osteoporosis (condition in which the bones become thin and weak ... of life,' end of regular menstrual periods). Zoledronic acid (Reclast) is also used to treat osteoporosis in ...

  15. PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells.

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    Anitua, Eduardo; Zalduendo, Mar; Troya, María; Orive, Gorka

    2016-04-01

    Bisphosphonates-related osteonecrosis of the jaw (BRONJ) is a common problem in patients undergoing long-term administration of highly potent nitrogen-containing bisphosphonates (N-BPs). This pathology occurs via bone and soft tissue mechanism. Zoledronic acid (ZA) is the most potent intravenous N-BP used to prevent bone loss in patients with bone dysfunction. The objective of this in vitro study was to evaluate the role of different ZA concentrations on the cells from human oral cavity, as well as the potential of plasma rich in growth factors (PRGF) to overcome the negative effects of this BP. Primary human gingival fibroblasts and primary human alveolar osteoblasts were used. Cell proliferation was evaluated by means of a fluorescence-based method. A colorimetric assay to detect DNA fragmentation undergoing apoptosis was used to determine cell death, and the expression of both NF-κB and pNF-κB were quantified by Western blot analysis. ZA had a cytotoxic effect on both human gingival fibroblasts and human alveolar osteoblasts. This BP inhibits cell proliferation, stimulates apoptosis, and induces inflammation. However, the addition of PRGF suppresses all these negative effects of the ZA. PRGF shows a cytoprotective role against the negative effects of ZA on primary oral cells. At present, there is no definitive treatment for bisphosphonates-related osteonecrosis of the jaw (BRONJ), being mainly palliatives. Our results revealed that PRGF has a cytoprotective role in cells exposed to zoledronic acid, thus providing a reliable adjunctive therapy for the treatment of BRONJ pathology.

  16. A randomized controlled trial to compare the efficacy of bisphosphonates in the management of painful bone metastasis

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    Krishnangshu Bhanja Choudhury

    2011-01-01

    Conclusion: The use of bisphosphonates for 6 months or more results in a statistical significant improvement in bone pain, more so with zoledronic acid. Hypercalcemia, an SRE, was significantly less in the zoledronic acid arm.

  17. Zoledronic acid and alendronate sodium and the implications in orthodontic movement.

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    Franzoni, J S; Soares, F M P; Zaniboni, E; Vedovello Filho, M; Santamaria, M P; Dos Santos, G M T; Esquisatto, M A M; Felonato, M; Mendonca, F A S; Franzini, C M; Santamaria, M

    2017-08-01

    To evaluate orthodontic tooth movement (OTM) in rats treated with two types of bisphosphonates (BPs), alendronate sodium (A) and zoledronic acid (Z). In all, 15 male Wistar rats were randomly divided into three groups. Group OTM+A: orthodontic tooth movement and subcutaneous administration of alendronate sodium (2.5 mg/kg); Group OTM+Z: orthodontic tooth movement and subcutaneous administration of zoledronic acid (0.02 mg/kg), and Group OTM: orthodontic tooth movement and subcutaneous injection of saline. The BPs were administered once a day during 25 days before OTM started and during 10 days of OTM. The left upper first molar was moved with a stainless-steel closed coil spring which delivered an initial force of 0.4N. OTM was measured with a digital caliper comparing the moved and the contralateral side. The histomorphometric analysis counted the number of osteoclasts, inflammatory cells, blood vessels and fibroblasts (n/10 4  m 2 ) in periodontal ligament (PDL) of the distobuccal root. A reduction of 58.3% of OTM was found in Group OTM+A and 99.6% in Group OTM+Z, when compared with Group OTM. There was a significant decrease of osteoclasts and inflammatory cells in BP-treated groups. Blood vessels and fibroblastic cells decreased mainly in Group OTM+Z. Alendronate sodium and zoledronic acid have similar effects on the periodontal tissue during orthodontic treatment in rats. Especially, zoledronic acid can affect orthodontic tooth movement. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial.

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    Grbic, John T; Landesberg, Regina; Lin, Shou-Qing; Mesenbrink, Peter; Reid, Ian R; Leung, Ping-Chung; Casas, Noemi; Recknor, Christopher P; Hua, Ye; Delmas, Pierre D; Eriksen, Erik F

    2008-01-01

    The authors determined incidence of osteonecrosis of the jaw (ONJ) in a large, prospective three-year clinical trial of zoledronic acid in women with postmenopausal osteoporosis (PMO). A total of 7,714 women with PMO received intravenous zoledronic acid 5 mg or a placebo. No spontaneous reports of ONJ were received. An independent, blinded adjudication committee searched the trial's adverse event database by using 60 terms. On an ongoing basis, the committee reviewed the identified events, and it defined ONJ as exposed bone in the maxillofacial area with delayed healing for more than six weeks despite appropriate care. One participant who received a placebo and one participant who received zoledronic acid experienced delayed healing associated with infection. Both conditions resolved after antibiotic therapy, débridement or both. The occurrence of ONJ is rare in a PMO population, and delayed healing of lesions can occur with and without bisphosphonate use over three years. The low incidence of ONJ must be assessed in the context of the clinical benefit of zoledronic acid therapy in reducing hip, vertebral and nonvertebral fractures in this at-risk population. There is no evidence to suggest that healthy patients with osteoporosis who are receiving bisphosphonates require any special treatment beyond routine dental care or to support altering standard treatment practices.

  19. Optimal Timing of Bisphosphonate Administration in Combination with Samarium-153 Oxabifore in the Treatment of Painful Metastatic Bone Disease

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    Rasulova, Nigora; Lyubshin, Vladimir; Arybzhanov, Dauranbek; Sagdullaev, Sh.; Krylov, Valery; Khodjibekov, Marat

    2013-01-01

    While bisphosphonates are indicated for prevention of skeletal-related events, radionuclide therapy is widely used for treatment of painful bone metastases. Combined radionuclide therapy with bisphosphonates has demonstrated improved effectiveness in achieving bone pain palliation in comparison to mono therapy with radionuclides or bisphosphonates alone. However, there are conflicting reports as to whether bisphosphonates adversely influence skeletal uptake of the bone-seeking radiotracers used for therapy. Recent studies analyzing influence of Zoledronic acid on total bone uptake of Samarium-153 EDTMP (Sm-153 EDTMP) by measuring cumulative urinary activity of Sm-153 on baseline study, as well as in combination with bisphosphonates (administrated 48 hours prior to Sm-153) did not provide any statistically significant difference in urinary excretion of Sm-153 between the two groups. It may be noted that the exact temporal sequence of bisphosphonate administration vis a vis radionuclide therapy has not yet been studied. One of the side effects of bisphosphonates is transient flare effect on bone pain. Radionuclide therapy may also have similar side effect. Keeping in view the above the current study was designed with the main objective of determining the exact timing of bisphosphonate administration in patients receiving combined therapy so as to achieve optimal efficacy of bone pain palliation. Ninety-three patients suffering from metastatic bone pain who received combination therapy with Sm-153 oxabifore (an analog of Sm-153 EDTMP) and Zoledronic acid were divided into three groups according to the timing of Zoledronic acid administration: Group I: 39 patients who received Zoledronic acid 7 or more days prior to Sm-153 oxabifore treatment; Group II: 32 patients who received Zoledronic acid 48-72 hours prior to Sm-153 oxabifore treatment and Group III: 22 patients who received Zoledronic acid 7 days after Sm-153 oxabifore treatment. Sm-153 oxabifore was administered

  20. Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism.

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    Otto, Sven; Pautke, Christoph; Opelz, Christine; Westphal, Ines; Drosse, Inga; Schwager, Joanna; Bauss, Frieder; Ehrenfeld, Michael; Schieker, Matthias

    2010-11-01

    Osteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro. The effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy. Both types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P key role in the pathogenesis of osteonecrosis of the jaw in patients receiving high doses of N-BPs for malignant diseases. Also the potency of N-BPs might be different, suggesting a greater risk of osteonecrosis of the jaw with zoledronate. Copyright © 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  1. A Modified method for reducing renal injury in zoledronic acid treatment of hypercalcemia and adverse skeletal events

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    Jiang Liu

    2013-01-01

    Full Text Available Aims: In this paper, we have reported a previously undescribed risk factor of deterioration of renal function in zoledronic acid treatment of skeletal metastasis - high serum calcium level. Based on this consideration, a modified method of treatment of hypercalcemia (HCM with zoledronic acid is suggested in this paper. Material and Methods: Bone scan findings of 1090 cancer patients were analyzed, of which 26 had intense renal parenchymal uptake as a result of HCM or bone metastases. Subsequently, a total of 56 bone metastases patients with zoledronic acid treatment were divided into three groups: HCM group who were pre-treated to normal serum calcium level (13 patients, HCM group (19 patients, and normal serum calcium group (24 patients. Results: More patients with intense renal parenchymal uptake were hyperglycemic, statistically significantly (18/26 versus 19/1064, P = 2.1, E-78. No more patients with intense renal parenchymal uptake were associated with bone metastases (14/26 versus 438/1064, P = 0.20. Subsequently, more HCM patients receiving zoledronic acid treatment showed renal injury compared to patients with normal serum calcium level (5/15 versus 2/24, P < 0.05 and HCM patients with pre-treatment to normal serum calcium level (5/15 versus 1/17, P < 0.05. Conclusions: Intense renal parenchymal uptake of bisphosphonates is closely related to HCM rather than to bone metastases in cancer patients. The serum calcium should be measured and reduced to normal level before zoledronic acid is used in managements of adverse skeletal events in order to decrease the risk of renal injury.

  2. Zoledronic acid improves bone mineral density, reduces bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis

    DEFF Research Database (Denmark)

    Simm, Peter J; Johannesen, Jesper; Briody, Julie

    2011-01-01

    There are limited data on the use of bisphosphonate therapy for secondary osteoporoses in childhood, and no previous reports of the use of zoledronic acid in this group. We report 20 children with a variety of underlying primary diagnoses with associated secondary osteoporosis, who were treated w...

  3. A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma

    Directory of Open Access Journals (Sweden)

    Jamil MO

    2017-06-01

    Full Text Available Muhammad Omer Jamil, Mary S Jerome, Deborah Miley, Katri S Selander, Francisco Robert Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA Purpose: Malignant pleural mesothelioma (MPM is a rare malignancy with a dismal median survival of <12 months with current therapy. Single and combination chemotherapy regimens have shown only modest clinical benefit. In preclinical studies, nitrogen-containing bisphosphonates (zoledronic acid inhibit growth of mesothelioma cells by different mechanisms: inhibition of mevalonate pathway, inhibition of angiogenesis, activation of apoptosis through caspase activation, and alteration in activity of matrix metalloproteinases, thereby affecting invasiveness of cancer cells.Patients and methods: We investigated the role of zoledronic acid in a pilot, single-arm trial of MPM patients with Eastern Cooperative Oncology Group (ECOG performance status (PS 0–2 who had progressed on prior treatments or had not received systemic therapy due to poor PS. Primary end point was composite response rate by modified response evaluation criteria in solid tumors and/or metabolic response by 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG positron emission tomography criteria. Secondary end points were progression-free survival (PFS and overall survival (OS. Exploratory end points include the effect of zoledronic acid therapy on vascular endothelial growth factor (VEGF, basic fibroblast growth factor, interleukin 8, transforming growth factor beta, mesothelin, and osteopontin levels.Results: Eight male patients (median age of 62 years with the following clinical characteristics were treated; ECOG PS was 0–2, 75% with epithelioid type, and 62% had prior chemotherapy. Overall composite response rate was 12.5% and the clinical benefit rate (response + stable disease was 37.5%. Median PFS was 2 months (0.5–21 months and median OS was

  4. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.

    Science.gov (United States)

    Wark, J D; Bensen, W; Recknor, C; Ryabitseva, O; Chiodo, J; Mesenbrink, P; de Villiers, T J

    2012-02-01

    Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p paracetamol or ibuprofen. Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

  5. Once-yearly zoledronic acid in hip fracture prevention

    Science.gov (United States)

    Demontiero, Oddom; Duque, Gustavo

    2009-01-01

    Osteoporosis is an escalating global problem. Hip fractures, the most catastrophic complication of osteoporosis, continue to cause significant mortality and morbidity despite increasing availability of effective preventative agents. Among these agents, oral bisphosphonates have been the first choice for the treatment and prevention of osteoporotic fractures. However, the use of oral bisphosphonates, especially in the older population, has been limited by their side effects and method of administration thus compromising their persistent use. The resultant low adherence by patients has undermined their full potential and has been associated with an increase in the incidence of fragility fractures. Recently, annual intravenous zoledronic acid (ZOL) has been approved for osteoporosis. Randomized controlled trials have demonstrated ZOL to be safe, have good tolerability and produce significant effect on bone mass and microarchitecture. Adherence has also been shown to be better with ZOL. Furthermore two large trials firmly demonstrated significant anti-osteoporotic effect (∼59% relative risk reduction of hip fractures) and mortality benefit (28% reduction in mortality) of ZOL in older persons with recent hip fractures. In this review, we report the current evidence on the use of ZOL for the prevention of hip fractures in the elderly. We also report the pharmacological characteristics and the advantages and disadvantages of ZOL in this particular group. PMID:19503777

  6. Acute bilateral uveitis and right macular edema induced by a single infusion of zoledronic acid for the treatment of postmenopausal osteoporosis as a substitution for oral alendronate: a case report.

    Science.gov (United States)

    Tian, Yiming; Wang, Rui; Liu, Lianyuan; Ma, Chunming; Lu, Qiang; Yin, Fuzai

    2016-02-11

    Zoledronic acid-induced uveitis (ZAIU) is rare but severe, and has been recently considered part of an acute phase reaction. Only 15 cases have been reported since 2005. Here we describe a case with macular edema, which is the first reported case observed after long-term alendronate tolerance. A 63-year-old Asian woman received her first intravenous zoledronic acid treatment for the management of postmenopausal osteoporosis as a more convenient substitute for oral alendronate. Twenty-four hours later, bilateral eye irritations, periorbital swelling, blurred vision, and diplopia presented. The complete blood count and transaminase levels were normal, but the erythrocytic sedimentation, C-reactive protein, and serum C4 levels were elevated. On detailed ophthalmological examination, a diagnosis of bilateral acute uveitis and macular edema in the right eye was made. The ocular symptoms were not improved until administration of topical and oral steroids. Complete resolution was achieved. There was no rechallenge of bisphosphonates, and no recurrence at 6 months follow-up. Based on an extensive review, abnormal fundus is rarely reported, especially in cases of macular edema. Rechallenge with zoledronic acid in five cases induced no additional uveitis, and changing the medication to pamidronate in another patient was also tolerated. Interestingly, our patient suffered from uveitis soon after intravenous zoledronate exposure after a two-year tolerance to oral alendronate. This is the first report of zoledronic acid induced uveitis with macular edema after long-term alendronate tolerance. Prior oral alendronate may not entirely prevent ZAIU. Steroids are usually necessary in the treatment of ZAIU. Bisphosphonate rechallenge is not fully contraindicated, and prior steroid administration may be a more reasonable treatment choice according to the available evidence.

  7. Osteoclasts but not osteoblasts are affected by a calcified surface treated with zoledronic acid in vitro

    International Nuclear Information System (INIS)

    Schindeler, Aaron; Little, David G.

    2005-01-01

    Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. Recent interest has centered on the effects of bisphosphonates on osteoblasts. Chronic dosing of osteoblasts with solubilized bisphosphonates has been reported to enhance osteogenesis and mineralization in vitro. However, this methodology poorly reflects the in vivo situation, where free bisphosphonate becomes rapidly bound to mineralized bone surfaces. To establish a more clinically relevant cell culture model, we cultured bone cells on calcium phosphate coated quartz discs pre-treated with the potent nitrogen-containing bisphosphonate, zoledronic acid (ZA). Binding studies utilizing [ 14 C]-labeled ZA confirmed that the bisphosphonate bound in a concentration-dependent manner over the 1-50 μM dose range. When grown on ZA-treated discs, the viability of bone-marrow derived osteoclasts was greatly reduced, while the viability and mineralization of the osteoblastic MC3T3-E1 cell line were largely unaffected. This suggests that only bone resorbing cells are affected by bound bisphosphonate. However, this system does not account for transient exposure to unbound bisphosphonate in the hours following a clinical dosing. To model this event, we transiently treated osteoblasts with ZA in the absence of a calcified surface. Osteoblasts proved highly resistant to all transitory treatment regimes, even when utilizing ZA concentrations that prevented mineralization and/or induced cell death when dosed chronically. This study represents a pharmacologically more relevant approach to modeling bisphosphonate treatment on cultured bone cells and implies that bisphosphonate therapies may not directly affect osteoblasts at bone surfaces

  8. Zoledronic acid in metastatic bone disease: an audit based discussion

    International Nuclear Information System (INIS)

    Akbar, R.A.; Gosh, S.

    2010-01-01

    Background: Metastatic bone disease is a common problem in patients with advanced cancer causing significant morbidity and poor quality of life. Effective and less toxic treatments, like bisphophonates, can reduce morbidity in such cases. Objectives: The objectives of this study were to determine whether Zoledronic acid was administered in accordance with current recommendations for its prescribing and to produce protocols for improved patient outcomes. Methods: The study was a retrospective audit of 39 consecutive patients with metastatic bone disease secondary to solid tumours who were treated with Zoledronic acid. The records were analysed to establish the administered dose of Zoledronic acid relative to creatinine clearance. The standards for Zoledronic acid therapy were defined from best practice guidelines. Results: The commonest diagnosis in patients receiving Zoledronic acid was carcinoma prostate 19/39 (49%) followed by carcinoma breast 11/39 (28%), gastrointestinal malignancies 4/39 (10%) and renal cell carcinoma 3/39 (8%). Indications for therapy were metastatic bone disease alone 31 (79%), hypercalcaemia alone 0/39 (0%), metastatic bone disease with hypercalcaemia 5/39 (13%), and prevention of chemotherapy induced bone loss 1/39 (3%). The dose of Zoledronic acid was appropriate to the creatinine clearance in 25/39 (6 4%), inappropriate in 5/39 (13%) and unclear from the notes in 9/39 (23%). Conclusions: Majority of patients received Zoledronic acid for the appropriate indications. The dose of Zoledronic acid was appropriate to serum creatinine clearance in a majority of patients. Poor documentation of data pertaining to Zoledronic acid treatment is observed which can potentially lead to major errors in prescribing. We recommend using a standard form to document each episode of therapy with Zoledronic acid. (author)

  9. Cost-effectiveness of denosumab versus zoledronic acid for preventing skeletal-related events in the Czech Republic.

    Science.gov (United States)

    Cristino, Joaquim; Finek, Jíndřich; Jandova, Petra; Kolek, Martin; Pásztor, Bálint; Giannopoulou, Christina; Qian, Yi; Brezina, Tomas; Lothgren, Mickael

    2017-08-01

    This study assessed the cost-effectiveness of the subcutaneous RANKL inhibitor, denosumab, vs the intravenous bisphosphonate, zoledronic acid, for the prevention of skeletal-related events (SREs) in patients with prostate cancer, breast cancer, and other solid tumors (OST) in the Czech Republic. A lifetime Markov model was developed to compare the effects of denosumab and zoledronic acid on costs (including drug costs and administration, patient management, SREs, and adverse events), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from a national payer perspective. Different discount rates, time horizons, SRE rates, distributions, and nature (asymptomatic vs all SREs), and the inclusion of treatment discontinuation were considered in scenario analyses. The robustness of the model was tested using deterministic and probabilistic sensitivity analyses. Across tumor types, denosumab was associated with fewer SREs, improved QALYs, and higher total costs over a lifetime. The incremental cost per QALY gained for denosumab vs zoledronic acid was 382,673 CZK for prostate cancer, 408,450 CZK for breast cancer, and 608,133 CZK for OST. Incremental costs per SRE avoided for the same tumor type were 54,007 CZK, 51,765 CZK, and 94,426 CZK, respectively. In scenario analyses, the results remained similar to baseline, when different discount rates and time horizons were considered. At a non-official willingness-to-pay threshold of 1.2 million CZK, the probabilities of denosumab being cost-effective vs zoledronic acid were 0.64, 0.67, and 0.49 for prostate cancer, breast cancer, and OST, respectively. The SRE rates used were obtained from clinical trials; studies suggest rates may be higher in clinical practice. Additional evidence on real-world SRE rates could further improve the accuracy of the modeling. Compared with zoledronic acid, denosumab provides a cost-effective treatment option for the prevention of SREs in patients with prostate cancer

  10. Urea dimethacrylates functionalized with bisphosphonate/bisphosphonic acid for improved dental materials

    OpenAIRE

    Güven, Melek Naz; Guven, Melek Naz; Akyol, Ece; Duman, Fatma Demir; Acar, Havva Yağcı; Acar, Havva Yagci; Karahan, Özlem; Karahan, Ozlem; Avcı, Duygu; Avci, Duygu

    2017-01-01

    Incorporation of bisphosphonate/bisphosphonic acid groups in dental monomer structures should increase interaction of these monomers with dental tissue as these groups have strong affinity for hydroxyapatite. Therefore, new urea dimethacrylates functionalized with bisphosphonate (1a, 1b) and bisphosphonic acid (2a, 2b) groups are synthesized and evaluated for dental applications. Monomers 1a and 1b are synthesized from 2isocyanatoethyl methacrylate (IEM) and two bisphosphonated amines (BPA1 a...

  11. In vitro and in vivo investigation of bisphosphonate-loaded hydroxyapatite particles for peri-implant bone augmentation.

    Science.gov (United States)

    Kettenberger, Ulrike; Luginbuehl, Vera; Procter, Philip; Pioletti, Dominique P

    2017-07-01

    Locally applied bisphosphonates, such as zoledronate, have been shown in several studies to inhibit peri-implant bone resorption and recently to enhance peri-implant bone formation. Studies have also demonstrated positive effects of hydroxyapatite (HA) particles on peri-implant bone regeneration and an enhancement of the anti-resorptive effect of bisphosphonates in the presence of calcium. In the present study, both hydroxyapatite nanoparticles (nHA) and zoledronate were combined to achieve a strong reinforcing effect on peri-implant bone. The nHA-zoledronate combination was first investigated in vitro with a pre-osteoclastic cell assay (RAW 264.7) and then in vivo in a rat model of postmenopausal osteoporosis. The in vitro study confirmed that the inhibitory effect of zoledronate on murine osteoclast precursor cells was enhanced by loading the drug on nHA. For the in vivo investigation, either zoledronate-loaded or pure nHA were integrated in hyaluronic acid hydrogel. The gels were injected in screw holes that had been predrilled in rat femoral condyles before the insertion of miniature screws. Micro-CT-based dynamic histomorphometry and histology revealed an unexpected rapid mineralization of the hydrogel in vivo through formation of granules, which served as scaffold for new bone formation. The delivery of zoledronate-loaded nHA further inhibited a degradation of the mineralized hydrogel as well as a resorption of the peri-implant bone as effectively as unbound zoledronate. Hyaluronic acid with zoledronate-loaded nHA, thanks to its dual effect on inducing a rapid mineralization and preventing resorption, is a promising versatile material for bone repair and augmentation. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Dgroup: DG00787 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00787 Chemical ... DGroup Zoledronic acid ... D08689 ... Zoledronic acid (INN) D01968 ... Zoledron...ic acid (USAN); Zoledronic acid hydrate (JAN) ... D06378 ... Zoledronate disodium (USAN) D06379 ... Zoledron...ate trisodium (USAN) D10515 ... Zoledronic acid hemipentahydrate (JAN) Other ... DG01600 ... Bisphosphonate ATC code: M05BA08 Bisphosphonates FDPS [HSA:2224] [KO:K00787] ...

  13. The bisphosphonate zoledronate prevents vertebral bone loss in mature estrogen-deficient rats as assessed by micro-computed tomography

    Directory of Open Access Journals (Sweden)

    Glatt M.

    2001-01-01

    Full Text Available The effect of long-term treatment with the bisphosphonate zoledronate on vertebral bone architecture was investigated in estrogen-deficient mature rats. 4-month-old rats were ovariectomized and development of cancellous osteopenia was assessed after 1 year. The change of bone architectural parameters was determined with a microtomographic instrument of high resolution. After 1 year of estrogen-deficiency, animals lost 55% of vertebral trabecular bone in comparison to sham operated control animals. Trabecular number (Tb.N and trabecular thickness (Tb.Th were significantly reduced in ovariectomized animals, whereas trabecular separation (Tb.Sp, bone surface to volume fraction (BS/BV and trabecular bone pattern factor (TBPf were significantly increased, indicating a loss of architectural integrity throughout the vertebral body. 3 groups of animals were treated subcutaneously with zoledronate for 1 year with 0.3, 1.5 and 7.5 microgram/kg/week to inhibit osteoclastic bone degradation. Administration started immediately after ovariectomy and treatment dose-dependently prevented the architectural bone deterioration and completely suppressed the effects of estrogen deficiency at the higher doses. The results show that microtomographic determination of static morphometric parameters can be used to quantitate the effects of drugs on vertebral bone architecture in small laboratory animals and that zoledronate is highly effective in this rat model.

  14. Effect of bisphosphonates on macrophagic THP-1 cell survival in bisphosphonate-related osteonecrosis of the jaw (BRONJ).

    Science.gov (United States)

    Hoefert, Sebastian; Sade Hoefert, Claudia; Munz, Adelheid; Schmitz, Inge; Grimm, Martin; Yuan, Anna; Northoff, Hinnak; Reinert, Siegmar; Alexander, Dorothea

    2016-03-01

    Immune deficiency and bacterial infection have been suggested to play a role in the pathophysiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Zoledronate was previously found to promote THP-1 cell death. To examine this hypothesis with all commonly prescribed bisphosphonates, we tested the effect of (nitrogen-containing) ibandronate, risedronate, alendronate, pamidronate, and (non-nitrogen-containing) clodronate on macrophagic THP-1 cells. Activated THP-1 cells were exposed to .5 to 50 μM of nitrogen-containing bisphosphonates and .5 to 500 μM of clodronate. Cell adherence and survival were assessed in vitro using the xCELLigence real-time monitoring system. Results were confirmed histologically and verified with Live/Dead staining. All bisphosphonates inhibited THP-1 cell adherence and survival dose and time dependently, significant for zoledronate, alendronate, pamidronate, and clodronate in high concentrations (50 μM and 500 μM; P THP-1 cell survival compared with controls (P THP-1 cells exhibited no cytomorphologic changes at all concentrations. Commonly prescribed bisphosphonates inhibit the survival of macrophagic THP-1 cells dose-dependently without altering morphology. This may suggest a local immune dysfunction reflective of individual bisphosphonate potency leading to the pathogenesis of BRONJ. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations

    Directory of Open Access Journals (Sweden)

    John Sunyecz

    2008-12-01

    Full Text Available John SunyeczMenopauseRx, Inc., Hopwood, PA, USAAbstract: Postmenopausal osteoporosis is common and underrecognized among elderly women. Osteoporotic fractures cause disability and disfigurement and threaten patients’ mobility, independence, and survival. Care for incident fractures in this age group must go beyond orthopedic repair, to assessment and treatment of the underlying bone fragility. Fracture risk can be reduced by vitamin D and calcium supplementation along with antiresorptive drug treatment. First-line osteoporosis pharmacotherapy employs nitrogen-containing bisphosphonates. The inconvenience of daily oral treatment has motivated development of weekly, monthly, and intermittent oral regimens, as well as quarterly and yearly intravenous (iv regimens. Ibandronate is the first bisphosphonate to have shown direct anti-fracture efficacy with a non-daily regimen; it was approved for once-monthly oral dosing in 2005 and for quarterly iv dosing in 2006. Intermittent oral risedronate and yearly iv zoledronic acid were approved in 2007. Newly available regimens with extended dosing intervals reduce the inconvenience of bisphosphonate therapy and provide patients with a range of options from which to select a maximally sustainable course of treatment. This review discusses the development, efficacy, safety, and tolerability of extended-interval bisphosphonate regimens and examines their potential to improve patient acceptance and long-term success of osteoporosis treatment.Keywords: ibandronate, alendronate, risedronate, zoledronic acid, adherence, persistence

  16. Reproductive hormone analyses and effects of adjuvant zoledronic acid in early breast cancer – An AZURE (BIG 01/04 sub-study

    Directory of Open Access Journals (Sweden)

    Caroline Wilson

    2017-11-01

    Full Text Available Purpose: Adjuvant bisphosphonates have been shown to improve disease outcomes in early breast cancer in women who are postmenopausal at the start of treatment. We explored the influence of pretreatment serum levels of reproductive hormones in the hypothalamic-pituitary-gonadal (HPG axis from a subset of patients included in the AZURE trial to investigate their impact on disease recurrence and whether reproductive hormone measurements are of value in selecting patients for treatment with adjuvant zoledronic acid.Patients and methods; The AZURE trial is an academic, multi-centre, international phase III trial that randomised patients to standard adjuvant therapy (chemotherapy and/or endocrine therapy±intravenous zoledronic acid, 4 mg for 5 years. Serum from 865 patients taken at randomisation was stored at −80 °C prior to central batch analysis for inhibin A, oestradiol and follicle stimulating hormone (FSH. We assessed the clinical value of pretreatment hormone levels for predicting invasive disease free survival (IDFS, skeletal recurrence and distant recurrence and response to treatment with zoledronic acid. Results: Oestradiol in the postmenopausal range (26 IU/l was associated with a longer time to bone as first recurrence (HR 0.66 95%CI: 0.41–1.04 p=0.072 compared to an FSH ≤26 IU/l. When all 3 hormone levels were within the assay specified postmenopausal range, a trend to improved IDFS was seen with addition of zoledronic acid in biochemically postmenopausal women only (postmenopausal HR=0.81; 95%CI: 0.54–1.22, non-postmenopausal HR=0.99; 95%CI: 0.69–1.39 with risk reductions that mirrored the results of the main AZURE study, although the interaction between menopausal status and treatment effect was not statistically significant (p=0.47. Conclusion: Oestradiol and FSH may influence the pattern of disease recurrence with postmenopausal levels possibly creating a less conducive environment for the

  17. Systemic effects of zoledronic acid in children with traumatic femoral head avascular necrosis and Legg-Calve-Perthes disease

    DEFF Research Database (Denmark)

    Johannesen, Jesper; Briody, Julie; McQuade, Mary

    2009-01-01

    Background: Intravenous bisphosphonate therapy is associated with preservation of femoral head sphericity and congruence in 77% of children with traumatic avascular necrosis. The aim was to describe the systemic effects of intravenous zoledronic acid (ZA) on bone and mineral metabolism in otherwise...... normal children and adolescents with femoral head AVN. Material and methods: 37 children (age 10.8+/-2.76 years) diagnosed with avascular necrosis AVN (Slipped Capital Femoral Epiphysis (SCFE), N=20 or Legg-Calve-Perthes disease (LCPD), N=17) were treated with at least 12 months of ZA. Bone mineral...

  18. Bisphosphonates and risk of cardiovascular events: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Dae Hyun Kim

    Full Text Available Some evidence suggests that bisphosphonates may reduce atherosclerosis, while concerns have been raised about atrial fibrillation. We conducted a meta-analysis to determine the effects of bisphosphonates on total adverse cardiovascular (CV events, atrial fibrillation, myocardial infarction (MI, stroke, and CV death in adults with or at risk for low bone mass.A systematic search of MEDLINE and EMBASE through July 2014 identified 58 randomized controlled trials with longer than 6 months in duration that reported CV events. Absolute risks and the Mantel-Haenszel fixed-effects odds ratios (ORs and 95% confidence intervals (CIs of total CV events, atrial fibrillation, MI, stroke, and CV death were estimated. Subgroup analyses by follow-up duration, population characteristics, bisphosphonate types, and route were performed.Absolute risks over 25-36 months in bisphosphonate-treated versus control patients were 6.5% versus 6.2% for total CV events; 1.4% versus 1.5% for atrial fibrillation; 1.0% versus 1.2% for MI; 1.6% versus 1.9% for stroke; and 1.5% versus 1.4% for CV death. Bisphosphonate treatment up to 36 months did not have any significant effects on total CV events (14 trials; ORs [95% CI]: 0.98 [0.84-1.14]; I2 = 0.0%, atrial fibrillation (41 trials; 1.08 [0.92-1.25]; I2 = 0.0%, MI (10 trials; 0.96 [0.69-1.34]; I2 = 0.0%, stroke (10 trials; 0.99 [0.82-1.19]; I2 = 5.8%, and CV death (14 trials; 0.88 [0.72-1.07]; I2 = 0.0% with little between-study heterogeneity. The risk of atrial fibrillation appears to be modestly elevated for zoledronic acid (6 trials; 1.24 [0.96-1.61]; I2 = 0.0%, not for oral bisphosphonates (26 trials; 1.02 [0.83-1.24]; I2 = 0.0%. The CV effects did not vary by subgroups or study quality.Bisphosphonates do not have beneficial or harmful effects on atherosclerotic CV events, but zoledronic acid may modestly increase the risk of atrial fibrillation. Given the large reduction in fractures with bisphosphonates, changes in

  19. Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial

    International Nuclear Information System (INIS)

    Banys, Malgorzata; Wackwitz, Birgit; Hirnle, Peter; Wallwiener, Diethelm; Fehm, Tanja; Solomayer, Erich-Franz; Gebauer, Gerhard; Janni, Wolfgang; Krawczyk, Natalia; Lueck, Hans-Joachim; Becker, Sven; Huober, Jens; Kraemer, Bernhard

    2013-01-01

    The presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome. Bisphosphonate treatment was shown to eradicate DTC from BM in several studies. This controlled randomized open-label multi-center study aimed to investigate the influence of zoledronic acid (ZOL) on DTC and survival of breast cancer patients (Clinical Trial Registration Number: NCT00172068). Patients with primary breast cancer and DTC-positive bone marrow were randomized to treatment with ZOL plus adjuvant systemic therapy (n = 40) or adjuvant systemic therapy alone (n = 46) between 03/2002 and 12/2004. DTC were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. The change in DTC numbers at 12 months and 24 months versus baseline, as well as patient outcomes were evaluated. 86 patients could be included into survival analysis (median follow-up: 88 months, range: 8–108 mths). Patients in the control group were more likely to die during follow-up than those in the ZOL-group (11% vs. 2%, p = 0.106). 15% of patients in the control group presented with relapse whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p = 0.205). At 24 months, 16% of patients from the control group were still DTC positive, whereas all patients treated with ZOL became DTC negative (p = 0.032). Patients presenting with persistent DTC 12 months after diagnosis had significantly shorter overall survival (p = 0.011). Bisphosphonate therapy contributes to eradication of disseminated tumor cells. The positive influence of bisphosphonates on survival in the adjuvant setting may be due to their effects on DTC. ClinicalTrials.gov Identifier: http://clinicaltrials.gov/show/NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)

  20. A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures.

    OpenAIRE

    Davis, S.; Martyn-St James, M.; Sanderson, J.; Stevens, J.; Goka, E.; Rawdin, A.; Sadler, S.; Wong, R.; Campbell, F.; Stevenson, M.; Strong, M.; Selby, P.; Gittoes, N.

    2016-01-01

    BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. OBJECTIVES: To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax(®) and Fosamax(®) Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel(®) and Actonel Once a Week(®), Warner Chilcott UK Ltd), ibandronic acid (Bonviva(®), Roche Products Ltd) and zoledronic acid (Aclasta(®), Novartis Pharmaceuticals UK Ltd)] for the p...

  1. Life-threatening hyperkalemia following zoledronic acid infusion for Paget's disease: a case report

    Directory of Open Access Journals (Sweden)

    Naysmith Morag

    2011-08-01

    Full Text Available Abstract Introduction Zoledronic acid is a highly effective treatment in Paget's disease for persistent bone pain and prevention of further progression of the disease. The commonest electrolyte abnormality is hypocalcemia. To the best of our knowledge this is the first case of hyperkalemia secondary to zoledronic acid to be published in the world literature. The commonest arrhythmia related to zoledronic acid is atrial fibrillation. Case presentation We describe the case of an 80-year-old Caucasian man, with a history of ischemic heart disease, who had an in-hospital cardiac arrest related to hyperkalemia. Increasing potassium levels were noted following his first zoledronic acid infusion for symptomatic control of bone pain secondary to Paget's disease. Our patient suffered a cardiac arrest 10 days following the zoledronic acid infusion. Our patient's biochemistry and electrocardiogram output were monitored until his death 26 days after his cardiac arrest. Our patient developed paroxysmal atrial fibrillation in the post-resuscitation period and there was persistent hyperkalemia that required prolonged treatment with calcium resonium. All other possible causes of hyperkalemia were excluded. Conclusion In our patient's case persistent hyperkalemia and life-threatening arrhythmias were associated with use of zoledronic acid. These side effects have not been reported before and the causative mechanism is far from clear as there are no obvious systemic effects of zoledronic acid. The combination of zoledronic acid with predisposing factors such as structural heart disease might account for the clinical picture we witnessed. As a result, electrolyte monitoring should be adopted early in zoledronic acid use. Further studies are required to elucidate the underlying mechanism of hyperkalemia and identify the target group of patients where zoledronic acid can be safely administered. Great caution is advised in patients with underlying heart conditions.

  2. Zoledronic acid and clinical fractures and mortality after hip fracture

    DEFF Research Database (Denmark)

    Lyles, Kenneth W; Colón-Emeric, Cathleen S; Magaziner, Jay S

    2007-01-01

    were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients...... receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar...

  3. Bisphosphonates enhance bacterial adhesion and biofilm formation on bone hydroxyapatite.

    Science.gov (United States)

    Kos, Marcin; Junka, Adam; Smutnicka, Danuta; Szymczyk, Patrycja; Gluza, Karolina; Bartoszewicz, Marzenna

    2015-07-01

    Because of the suspicion that bisphosphonates enhance bacterial colonization, this study evaluated adhesion and biofilm formation by Streptococcus mutans 25175, Staphylococcus aureus 6538, and Pseudomonas aeruginosa 14454 reference strains on hydroxyapatite coated with clodronate, pamidronate, or zoledronate. Bacterial strains were cultured on bisphosphonate-coated and noncoated hydroxyapatite discs. After incubation, nonadhered bacteria were removed by centrifugation. Biofilm formation was confirmed by scanning electron microscopy. Bacterial colonization was estimated using quantitative cultures compared by means with Kruskal-Wallis and post-hoc Student-Newman-Keuls tests. Modeling of the interactions between bisphosphonates and hydroxyapatite was performed using the Density Functional Theory method. Bacterial colonization of the hydroxyapatite discs was significantly higher for all tested strains in the presence of bisphosphonates vs. Adherence in the presence of pamidronate was higher than with other bisphosphonates. Density Functional Theory analysis showed that the protonated amine group of pamidronate, which are not present in clodronate or zoledronate, forms two additional hydrogen bonds with hydroxyapatite. Moreover, the reactive cationic amino group of pamidronate may attract bacteria by direct electrostatic interaction. Increased bacterial adhesion and biofilm formation can promote osteomyelitis, cause failure of dental implants or bisphosphonate-coated joint prostheses, and complicate bone surgery in patients on bisphosphonates. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  4. Local application of zoledronate for maximum anchorage during space closure.

    Science.gov (United States)

    Ortega, Adam J A J; Campbell, Phillip M; Hinton, Robert; Naidu, Aparna; Buschang, Peter H

    2012-12-01

    Orthodontists have used various compliance-dependent physical means such as headgears and intraoral appliances to prevent anchorage loss. The aim of this study was to determine whether 1 local application of the bisphosphonate zoledronate could be used to prevent anchorage loss during extraction space closure in rats. Thirty rats had their maxillary left first molars extracted and their maxillary left second molars protracted into the extraction space with a 10-g nickel-titanium closing coil for 21 days. Fifteen control rats received a local injection of phosphate-buffered saline solution, and 15 experimental rats received 16 μg of the bisphosphonate zoledronate. Bisphosphonate was also delivered directly into the extraction site and left undisturbed for 5 minutes. Cephalograms and incremental thickness gauges were used to measure tooth movements. Tissues were analyzed by microcomputed tomography and histology. The control group demonstrated significant (P <0.05) tooth movements throughout the 21-day period. They showed significantly greater tooth movements than the experimental group beginning in the second week. The experimental group showed no significant tooth movement after the first week. The microcomputed tomography and histologic observations showed significant bone loss in the extraction sites and around the second molars of the controls. In contrast, the experimental group had bone preservation and bone fill. There was no evidence of bisphosphonate-associated osteonecrosis in any sample. A single small, locally applied dose of zoledronate provided maximum anchorage and prevented significant bone loss. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  5. Unilateral anterior uveitis complicating zoledronic acid therapy in breast cancer

    Directory of Open Access Journals (Sweden)

    El Saghir Nagi S

    2005-12-01

    Full Text Available Abstract Background Zoledronic acid is very widely used in patients with metastatic bone disease and osteoporosis. Only one case of bilateral uveitis was recently reported related to its use. Case presentation We report the first case of severe unilateral anterior uveitis in a patient with breast cancer and an intraocular lens. Following zoledronic acid infusion, the patient developed severe and dramatic right eye pain with decreased visual acuity within 24 hours and was found to have a fibrinous anterior uveitis of moderate severity The patient was treated with topical prednisone and atropine eyedrops and recovered slowly over several months. Conclusion Internists, oncologists, endocrinologists, and ophtalmologists should be aware of uveitis as a possible complication of zoledronic acid therapy. Patients should be instructed to report immediately to their physicians and treatment with topical prednisone and atropine eyedrops should be instituted immediately at the onset of symptoms. This report documents anterior uveitis as a complication of zoledronic acid therapy. This reaction could be an idiosyncratic one but further research may shed more light on the etiology.

  6. Association between timing of zoledronic acid infusion and hip fracture healing

    DEFF Research Database (Denmark)

    Colón-Emeric, C; Nordsletten, L; Olson, S

    2011-01-01

    Patients in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial were assessed for evidence of delayed hip fracture healing. No association was observed between zoledronic acid (ZOL) and delayed healing. We conclude that ZOL has no clinical...

  7. Association between timing of zoledronic acid infusion and hip fracture healing

    DEFF Research Database (Denmark)

    Colón-Emeric, C; Nordsletten, L; Olson, S

    2010-01-01

    Patients in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial were assessed for evidence of delayed hip fracture healing. No association was observed between zoledronic acid (ZOL) and delayed healing. We conclude that ZOL has no clinical...

  8. Zoledronic Acid in Reducing Clinical Fracture and Mortality after Hip Fracture

    DEFF Research Database (Denmark)

    Lyles, Kenneth W; Colón-Emeric, Cathleen S; Magaziner, Jay S

    2007-01-01

    analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic-acid group (P = 0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia......, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual...

  9. Pleiotropic effects of bisphosphonates on osteosarcoma.

    Science.gov (United States)

    Ohba, Tetsuro; Cates, Justin M M; Cole, Heather A; Slosky, David A; Haro, Hirotaka; Ichikawa, Jiro; Ando, Takashi; Schwartz, Herbert S; Schoenecker, Jonathan G

    2014-06-01

    Osteosarcoma is the most common primary malignant tumor of bone and accounts for half of all primary skeletal malignancies in children and teenagers. The prognosis for patients who fail or progress on first-line chemotherapy protocols is poor, therefore, additional adjuvant therapeutic strategies are needed. A recent feasibility study has demonstrated that the nitrogen-containing bisphosphonate zoledronic acid (ZOL) can be combined safely with conventional chemotherapy. However, the pharmacodynamics of bisphosphonate therapy is not well characterized. Osteosarcoma is a highly angiogenic tumor. Recent reports of the anti-angiogenic effects of bisphosphonates prompted us to determine whether nitrogen-containing bisphosphonate (ZOL and alendronate) treatment attenuates osteosarcoma growth by inhibition of osteoclast activity, tumor-mediated angiogenesis, or direct inhibitory effects on osteosarcoma. Here, we demonstrate that bisphosphonates directly inhibit VEGFR2 expression in endothelial cells, as well as endothelial cell proliferation and migration. Additionally, bisphosphonates also decrease VEGF-A expression in osteosarcoma (K7M3) cells, resulting in reduced stimulation of endothelial cell migration in co-culture assays. ZOL also decreases VEGFR1 expression in aggressive osteosarcoma cell lines (K7M3, 143B) and induces apoptosis of these cells, but has negligible effects on less aggressive osteosarcoma cell lines (K12 and TE85). In vivo ZOL treatment results in significant reduction in osteosarcoma-initiated angiogenesis and tumor growth in a murine model of osteosarcoma. In conclusion, bisphosphonates have diverse growth inhibitory effects on osteosarcoma through: (1) activation of apoptosis and inhibition of cell proliferation, (2) inhibition of VEGF-A and VEGFR1 expression by tumor cells, (3) inhibition of tumor-induced angiogenesis, and (4) direct inhibitory actions on endothelial cells. Published by Elsevier Inc.

  10. Dystrophic Cutaneous Calcification and Metaplastic Bone Formation due to Long Term Bisphosphonate Use in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ali Murat Tatlı

    2013-01-01

    Full Text Available Bisphosphonates are widely used in the treatment of breast cancer with bone metastases. We report a case of a female with breast cancer presented with a rash around a previous mastectomy site and a discharge lesion on her right chest wall in August 2010. Biopsy of the lesion showed dystrophic calcification and metaplastic bone formation. The patient’s history revealed a long term use of zoledronic acid for the treatment of breast cancer with bone metastasis. We stopped the treatment since we believed that the cutaneous dystrophic calcification could be associated with her long term bisphosphonate therapy. Adverse cutaneous events with bisphosphonates are very rare, and dystrophic calcification has not been reported previously. The dystrophic calcification and metaplastic bone formation in this patient are thought to be due to long term bisphosphonate usage.

  11. Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

    Science.gov (United States)

    Kopecka, Joanna; Gazzano, Elena; Sara, Orecchia; Ghigo, Dario; Riganti, Chiara

    2015-01-01

    The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells. PMID:25544757

  12. Fracture risk and zoledronic acid therapy in men with osteoporosis

    DEFF Research Database (Denmark)

    Boonen, Steven; Reginster, Jean-Yves; Kaufman, Jean-Marc

    2012-01-01

    Fractures in men are a major health issue, and data on the antifracture efficacy of therapies for osteoporosis in men are limited. We studied the effect of zoledronic acid on fracture risk among men with osteoporosis.......Fractures in men are a major health issue, and data on the antifracture efficacy of therapies for osteoporosis in men are limited. We studied the effect of zoledronic acid on fracture risk among men with osteoporosis....

  13. Established role of bisphosphonate therapy for prevention of skeletal complications from myeloma bone disease.

    Science.gov (United States)

    Terpos, Evangelos; Dimopoulos, Meletios A; Berenson, James

    2011-02-01

    Patients with advanced multiple myeloma (MM) often have increased osteolytic activity of osteoclasts and impaired osteogenesis by osteoblasts, resulting in osteolytic bone lesions that increase the risk of skeletal-related events (SREs) including pathologic fracture, the need for radiotherapy or surgery to bone, and spinal cord compression. Such SREs are potentially life-limiting, and can reduce patients' functional independence and quality of life. Bisphosphonates (e.g., oral clodronate and intravenous pamidronate and zoledronic acid) can inhibit osteoclast-mediated osteolysis, thereby reducing the risk of SREs, ameliorating bone pain, and potentially prolonging survival in patients with MM. Extensive clinical experience demonstrates that bisphosphonates are generally well tolerated, and common adverse events are typically mild and manageable. Studies are ongoing to optimize the timing and duration of bisphosphonate therapy in patients with bone lesions from MM. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. Anticancer Activity of Polyoxometalate-Bisphosphonate Complexes: Synthesis, Characterization, In Vitro and In Vivo Results.

    Science.gov (United States)

    Boulmier, Amandine; Feng, Xinxin; Oms, Olivier; Mialane, Pierre; Rivière, Eric; Shin, Christopher J; Yao, Jiaqi; Kubo, Tadahiko; Furuta, Taisuke; Oldfield, Eric; Dolbecq, Anne

    2017-07-03

    We synthesized a series of polyoxometalate-bisphosphonate complexes containing Mo VI O 6 octahedra, zoledronate, or an N-alkyl (n-C 6 or n-C 8 ) zoledronate analogue, and in two cases, Mn as a heterometal. Mo 6 L 2 (L = Zol, ZolC 6 , ZolC 8 ) and Mo 4 L 2 Mn (L = Zol, ZolC 8 ) were characterized by using single-crystal X-ray crystallography and/or IR spectroscopy, elemental and energy dispersive X-ray analysis and 31 P NMR. We found promising activity against human nonsmall cell lung cancer (NCI-H460) cells with IC 50 values for growth inhibition of ∼5 μM per bisphosphonate ligand. The effects of bisphosphonate complexation on IC 50 decreased with increasing bisphosphonate chain length: C 0 ≈ 6.1×, C 6 ≈ 3.4×, and C 8 ≈ 1.1×. We then determined the activity of one of the most potent compounds in the series, Mo 4 Zol 2 Mn(III), against SK-ES-1 sarcoma cells in a mouse xenograft system finding a ∼5× decrease in tumor volume than found with the parent compound zoledronate at the same compound dosing (5 μg/mouse). Overall, the results are of interest since we show for the first time that heteropolyoxomolybdate-bisphosphonate hybrids kill tumor cells in vitro and significantly decrease tumor growth, in vivo, opening up new possibilities for targeting both Ras as well as epidermal growth factor receptor driven cancers.

  15. Implants delivering bisphosphonate locally increase periprosthetic bone density in an osteoporotic sheep model. A pilot study

    Directory of Open Access Journals (Sweden)

    GVA Stadelmann

    2008-07-01

    Full Text Available It is a clinical challenge to obtain a sufficient orthopaedic implant fixation in weak osteoporotic bone. When the primary implant fixation is poor, micromotions occur at the bone-implant interface, activating osteoclasts, which leads to implant loosening. Bisphosphonate can be used to prevent the osteoclastic response, but when administered systemically its bioavailability is low and the time it takes for the drug to reach the periprosthetic bone may be a limiting factor. Recent data has shown that delivering bisphosphonate locally from the implant surface could be an interesting solution. Local bisphosphonate delivery increased periprosthetic bone density, which leads to a stronger implant fixation, as demonstrated in rats by the increased implant pullout force. The aim of the present study was to verify the positive effect on periprosthetic bone remodelling of local bisphosphonate delivery in an osteoporotic sheep model. Four implants coated with zoledronate and two control implants were inserted in the femoral condyle of ovariectomized sheep for 4 weeks. The bone at the implant surface was 50% higher in the zoledronate-group compared to control group. This effect was significant up to a distance of 400µm from the implant surface. The presented results are similar to what was observed in the osteoporotic rat model, which suggest that the concept of releasing zoledronate locally from the implant to increase the implant fixation is not species specific. The results of this trial study support the claim that local zoledronate could increase the fixation of an implant in weak bone.

  16. Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells. : resistance of osteosarcoma to nitrogen bisphosphonates

    OpenAIRE

    Ory , Benjamin; Moriceau , Gatien; Trichet , Valérie; Blanchard , Frédéric; Berreur , Martine; Rédini , Françoise; Rogers , Michael; Heymann , Dominique

    2008-01-01

    International audience; We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and ...

  17. Short-term intravenous zoledronic acid in severe osteogenesis imperfecta : A report of three siblings of children

    Directory of Open Access Journals (Sweden)

    Hadyanto Lim

    2008-06-01

    Full Text Available This report documented the clinical and biochemical side effects on the first dose of intravenous zoledronic acid therapy in three siblings with severe osteogenesis imperfecta. Zoledronic acid was administered in 50 ml 0.9% saline solution over a period of 30 minutes. All patients had fever during the first 6 to 48 hours after the first infusion. There were no renal side effects, apart from asymptomatic hypocalcemia and hypophosphatemia at 48 and 72 hours after zoledronic acid infusion. The minimal clinical side effects were easily manageable. (Med J Indones 2008; 17: 127-30Keywords: zoledronic acid, osteogenesis imperfecta, side effects

  18. Zoledronate inhibits ischemia-induced neovascularization by impairing the mobilization and function of endothelial progenitor cells.

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    Shih-Hung Tsai

    Full Text Available BACKGROUND: Bisphosphonates are a class of pharmacologic compounds that are commonly used to treat postmenopausal osteoporosis and malignant osteolytic processes. Studies have shown that bone marrow-derived endothelial progenitor cells (EPCs play a significant role in postnatal neovascularization. Whether the nitrogen-containing bisphosphonate zoledronate inhibits ischemia-induced neovascularization by modulating EPC functions remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: Unilateral hindlimb ischemia was surgically induced in wild-type mice after 2 weeks of treatment with vehicle or zoledronate (low-dose: 30 μg/kg; high-dose: 100 μg/kg. Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio was significantly lower in wild-type mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in controls 4 weeks after ischemic surgery (control vs. low-dose vs. high-dose: 87±7% vs. *61±18% vs. **49±17%, *p<0.01, **p<0.005 compared to control. Capillary densities were also significantly lower in mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in control mice. Flow cytometry analysis showed impaired mobilization of EPC-like cells (Sca-1(+/Flk-1(+ after surgical induction of ischemia in mice treated with zoledronate but normal levels of mobilization in mice treated with vehicle. In addition, ischemic tissue from mice that received zoledronate treatment exhibited significantly lower levels of the active form of MMP-9, lower levels of VEGF, and lower levels of phosphorylated eNOS and phosphorylated Akt than ischemic tissue from mice that received vehicle. Results of the in vitro studies showed that incubation with zoledronate inhibited the viability, migration, and tube-forming capacities of EPC. CONCLUSIONS/SIGNIFICANCE: Zoledronate inhibited ischemia-induced neovascularization by impairing EPC mobilization and angiogenic functions

  19. Short-term effect of zoledronic acid upon fracture resistance of the mandibular condyle and femoral head in an animal model.

    Science.gov (United States)

    Camacho-Alonso, Fabio; López-Jornet, Pía; Vicente-Hernández, Ascensión

    2013-05-01

    The aim of this study was to compare the effects in terms of resistance to fracture of the mandibular condyle and femoral head following different doses of zoledronic acid in an animal model. A total of 80 adult male Sprague-Dawley rats were included in a prospective randomized study. The animals were randomly divided into four groups of 20 rats each. Group 1 (control) received sterile saline solution, while groups 2, 3 and 4 received a accumulated dose of 0.2 mg, 0.4 mg and 0.6 mg of zoledronic acid, respectively. The animals were sacrificed 28 days after the last dose, and the right hemimandible and the right femur were removed. The fracture strength was measured (in Newtons) with a universal test machine using a 1 kN load connected to a metal rod with one end angled at 30 degrees. The cross-head speed was 1 mm/min. Later, the specimens were observed under a scanning electron microscope with backscattered electron imaging (SEM-BSE). At last, chemical analysis and elemental mapping of the mineral bone composition were generated using a microanalytical system based on energy-dispersive and X-ray spectrometry (EDX). A total of 160 fracture tests were performed. The fracture resistance increased in mandible and femur with a higher accumulated dose of zoledronic acid. Statistically significant differences were recorded versus the controls with all the studies groups. The chemical analysis in mandible showed a significantly increased of calcium and phosphorous to compare the control with all of the study groups; however, in femur no statistically significant differences between the four study groups were observed. The administration of bisphosphonates increases the fracture resistance in mandible and femur.

  20. Is retention of zoledronic acid onto bone different in multiple myeloma and breast cancer patients with bone metastasis?

    DEFF Research Database (Denmark)

    Søe, Kent; Plesner, Torben; Jakobsen, Erik H

    2013-01-01

    Zoledronic acid (Zol) is used to treat bone disease in both multiple myeloma (MM) and breast cancer patients with bone metastasis (BC). However, bones of MM and BC patients show a difference in retention of the bisphosphonate used for bone scintigraphy. Therefore, we hypothesized that disease...... of Zol correlated with bone-specific alkaline phosphatase (bALP) levels in BC (p = 0.001), and with CTX/bALP in Zol naive MM patients (p = 0.012). Especially in BC patients, WBrt correlated with age (p = 0.014) independently of kidney function. In MM patients WBrt was found to primarily correlate...... with the extent of bone disease (p = 0.028). Multivariate linear regression analyses of the entire cohort pointed out that WBrt of Zol was best predicted by age (p ...

  1. Combined Use of Zoledronic Acid Augments Ursolic Acid-Induced Apoptosis in Human Osteosarcoma Cells through Enhanced Oxidative Stress and Autophagy

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    Chia-Chieh Wu

    2016-11-01

    Full Text Available Ursolic acid (UA, a naturally occurring pentacyclic triterpene acid found in many medicinal herbs and edible plants, triggers apoptosis in several tumor cell lines but not in human bone cancer cells. Most recently, we have demonstrated that UA exposure reduces the viability of human osteosarcoma MG-63 cells through enhanced oxidative stress and apoptosis. Interestingly, an inhibitor of osteoclast-mediated bone resorption, zoledronic acid (ZOL, also a third-generation nitrogen-containing bisphosphonate, is effective in the treatment of bone metastases in patients with various solid tumors. In this present study, we found that UA combined with ZOL to significantly suppress cell viability, colony formation, and induce apoptosis in two lines of human osteosarcoma cells. The pre-treatment of the antioxidant had reversed the oxidative stress and cell viability inhibition in the combined treatment, indicating that oxidative stress is important in the combined anti-tumor effects. Moreover, we demonstrated that ZOL combined with UA significantly induced autophagy and co-administration of autophagy inhibitor reduces the growth inhibitory effect of combined treatment. Collectively, these data shed light on the pathways involved in the combined effects of ZOL and UA that might serve as a potential therapy against osteosarcoma.

  2. An open-label, prospective, observational study of the efficacy of bisphosphonate therapy for painful osteoid osteoma

    Energy Technology Data Exchange (ETDEWEB)

    Bousson, Valerie; Parlier-Cuau, Caroline; Laredo, Jean-Denis [AP-HP, Hopital Lariboisiere, Service de Radiologie Osteo-Articulaire, Paris (France); Universite Paris Diderot, Sorbonne Paris Cite, Paris (France); Leturcq, Tifenn; Ea, Hang-Korng; Orcel, Philippe [AP-HP, Hopital Lariboisiere, Service de Rhumatologie, Paris (France); Universite Paris Diderot, Sorbonne Paris Cite, Paris (France); Hauger, Olivier [CHU Pellegrin Bordeaux, Service d' Imagerie Diagnostique et Therapeutique de l' Adulte, Bordeaux (France); Mehsen-Cetre, Nadia; Schaeverbeke, Thierry [CHU Pellegrin Bordeaux, Service de Rhumatologie, Bordeaux (France); Hamze, Bassam [AP-HP, Hopital Lariboisiere, Service de Radiologie Osteo-Articulaire, Paris (France)

    2018-02-15

    To assess the efficacy of bisphosphonate therapy on bone pain in patients with osteoid osteoma (OO) (main objective), and to describe bisphosphonate-induced changes in nidus mineralisation and regional bone-marrow oedema (BMO). A prospective, observational study was conducted from 2011 to 2014. Patients with risk factors for complications of percutaneous or surgical ablation or recurrence after ablation, were offered once monthly intravenous bisphosphonate treatment until significant pain alleviation was achieved. We included 23 patients. The first two patients received pamidronate and the next 21 zoledronic acid (mean, 2.95 infusions per patient). Bisphosphonate therapy was successful in 19 patients (83%), whose mean pain visual analogue scale score decreased by 76.7%; this pain-relieving effect persisted in 17 patients (74%) with a mean follow-up time of 36 months. Computed tomography (CT) demonstrated a mean nidus density increase of 177.7% (p = 0.001). By magnetic resonance imaging (MRI), mean decreases were 38.4% for BMO surface area and 30.3% for signal intensity (p = 0.001 and p = 0.000, respectively). In 17/23 patients with painful OO managed conservatively with bisphosphonates, long-term final success was achieved. Bisphosphonates may accelerate the spontaneous healing of OO. (orig.)

  3. Microscopic Evaluation of the Effect of Oral Microbiota on the Development of Bisphosphonate-Related Osteonecrosis of the Jaws in Rats

    Directory of Open Access Journals (Sweden)

    Felipe M. Silveira

    2017-01-01

    Full Text Available Objectives: Osteonecrosis of the jaws is a side effect associated with the use of bisphosphonates. Using histologic analysis, this study aimed to evaluate the influence of microbial colonies in the development of osteonecrosis in the jaws of rats subjected to nitrogenous and non-nitrogenous bisphosphonates, undergoing surgical procedures. Material and Methods: Thirty-four rats (Rattus norvegicus, Wistar strain were allocated randomly into three groups: 12 animals treated with zoledronic acid; 12 animals treated with clodronate; and 10 animals treated with saline. Sixty days after the start of treatment, the animals underwent three extractions of the upper right molars. After 120 days of drug administration, the rats were killed. Histologic analysis was performed on specimens stained with hematoxylin and eosin by the technique of manual counting points using Image-Pro Plus software on images of the right hemimaxilla. Results: Osteonecrosis was induced in the test groups. There was no statistically significant association between the presence of microbial colonies and the presence of non-vital bone (Kruskal-Wallis, P > 0.05. Conclusions: Use of zoledronic acid was associated with non-vital bone and the results suggested that the presence of microbial colonies does not lead to osteonecrosis.

  4. The influence of bisphosphonates on human osteoblast migration and integrin aVb3/tenascin C gene expression in vitro

    Directory of Open Access Journals (Sweden)

    Said Yekta Sareh

    2011-02-01

    Full Text Available Abstract Background Bisphosphonates are therapeutics of bone diseases, such as Paget's disease, multiple myeloma or osteoclastic metastases. As a severe side effect the bisphosphonate induced osteonecrosis of the jaw (BONJ often requires surgical treatment and is accompanied with a disturbed wound healing. Therefore, the influence on adhesion and migration of human osteoblasts (hOB after bisphosphonate therapy has been investigated by morphologic as well as gene expression methods. Methods By a scratch wound experiment, which measures the reduction of defined cell layer gap, the morphology and migration ability of hOB was evaluated. A test group of hOB, which was stimulated by zoledronate 5 × 10-5M, and a control group of unstimulated hOB were applied. Furthermore the gene expression of integrin aVb3 and tenascin C was quantified by Real-Time rtPCR at 5data points over an experimental period of 14 days. The bisphosphonates zoledronate, ibandronate and clodronate have been compared with an unstimulated hOB control. Results After initially identical migration and adhesion characteristics, zoledronate inhibited hOB migration after 50 h of stimulation. The integrinavb3 and tenascin C gene expression was effected by bisphosphonates in a cell line dependent manner with decreased, respectively inconsistent gene expression levels over time. The non-nitrogen containing bisphosphonates clodronate led to decreased gene expression levels. Conclusion Bisphosphonates seem to inhibit hOB adhesion and migration. The integrin aVb3 and tenascin C gene expression seem to be dependent on the cell line. BONJ could be enhanced by an inhibition of osteoblast adhesion and migration. The gene expression results, however, suggest a cell line dependent effect of bisphosphonates, which could explain the interindividual differences of BONJ incidences.

  5. USE OF ZOLEDRONIC ACID AND A RАNK LIGAND INHIBITOR IN THE PALLIATIVE TREATMENT OF CANCERS OF THE PROSTATE WITH BONE METASTASES

    Directory of Open Access Journals (Sweden)

    S. V. Mushigin

    2013-01-01

    Full Text Available In the metastatic patterns of the cancer, the tumor foci are located more frequently in the tubular bones and vertebral column, just less frequently in the bones of the pelvis, and even more rarely in those of the shoulder and skull. Bone pain is usually related to the involvement of the periosteum that has an extensive network of nociceptors. Auxiliary exposures that directly affect the intensity of pain syndrome and the strength of bone structures are used in addition to basic therapy options for cancer of the prostate. Among these agents there are bisphosphonates. Once ingested, bisphosphonates are transported by blood to the areas of active bone tissue rearrangement where they are tightly bound to the mineral matrix. Their administration causes a considerable reduction in pain syndrome, a decrease in the frequency of complications of bone metastases, and an increase in time before a first bone complication. Antiresorptive therapy including particularly zoledronic acid (resorba or denosumab is a necessary treatment option in the above category of patients with bone metastases.

  6. USE OF ZOLEDRONIC ACID AND A RАNK LIGAND INHIBITOR IN THE PALLIATIVE TREATMENT OF CANCERS OF THE PROSTATE WITH BONE METASTASES

    Directory of Open Access Journals (Sweden)

    S. V. Mushigin

    2014-07-01

    Full Text Available In the metastatic patterns of the cancer, the tumor foci are located more frequently in the tubular bones and vertebral column, just less frequently in the bones of the pelvis, and even more rarely in those of the shoulder and skull. Bone pain is usually related to the involvement of the periosteum that has an extensive network of nociceptors. Auxiliary exposures that directly affect the intensity of pain syndrome and the strength of bone structures are used in addition to basic therapy options for cancer of the prostate. Among these agents there are bisphosphonates. Once ingested, bisphosphonates are transported by blood to the areas of active bone tissue rearrangement where they are tightly bound to the mineral matrix. Their administration causes a considerable reduction in pain syndrome, a decrease in the frequency of complications of bone metastases, and an increase in time before a first bone complication. Antiresorptive therapy including particularly zoledronic acid (resorba or denosumab is a necessary treatment option in the above category of patients with bone metastases.

  7. Oral bisphosphonates and risk of atrial fibrillation and flutter in women: a self-controlled case-series safety analysis.

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    Anthony Grosso

    Full Text Available A recent trial unexpectedly reported that atrial fibrillation, when defined as serious, occurred more often in participants randomized to an annual infusion of the relatively new parenteral bisphosphonate, zoledronic acid, than among those given placebo, but had limited power. Two subsequent population-based case-control studies of patients receiving a more established oral bisphosphonate, alendronic acid, reported conflicting results, possibly due to uncontrolled confounding factors.We used the United Kingdom General Practice Research Database to assess the risk of atrial fibrillation and flutter in women exposed to the oral bisphosphonates, alendronic acid and risedronate sodium. The self-controlled case-series method was used to minimise the potential for confounding. The age-adjusted incidence rate ratio for atrial fibrillation or flutter in individuals during their exposure to these oral bisphosphonates (n = 2195 was 1.07 (95% CI 0.94-1.21. The age-adjusted incidence rate ratio for alendronic acid (n = 1489 and risedronate sodium (n = 649 exposed individuals were 1.09 (95% CI 0.93-1.26 and 0.99 (95% CI 0.78-1.26 respectively. In post-hoc analyses, an increased risk of incident atrial fibrillation or flutter was detected for patients during their first few months of alendronic acid therapy.We found no robust evidence of an overall long-term increased risk of atrial fibrillation or flutter associated with continued exposure to the oral bisphosphonates, alendronic acid and risedronate sodium. A possible signal for an increase in risk during the first few months of therapy with alendronic acid needs to be re-assessed in additional studies.

  8. Zoledronate induces apoptosis in cells from fibro-cellular membrane of unicameral bone cyst (UBC).

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    Yu, John; Chang, Seong-Sil; Suratwala, Sanjeev; Chung, Woo-Sik; Abdelmessieh, Peter; Lee, Hahn-Jun; Yang, Jay; Lee, Francis Young-In

    2005-09-01

    Unicameral bone cyst (UBC) is a benign cystic lesion in children which is prone to fracture. Various treatments are available, but recurrence after different types of percutaneous injection therapy can cause bone destruction and pathologic fracture. The potential therapeutic effects of anti-resorptive agents, such as bisphosphonates, have not been investigated for UBC. The objective of this study was to characterize the cells from the fibro-cellular membrane of unicameral bone cyst (UBC cells) and to determine whether zoledronate, a nitrogen-containing bisphosphonate, could induce apoptosis in UBC cells. Flow cytometry and immunoblotting were performed in order to determine whether zoledronate induced apoptosis. Cells derived from normal human trabecular bones were used as controls against UBC cells to compare the effect of zoledronate in inducing apoptosis. Immunohisto/cytochemistry (IHC/ICC) and mini-array analyses were performed on tissues and cultured cells. Isolated peripheral blood mononuclear cells were incubated with conditioned media from the UBC cells to determine whether they are capable of inducing osteoclastogenesis. UBC membrane is composed of cells staining positively with CD68, SDF-1, STRO-1 and RANKL, but in vitro cells showed no staining with antibodies to CD68 and STRO-1, suggesting that there was a clonal selection of stromal cells during cell culture. UBC cells also express RUNX2 (runt-related transcription factor-2, core binding factor-1), a key transcription factor for osteoblastic differentiation. In addition, media collected from UBC cells induced a generation of multi-nucleated osteoclast-like cells of peripheral blood mononuclear cells. Zoledronate induced apoptosis of UBC cells in a dose-dependent manner. Apoptosis was evidenced by induction of the active cleaved form of caspase-3. The baseline apoptotic fractions were similar in UBC cells and trabecular bone cells. However, in the overall apoptotic fractions in this study, trabecular

  9. Bisphosphonate-related osteonecrosis of the jaw: historical, ethical, and legal issues associated with prescribing.

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    Faiman, Beth; Pillai, Aiswarya Lekshmi Pillai Chandran; Benghiac, Ana Gabriela

    2013-01-01

    The long-term effects of many drugs are unknown. Established risks are communicated to patients who participate in clinical trials during the informed consent process. However, unknown and unanticipated side effects of medications may occur years after treatment. Patients with metastatic bone cancer experience an imbalance between tumor cells and the bone marrow microenvironment. Increased cytokine release, osteoclastic activity, and uncoupled osteoblastic activity lead to weakened bone structure and osteolytic lesions. The bisphosphonates are a class of drugs available in IV and oral formulations to treat and prevent bone loss and decrease the risk of skeletal-related events. Intravenous bisphosphonates such as zoledronic acid and pamidronate disodium are approved by the US Food and Drug Administration for the treatment of bone pain and hypercalcemia of malignancy and the prevention of painful bone fractures in patients with metastatic bone cancer. Oral bisphosphonates such as alendronate, risedronate, and etidronate are used to reduce the risk of skeletal fractures in patients with osteoporosis and in breast cancer. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but painful complication of treatment characterized by infection, exposed bone, and poor wound healing. In this article, we discuss BRONJ and identify past, present, and future ethical and legal issues surrounding bisphosphonate administration.

  10. Cranial base pathology in pediatric osteogenesis imperfecta patients treated with bisphosphonates.

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    Arponen, Heidi; Vuorimies, Ilkka; Haukka, Jari; Valta, Helena; Waltimo-Sirén, Janna; Mäkitie, Outi

    2015-03-01

    Cranial base pathology is a serious complication of osteogenesis imperfecta (OI). Our aim was to analyze whether bisphosphonate treatment, used to improve bone strength, could also prevent the development of craniocervical junction pathology (basilar impression, basilar invagination, or platybasia) in children with OI. In this single-center retrospective study the authors analyzed the skull base morphology from lateral skull radiographs and midsagittal MR images (total of 94 images), obtained between the ages of 0 and 25 years in 39 bisphosphonate-treated OI patients. The results were compared with age-matched normative values and with findings in 70 OI patients who were not treated with bisphosphonates. In addition to cross-sectional data, longitudinal data were available from 22 patients with an average follow-up period of 7.6 years. The patients, who had OI types I, III, IV, VI, and VII, had been treated with zoledronic acid, pamidronate, or risedronate for 3.2 years on average. Altogether 33% of the 39 bisphosphonate-treated patients had at least 1 cranial base anomaly, platybasia being the most prevalent diagnosis (28%). Logistic regression analysis suggested a higher risk of basilar impression or invagination in patients with severe OI (OR 22.04) and/or older age at initiation of bisphosphonate treatment (OR 1.45), whereas a decreased risk was associated with longer duration of treatment (OR 0.28). No significant associations between age, height, or cumulative bisphosphonate dose and the risk for cranial base anomaly were detected. In longitudinal evaluation, Kaplan-Meier curves suggested delayed development of cranial base pathology in patients treated with bisphosphonates but the differences from the untreated group were not statistically significant. These findings indicate that cranial base pathology may develop despite bisphosphonate treatment. Early initiation of bisphosphonate treatment may delay development of craniocervical junction pathology

  11. Current perspectives on bisphosphonate treatment in Paget’s disease of bone

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    Wat WZM

    2014-11-01

    Full Text Available Winnie Zee Man Wat Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong Abstract: Paget’s disease of bone is a chronic metabolic bone disease with focal increase in bone turnover. The exact etiology of the disease is uncertain, although genetic and environmental factors are believed to be important. Bisphosphonate is the main class of medication being used to control disease activity via its antiresorptive effect. This review discusses the controversies concerning the use of bisphosphonates in the treatment of Paget’s disease of bone, the efficacy of different bisphosphonates in controlling disease activity, and the possible rare side effects of bisphosphonates. Symptoms are the main indication for treatment in Paget’s disease of bone. As treatment benefits in asymptomatic individuals remain controversial and nonevidence based, the decision to treat these patients should be individualized to their risk and benefit profiles. There are several trials conducted to evaluate and compare the efficacy of different regimes of bisphosphonates for treating Paget’s disease of bone. Most trials used biochemical markers rather than clinical symptoms or outcomes as parameters for comparison. Zoledronate is an attractive option as it can achieve high rates of biochemical remission and sustain long duration of suppression by a single dose. Atypical femoral fracture and osteonecrosis of the jaw are two rare and severe side effects reported, possibly related to the use of bisphosphonates in patients with osteoporosis and malignancy-induced hypercalcemia. As the regimes of bisphosphonates used for treating Paget’s disease of bone are different from those two diseases, the risks of developing these two possible side effects are expected to be very low, although this remains unknown. Vitamin D and calcium supplement should be given to patients at risk of vitamin D insufficiency when given zoledronate, as symptomatic

  12. Effect of zoledronic acid on bone density and markers of bone turnover in a community clinic.

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    Lim, Ria; Zailskas, Susan; Goldsby, Tashauna U; Lukens, Carrie; Muravev, Rostislav; Dulipsingh, Latha

    2013-01-01

    This study aims to document the efficacy of zoledronic acid by comparing bone densities and markers of bone turnover, in patients with osteoporosis. Bone mineral density (BMD) and urinary N-telopeptide, a marker of bone turnover, were compared before and after treatment with intravenous zoledronic acid. 52 participants had atleast two doses of zoledronic acid over 36 months. Significant increases in BMD were found in the spine (t=4.38, Pturnover marker N-telopeptide (t=3.30, P=0.002). Small but significant correlations were determined between prior steroid use and change in BMD in the spine (r=0.35, P<0.05), and family history of osteoporosis and change in BMD in the right femur (r=0.38, P<0.05). Annual infusions of zoledronic acid for at least two years, revealed a significant increase in bone density at the spine and a decrease in urinary N-telopeptide in patients treated at our center.

  13. The long-term effects of switching from active intravenous bisphosphonate treatment to low-dose maintenance therapy in children with osteogenesis imperfecta.

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    Biggin, Andrew; Zheng, Linda; Briody, Julie N; Coorey, Craig P; Munns, Craig F

    2015-01-01

    Intravenous bisphosphonate therapy is the first-line treatment in moderate-to-severe osteogenesis imperfecta (OI), but there are varied treatment protocols with little data on long-term efficacy. This study evaluates the clinical outcomes when transitioning from active bisphosphonate treatment to maintenance therapy. A retrospective review was conducted on 17 patients before treatment, following active treatment (zoledronate 0.05 mg/kg 6-monthly or pamidronate 6-9 mg/kg/year) and after establishment on maintenance treatment for more than 2 years (zoledronate 0.025 mg/kg 6-monthly or pamidronate lean tissue mass increased during active treatment. These improvements were maintained during the period of maintenance treatment. Vertebral height improved in fractured thoracic vertebrae from pre-treatment to active therapy and improved further during maintenance treatment. Metacarpal cortical thickness and relative cortical area also increased over the treatment periods. Maintenance intravenous bisphosphonate therapy preserved the beneficial effects of active treatment at the doses stated above. Further studies are required to determine the optimal bisphosphonate treatment regimen in the management of children with OI. © 2015 S. Karger AG, Basel.

  14. Biostimulatory effects of low-level laser therapy on epithelial cells and gingival fibroblasts treated with zoledronic acid

    International Nuclear Information System (INIS)

    Basso, F G; Pansani, T N; Turrioni, A P S; Hebling, J; De Souza Costa, C A; Kurachi, C; Bagnato, V S

    2013-01-01

    Low-level laser therapy (LLLT) has been considered as an adjuvant treatment for bisphosphonate-related osteonecrosis, presenting positive clinical outcomes. However, there are no data regarding the effect of LLLT on oral tissue cells exposed to bisphosphonates. This study aimed to evaluate the effects of LLLT on epithelial cells and gingival fibroblasts exposed to a nitrogen-containing bisphosphonate—zoledronic acid (ZA). Cells were seeded in wells of 24-well plates, incubated for 48 h and then exposed to ZA at 5 μM for an additional 48 h. LLLT was performed with a diode laser prototype—LaserTABLE (InGaAsP—780 nm ± 3 nm, 25 mW), at selected energy doses of 0.5, 1.5, 3, 5, and 7 J cm −2 in three irradiation sessions, every 24 h. Cell metabolism, total protein production, gene expression of vascular endothelial growth factor (VEGF) and collagen type I (Col-I), and cell morphology were evaluated 24 h after the last irradiation. Data were statistically analyzed by Kruskal–Wallis and Mann–Whitney tests at 5% significance. Selected LLLT parameters increased the functions of epithelial cells and gingival fibroblasts treated with ZA. Gene expression of VEGF and Col-I was also increased. Specific parameters of LLLT biostimulated fibroblasts and epithelial cells treated with ZA. Analysis of these in vitro data may explain the positive in vivo effects of LLLT applied to osteonecrosis lesions. (paper)

  15. Biostimulatory effects of low-level laser therapy on epithelial cells and gingival fibroblasts treated with zoledronic acid

    Science.gov (United States)

    Basso, F. G.; Pansani, T. N.; Turrioni, A. P. S.; Kurachi, C.; Bagnato, V. S.; Hebling, J.; de Souza Costa, C. A.

    2013-05-01

    Low-level laser therapy (LLLT) has been considered as an adjuvant treatment for bisphosphonate-related osteonecrosis, presenting positive clinical outcomes. However, there are no data regarding the effect of LLLT on oral tissue cells exposed to bisphosphonates. This study aimed to evaluate the effects of LLLT on epithelial cells and gingival fibroblasts exposed to a nitrogen-containing bisphosphonate—zoledronic acid (ZA). Cells were seeded in wells of 24-well plates, incubated for 48 h and then exposed to ZA at 5 μM for an additional 48 h. LLLT was performed with a diode laser prototype—LaserTABLE (InGaAsP—780 nm ± 3 nm, 25 mW), at selected energy doses of 0.5, 1.5, 3, 5, and 7 J cm-2 in three irradiation sessions, every 24 h. Cell metabolism, total protein production, gene expression of vascular endothelial growth factor (VEGF) and collagen type I (Col-I), and cell morphology were evaluated 24 h after the last irradiation. Data were statistically analyzed by Kruskal-Wallis and Mann-Whitney tests at 5% significance. Selected LLLT parameters increased the functions of epithelial cells and gingival fibroblasts treated with ZA. Gene expression of VEGF and Col-I was also increased. Specific parameters of LLLT biostimulated fibroblasts and epithelial cells treated with ZA. Analysis of these in vitro data may explain the positive in vivo effects of LLLT applied to osteonecrosis lesions.

  16. Pharmacoeconomics of bisphosphonates for skeletal-related event prevention in metastatic non-breast solid tumours.

    Science.gov (United States)

    Carter, John A; Joshi, Avani D; Kaura, Satyin; Botteman, Marc F

    2012-05-01

    Bisphosphonates reduce the risk of skeletal-related events (SREs; i.e. spinal cord compression, pathological fracture, radiation or surgery to the bone, and hypercalcaemia) in patients with metastatic cancer. A number of analyses have been conducted to assess the cost effectiveness of bisphosphonates in patients with bone metastases secondary to breast cancer, but few in other solid tumours. This is a review of cost-effectiveness analyses in patients with non-breast solid tumours and bone metastases. A literature search was conducted to identify cost-effectiveness analyses reporting the cost per QALY gained of bisphosphonates in patients with metastatic bone disease secondary to non-breast solid tumours. Four analyses met inclusion criteria. These included two in prostate cancer (one of which used a global perspective but expressed results in $US, and the other reported from a multiple country perspective: France, Germany, Portugal and the Netherlands). The remaining analyses were in lung cancer (in the UK, France, Germany, Portugal and the Netherlands), and renal cell carcinoma (in the UK, France and Germany). In each analysis, the cost effectiveness of zoledronic acid versus placebo was analysed. Zoledronic acid was found to be cost effective in all European countries across all three indications but not in the sole global prostate cancer analysis. Across countries and indications, assumptions regarding patient survival, drug cost and baseline utility (i.e. patient utility with metastatic disease but without an SRE) were the most robust drivers of modelled estimates. Assumptions of SRE-related costs were most often the second strongest cost driver. Further review indicated that particular attention should be paid to the inclusion or exclusion of nonsignificant survival benefits, whether health state utilities were elicited from community or patient samples or author assumptions, delineation between symptomatic and asymptomatic SREs, and the methods with which SRE

  17. A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures.

    Science.gov (United States)

    Davis, Sarah; Martyn-St James, Marrissa; Sanderson, Jean; Stevens, John; Goka, Edward; Rawdin, Andrew; Sadler, Susi; Wong, Ruth; Campbell, Fiona; Stevenson, Matt; Strong, Mark; Selby, Peter; Gittoes, Neil

    2016-10-01

    Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax ® and Fosamax ® Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel ® and Actonel Once a Week ® , Warner Chilcott UK Ltd), ibandronic acid (Bonviva ® , Roche Products Ltd) and zoledronic acid (Aclasta ® , Novartis Pharmaceuticals UK Ltd)] for the prevention of fragility fracture and to assess their cost-effectiveness at varying levels of fracture risk. For the clinical effectiveness review, six electronic databases and two trial registries were searched: MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science and BIOSIS Previews, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform. Searches were limited by date from 2008 until September 2014. A systematic review and network meta-analysis (NMA) of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years (QALYs) for each bisphosphonate treatment strategy and a strategy of no treatment for a simulated cohort of patients with heterogeneous characteristics. The model was populated with effectiveness evidence from the systematic review and NMA. All other parameters were estimated from published sources. A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture ® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX ® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net benefit (INB) was

  18. Time associated with intravenous zoledronic acid administration in patients with breast or prostate cancer and bone metastasis

    Directory of Open Access Journals (Sweden)

    Richhariya A

    2012-02-01

    Full Text Available Akshara Richhariya1, Yi Qian2, Yufan Zhao2, Karen Chung11Amgen Inc, Global Health Economics, Thousand Oaks, CA, USA; 2Amgen Inc, Global Biostatistical Sciences, Thousand Oaks, CA, USAPurpose: Intravenous (IV zoledronic acid (ZA is commonly used to delay skeletal complications secondary to bone metastases. However, the time associated with ZA administration may represent a significant burden to healthcare providers and patients. This study assessed the time associated with IV ZA infusion in patients with bone metastases secondary to breast or prostate cancer (BC or PC in the clinic setting.Methods: Eligible BC or PC patients with bone metastases scheduled to receive IV ZA were observed at seven US-based oncology clinics. Trained observers recorded the time for preinfusion tasks, ZA drug preparation, intravenous infusion, and follow-up activities.Results: Data are reported for 39 patients (BC: 24; PC: 15. Mean administration time was 69 (standard deviation [SD] 42 minutes for all patients combined, 72 (SD 47 minutes for BC, and 65 (SD 33 minutes for PC. Activity times were comparable between tumor types. Mean time for preinfusion tasks (eg, assessment of vital signs, blood draw and ZA preparation were 12 (SD 20 minutes and 2 (SD 1 minutes, respectively. Mean time required for intravenous infusion (ZA infusion and hydration, when provided and follow-up activities were 54 (SD 31 minutes and 2 (SD 1 minutes, respectively.Conclusion: Infusion time was the greatest time commitment associated with IV ZA administration, representing 78% of the total time on average. Time for preinfusion activities varied substantially. Overall, the mean time for ZA administration represents a notable time burden for healthcare providers and patients.Keywords: time and motion, bisphosphonates, zoledronic acid, intravenous administration

  19. Tooth alterations in areas of bisphosphonate-induced osteonecrosis.

    Science.gov (United States)

    de Camargo Moraes, Paulo; Silva, Carolina Amália Barcellos; Soares, Andresa Borges; Passador-Santos, Fabrício; Corrêa, Maria Elvira Pizzigatti; de Araújo, Ney Soares; de Araújo, Vera Cavalcanti

    2015-03-01

    Osteonecrosis of the jaw is a potential side effect when using bisphosphonates. Most studies on the effects of bisphosphonates on teeth have been conducted in vitro or in animal models of tooth development. Therefore, the aim of this study was to describe alterations found in human teeth extracted from areas of bisphosphonate-induced osteonecrosis. Using a retrospective study design, 16 teeth from 13 patients were extracted from areas of bisphosphonate-induced osteonecrosis during surgical debridement. The specimens were decalcified and embedded in paraffin. A series of 5-μm sections were prepared, stained with hematoxylin and eosin (H&E) and observed under a light microscope. The majority of the patients were female (53.85 %), with a mean age of 60.23 ± 13.18 years. Zoledronate (IV) was the most common bisphosphonate used (92.3 %), over a mean period of 2 years. The commonest alteration observed was hypercementosis (87.5 %), followed by pulpar necrosis (81.25 %), pulp stones attached to the dentine and loose pulp stones in the pulp chamber and root canals in addition to linear calcifications (68.75 %), dentinoid/osteoid material formation (18.75 %), and dental ankylosis (6.25 %). Patients undergoing bisphosphonate therapy present diverse tooth alterations, which should be closely monitored by clinicians to prevent complications. It is paramount that the teeth involved in oral lesions are always examined. Attention should be drawn to the need to establish preventive measures, in terms of dental treatment, for patients prior to starting bisphosphonate therapy.

  20. Once-Yearly Zoledronic Acid and Days of Disability, Bed Rest, and Back Pain: Randomized, Controlled HORIZON Pivotal Fracture Trial

    Science.gov (United States)

    Cauley, Jane A.; Black, Dennis; Boonen, Steven; Cummings, Steven R.; Mesenbrink, Peter; Palermo, Lisa; Man, Zulema; Hadji, Peyman; Reid, Ian R.

    2016-01-01

    The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90–0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87–1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47–0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58–0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that

  1. Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: a paradigm of synergistic molecular targeting treatment for ovarian cancer

    Directory of Open Access Journals (Sweden)

    Kısım Aslı

    2010-07-01

    Full Text Available Abstract Background Ovarian cancer is the most fatal gynecologic malignancies in the world. Although, platinum based treatments are widely used, the disease becomes treatment refractory within two years, and novel treatment options should be searched. All- trans retinoic acid (ATRA induces growth arrest, differentiation and cell death in some types of cancer cells and its combination with various anticancer agents results in enhanced cytotoxicity. Zoledronic acid is a common bisphosphonate known for its anticancer effects beyond its current use in the treatment of cancer-induced bone disease. We aimed to investigate the possible additive/synergistic effect of both agents in OVCAR-3 and MDAH-2774 ovarian cancer cell lines, since both agents show superiority to conventional cytotoxics in terms of adverse events. Methods XTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. OligoGeArray® which consists of 112 apoptosis related genes was used to elucidate the genetic changes within cancer cells. To validate our oligoarray results, quantitative real-time PCR was performed on four selected genes that were maximally effected by the combination treatment: lymphotoxin beta receptor (LTBR, myeloid cell leukemia-1 (MCL-1, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A, TNFRSF1A-associated death domain protein (TRADD. Results We demonstrated that a novel combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in both ovarian cancer cells. While the combination therapy significantly induced proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF, TRADD and caspase 4, some of the antiapoptotic genes such as members of MCL-1, LTBR, BAG3 and Bcl-2 family members were inhibited. Conclusions These are the preliminary molecular results of a novel combination treatment of

  2. Assessment on zoledronic acid use in patients with bone metastatic breast cancer

    International Nuclear Information System (INIS)

    Soriano Garcia, Jorge L; Batista Albuerne, Noyde; Lima Perez, Mayte

    2010-01-01

    The biphosphonates are the cornerstone in the bone metastases treatment. In present paper the effectiveness and safety of the zoledronic acid (ZA) use in patients with bone metastatic breast cancer (MBC)

  3. Novel therapeutic intervention for osteoporosis prepared with strontium hydroxyapatite and zoledronic acid: In vitro and pharmacodynamic evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Khajuria, Deepak Kumar, E-mail: deepak_kumarkhajuria@yahoo.co.in [The Musculoskeletal Genetics Laboratory, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed (Israel); Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore (India); Vasireddi, Ramakrishna; Trebbin, Martin [Hamburg Center for Ultrafast Imaging, University of Hamburg, Hamburg (Germany); Karasik, David [The Musculoskeletal Genetics Laboratory, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed (Israel); Razdan, Rema [Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore (India)

    2017-02-01

    Osteoporosis therapeutics has been monopolized mainly by bisphosphonates, which are potent anti-osteoporotic drugs, while they do not promote bone formation or replenish the already resorbed bone. Although strontium substituted hydroxyapatite (SrHA) has been proclaimed to improve bone properties in an osteoporotic animal model, there is no published data on direct delivery of SrHA nanoparticles by bisphosphonate-like zoledronic acid (ZOL) to the bone. Therefore, this study was designed to investigate the potential of using SrHA/ZOL nanoparticle-based drug formulation in an ovariectomized rat model of postmenopausal osteoporosis. SrHA and SrHA/ZOL nanoparticles were prepared and characterized by field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Twelve weeks after ovariectomy, rats were treated with either single intravenous dose of SrHA/ZOL (100, 50 or 25 μg/kg); ZOL (100 μg/kg); or SrHA (100 μg/kg). Saline-treated OVX and SHAM-OVX groups served as controls. The energy-dispersive X-ray (EDX) microanalysis of bone specimen obtained from SrHA/ZOL groups yielded range between 64.3 ± 6.7 to 66.9 ± 6.8 of calcium weight (wt) % and 1.64 ± 0.6 to 1.74 ± 0.8 of calcium/phosphorus (Ca/P) ratio which was significantly higher when compared with 39.7 ± 9.3 calcium and 1.30 ± 0.2 Ca/P ratio for OVX group. Moreover, the strontium wt% in SrHA/ZOL group (between 3.1 ± 0.5 and 6.8 ± 0.4) was significantly higher than SrHA group (1.8 ± 0.9). These results confirmed targeted delivery of SrHA nanoparticles by ZOL to the bone. Therapy with SrHA/ZOL showed significant improvements in trabecular bone microarchitecture and mechanical strength as compared to ZOL or SrHA (p < 0.05). Moreover, treatment with SrHA/ZOL significantly precluded an increase in serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase than either ZOL or SrHA (p < 0.05). These results strongly implicate

  4. Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer.

    Science.gov (United States)

    Tardoski, Sophie; Ngo, Jacqueline; Gineyts, Evelyne; Roux, Jean-Paul; Clézardin, Philippe; Melodelima, David

    2015-11-18

    Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailability for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonate from the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonate anticancer activity in bone metastases and in primary tumors.

  5. Effect of Nd:YAG laser light on post-extractive socket healing in rats treated with zoledronic acid and dexamethasone

    Science.gov (United States)

    Mergoni, Giovanni; Merigo, Elisabetta; Passerini, Pietro; Corradi, Domenico; Maestri, Roberta; Bussolati, Ovidio; Bianchi, Massimiliano; Sala, Roberto; Govoni, Paolo; Namour, Samir; Vescovi, Paolo

    2016-03-01

    Introduction The effect of low level laser therapy (LLLT) on the healing process could be useful for the prevention of post-extractive Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ). The aim of the study was to investigate the effect of LLLT on the post-extractive socket healing in rats treated with zoledronic acid and dexamethasone. Material and Methods Thirty male Sprague-Dawley rats were divided in 4 groups: control group (C, n = 5), laser group (L, n = 5), treatment group (T, n = 10) and treatment plus laser group (T+L, n = 10). Rats of group T and T+L received zoledronate 0,1 mg/Kg and dexamethasone 1 mg/Kg every 2 days for 10 weeks. Rats of group C and L were infused with vehicle. After 9 weeks the first maxillary molars were extracted in all rats. Rats of groups L and T+L received laser therapy (Nd:YAG, 1064 nm, 1.25W, 15Hz, 5 min, 14.37 J/cm2) in the socket area at days 0, 2, 4 and 6 after surgery. At 8 days from extraction, the sockets were clinically assessed with a grading score and the wound area was measured with a dedicate software. Histomorphometric evaluation and western blot analysis of osteopontin and osteocalcin expression were performed. Results Group T+L showed a trend toward a better clinical grading score compared to group T (grade I 22% Vs 28 % - grade II 56% Vs 28% - grade III 22% Vs 44%, respectively). The average wound area was similar among the groups. Inhibition of osteoclastic alveolar bone resorption was found in groups T and T+L (Phealing in conditions at risk for MRONJ development.

  6. Sclerostin Blockade and Zoledronic Acid Improve Bone Mass and Strength in Male Mice With Exogenous Hyperthyroidism.

    Science.gov (United States)

    Tsourdi, Elena; Lademann, Franziska; Ominsky, Michael S; Rijntjes, Eddy; Köhrle, Josef; Misof, Barbara M; Roschger, Paul; Klaushofer, Klaus; Hofbauer, Lorenz C; Rauner, Martina

    2017-11-01

    Hyperthyroidism in mice is associated with low bone mass, high bone turnover, and high concentrations of sclerostin, a potent Wnt inhibitor. Here, we explored the effects of either increasing bone formation with sclerostin antibodies (Scl-Ab) or reducing bone turnover with bisphosphonates on bone mass and strength in hyperthyroid mice. Twelve-week-old C57BL/6 male mice were rendered hyperthyroid using l-thyroxine (T4; 1.2 µg/mL added to the drinking water) and treated with 20 mg/kg Scl-Ab twice weekly or 100 µg/kg zoledronic acid (ZOL) once weekly or phosphate-buffered saline for 4 weeks. Hyperthyroid mice displayed a lower trabecular bone volume at the spine (-42%, P hyperthyroid mice increased trabecular bone volume at the spine by threefold and twofold, respectively. Serum bone formation and resorption markers were increased in hyperthyroid mice and suppressed by treatment with ZOL but not Scl-Ab. Trabecular bone stiffness at the lumbar vertebra was 63% lower in hyperthyroid mice (P hyperthyroidism, was increased by Scl-Ab by 71% and ZOL by 22% (both P hyperthyroid mice was restored by treatment with Scl-Ab and ZOL. Thus, bone-forming and antiresorptive drugs prevent bone loss in hyperthyroid mice via different mechanisms. Copyright © 2017 Endocrine Society.

  7. BONE TURNOVER IN OSTEOPOROTIC WOMEN DURING LONG-TERM ORAL BISPHOSPHONATES TREATMENT: IMPLICATIONS FOR TREATMENT FAILURE AND "DRUG HOLIDAY" IN THE REAL WORLD.

    Science.gov (United States)

    Liel, Yair; Plakht, Ygal; Tailakh, Muhammad Abu

    2017-07-01

    Little data exist to support concerns over bone turnover suppression during prolonged oral bisphosphonate treatment and on consequences of the recommended "drug holiday." This study was performed to assess bone resorption rates in postmenopausal osteoporotic women on prolonged oral bisphosphonate treatment and in response to switching to "drug holiday" intravenous bisphosphonate, or continuation of oral bisphosphonates. The frequency distribution of the bone resorption marker urinary deoxypyridinoline crosslinks (uDPD), was obtained retrospectively from 211 osteoporotic women attended at an academic hospital endocrine clinic, treated for >2 years with oral bisphosphonates. In some patients, uDPD was re-assessed following modification or continuation of treatment. The mean duration of oral bisphosphonates treatment was 7.2 ± 3.1 years. uDPD was within reference range for premenopausal women in 61.6% of the patients, below in 7.6% of the patients, and above upper limit in 30.8%. uDPD decreased significantly following intravenous zoledronic acid, increased significantly during "drug holiday," and slightly decreased in those continued on oral bisphosphonate treatment. In this real-world study, the majority of women on prolonged oral bisphosphonates maintained bone resorption rates within the normal reference range for premenopausal women. The likelihood for inadequate suppression was considerably greater than that of over-suppression. Implementing a "drug holiday" resulted in a marked increase in bone resorption rates. Additional studies should explore the potential role of bone turnover markers in the evaluation of patients on prolonged oral bisphosphonates and during "drug holiday" in different settings and using additional markers. BMD = bone mineral density; IQR = interquartile range; uDPD = urinary deoxypyridinoline crosslinks.

  8. The Pharmacological Profile of a Novel Highly Potent Bisphosphonate, OX14 (1-Fluoro-2-(Imidazo-[1,2-α]Pyridin-3-yl)-Ethyl-Bisphosphonate).

    Science.gov (United States)

    Lawson, Michelle A; Ebetino, Frank H; Mazur, Adam; Chantry, Andrew D; Paton-Hough, Julia; Evans, Holly R; Lath, Darren; Tsoumpra, Maria K; Lundy, Mark W; Dobson, Roy Lm; Quijano, Michael; Kwaasi, Aaron A; Dunford, James E; Duan, Xuchen; Triffitt, James T; Jeans, Gwyn; Russell, R Graham G

    2017-09-01

    Bisphosphonates are widely used in the treatment of clinical disorders characterized by increased bone resorption, including osteoporosis, Paget's disease, and the skeletal complications of malignancy. The antiresorptive potency of the nitrogen-containing bisphosphonates on bone in vivo is now recognized to depend upon two key properties, namely mineral binding affinity and inhibitory activity on farnesyl pyrophosphate synthase (FPPS), and these properties vary independently of each other in individual bisphosphonates. The better understanding of structure activity relationships among the bisphosphonates has enabled us to design a series of novel bisphosphonates with a range of mineral binding properties and antiresorptive potencies. Among these is a highly potent bisphosphonate, 1-fluoro-2-(imidazo-[1,2 alpha]pyridin-3-yl)-ethyl-bisphosphonate, also known as OX14, which is a strong inhibitor of FPPS, but has lower binding affinity for bone mineral than most of the commonly studied bisphosphonates. The aim of this work was to characterize OX14 pharmacologically in relation to several of the bisphosphonates currently used clinically. When OX14 was compared to zoledronate (ZOL), risedronate (RIS), and minodronate (MIN), it was as potent at inhibiting FPPS in vitro but had significantly lower binding affinity to hydroxyapatite (HAP) columns than ALN, ZOL, RIS, and MIN. When injected i.v. into growing Sprague Dawley rats, OX14 was excreted into the urine to a greater extent than the other bisphosphonates, indicating reduced short-term skeletal uptake and retention. In studies in both Sprague Dawley rats and C57BL/6J mice, OX14 inhibited bone resorption, with an antiresorptive potency equivalent to or greater than the comparator bisphosphonates. In the JJN3-NSG murine model of myeloma-induced bone disease, OX14 significantly prevented the formation of osteolytic lesions (p < 0.05). In summary, OX14 is a new, highly potent bisphosphonate with lower bone binding

  9. Addition of docetaxel and/or zoledronic acid to standard of care for hormone-naive prostate cancer: a cost-effectiveness analysis.

    Science.gov (United States)

    Zhang, Pengfei; Wen, Feng; Fu, Ping; Yang, Yu; Li, Qiu

    2017-07-31

    The effectiveness of the addition of docetaxel and/or zoledronic acid to the standard of care (SOC) for hormone-naive prostate cancer has been evaluated in the STAMPEDE trial. The object of the present analysis was to evaluate the cost-effectiveness of these treatment options in the treatment of advanced hormone-naive prostate cancer in China. A cost-effectiveness analysis using a Markov model was carried out from the Chinese societal perspective. The efficacy data were obtained from the STAMPEDE trial and health utilities were derived from previous studies. Transition probabilities were calculated based on the survival in each group. The primary endpoint in the analysis was the incremental cost-effectiveness ratio (ICER), and model uncertainties were explored by 1-way sensitivity analysis and probabilistic sensitivity analysis. SOC alone generated an effectiveness of 2.65 quality-adjusted life years (QALYs) at a lifetime cost of $20,969.23. At a cost of $25,001.34, SOC plus zoledronic acid was associated with 2.69 QALYs, resulting in an ICER of $100,802.75/QALY compared with SOC alone. SOC plus docetaxel gained an effectiveness of 2.85 QALYs at a cost of $28,764.66, while the effectiveness and cost data in the SOC plus zoledronic acid/docetaxel group were 2.78 QALYs and $32,640.95. Based on the results of the analysis, SOC plus zoledronic acid, SOC plus docetaxel, and SOC plus zoledronic acid/docetaxel are unlikely to be cost-effective options in patients with advanced hormone-naive prostate cancer compared with SOC alone.

  10. Zoledronic acid in children with osteogenesis imperfecta and Bruck syndrome: a 2-year prospective observational study.

    Science.gov (United States)

    Otaify, G A; Aglan, M S; Ibrahim, M M; Elnashar, M; El Banna, R A S; Temtamy, S A

    2016-01-01

    Treatment with zoledronic acid (ZA) over 2 years, among 33 children with osteogenesis imperfecta (OI) and five Bruck syndrome cases, showed reduction in fracture rates, pain, and improvement in bone mineral density (BMD) and motor milestones of development. This is the first study reporting the use of bisphosphonates in patients with Bruck syndrome (BS). OI and BS are genetic disorders that result in bone fragility and reduced BMD. There is little literature describing the efficacy and safety of ZA in this population. In this study, we assess the response to treatment with ZA at six monthly intervals in Egyptian children with OI and BS for a period of 2 years. Thirty-three patients with OI and five patients with BS were treated with 0.1 mg/kg ZA intravenously every 6 months for 2 years during which they were followed up using different parameters. A clinical severity score (CSS) was applied to the patients before and 2 years after the start of therapy. Comparison of disease severity and response to ZA treatment between autosomal-dominant (AD) and autosomal-recessive (AR) OI patients was also done. After 6 months of treatment, OI and BS patients showed a significant increase in BMD Z-scores (P < 0.003 in the spine and P < 0.004 in the hip), together with a significant drop in fracture rate (P < 0.001), relief of pain (P < 0.001), and improvement in ambulation (P < 0.001). CSS was significantly reduced after 2 years of treatment in both OI and BS patients. AR-OI patients were more severely affected than AD-OI patients and showed more significant improvement. Zoledronic acid proved to be safe and effective in the treatment of OI and BS. The biannual infusion protocol was convenient to patients. There was a positive correlation between disease severity and benefits of the treatment. The use of the CSS proved to be of value in the assessment of the degree of severity in OI, and with some modifications, it was a valuable tool for the assessment of

  11. Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study.

    Science.gov (United States)

    Nuzzo, F; Gallo, C; Lastoria, S; Di Maio, M; Piccirillo, M C; Gravina, A; Landi, G; Rossi, E; Pacilio, C; Labonia, V; Di Rella, F; Bartiromo, A; Buonfanti, G; De Feo, G; Esposito, G; D'Aniello, R; Maiolino, P; Signoriello, S; De Maio, E; Tinessa, V; Colantuoni, G; De Laurentiis, M; D'Aiuto, M; Di Bonito, M; Botti, G; Giordano, P; Daniele, G; Morabito, A; Normanno, N; de Matteis, A; Perrone, F

    2012-08-01

    To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P<0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole+zoledronic acid versus letrozole comparison (P<0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P=0.004 and 0.47, respectively). In the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.

  12. Zoledronic acid enhances the effect of radiotherapy for bone metastases from renal cell carcinomas. More than a 24-month median follow-up

    International Nuclear Information System (INIS)

    Takeda, Naoki; Isu, Kazuo; Hiraga, Hiroaki; Shinohara, Nobuo; Minami, Akio; Kamata, Hajime

    2012-01-01

    Renal cell carcinoma (RCC) is thought to respond unreliably to radiotherapy (RT). Zoledronic acid significantly reduces the risk of skeletal complications. This study investigated whether RT with zoledronic acid prolonged the time to bone-lesion progression in comparison with RT alone. Twenty-seven patients (34 lesions) with bone metastases secondary to RCC undergoing treatment with RT with or without zoledronic acid were retrospectively evaluated at two institutions between 1999 and 2009. Twelve patients were treated with RT alone from 1999 to 2008 (RT group). Fifteen patients were treated with RT and zoledronic acid from 2006 to 2009 (RT+Z group). The time to skeletal-related events and pain progression were assessed from patients' medical records. The median (range) follow-up was 26 (3-75) and 24 (3-55) months in the RT and RT+Z groups, respectively. Three patients (three lesions) in the RT+Z group had skeletal-related events (SREs). In contrast, six patients (eight lesions) in the RT group had SREs. SREs comprised pathological fractures in five, additional surgeries in three, spinal cord or cauda equine compression in two, and repeat RT in one. There was a significant difference in SRE-free survival time and duration of site-specific pain response between groups. RT combined with zoledronic acid significantly prolonged SRE-free survival and duration of pain response compared with RT alone in the treatment of osseous metastases from RCC. (author)

  13. Local effect of zoledronic acid on new bone formation in posterolateral spinal fusion with demineralized bone matrix in a murine model.

    Science.gov (United States)

    Zwolak, Pawel; Farei-Campagna, Jan; Jentzsch, Thorsten; von Rechenberg, Brigitte; Werner, Clément M

    2018-01-01

    Posterolateral spinal fusion is a common orthopaedic surgery performed to treat degenerative and traumatic deformities of the spinal column. In posteriolateral spinal fusion, different osteoinductive demineralized bone matrix products have been previously investigated. We evaluated the effect of locally applied zoledronic acid in combination with commercially available demineralized bone matrix putty on new bone formation in posterolateral spinal fusion in a murine in vivo model. A posterolateral sacral spine fusion in murine model was used to evaluate the new bone formation. We used the sacral spine fusion model to model the clinical situation in which a bone graft or demineralized bone matrix is applied after dorsal instrumentation of the spine. In our study, group 1 received decortications only (n = 10), group 2 received decortication, and absorbable collagen sponge carrier, group 3 received decortication and absorbable collagen sponge carrier with zoledronic acid in dose 10 µg, group 4 received demineralized bone matrix putty (DBM putty) plus decortication (n = 10), and group 5 received DBM putty, decortication and locally applied zoledronic acid in dose 10 µg. Imaging was performed using MicroCT for new bone formation assessment. Also, murine spines were harvested for histopathological analysis 10 weeks after surgery. The surgery performed through midline posterior approach was reproducible. In group with decortication alone there was no new bone formation. Application of demineralized bone matrix putty alone produced new bone formation which bridged the S1-S4 laminae. Local application of zoledronic acid to demineralized bone matrix putty resulted in significant increase of new bone formation as compared to demineralized bone matrix putty group alone. A single local application of zoledronic acid with DBM putty during posterolateral fusion in sacral murine spine model increased significantly new bone formation in situ in our model. Therefore, our

  14. Oral squamous cell carcinoma arising in a patient after hematopoietic stem cell transplantation with bisphosphonate-related osteonecrosis of the jaws.

    Science.gov (United States)

    Arduino, Paolo G; Scully, Crispian; Chiusa, Luigi; Broccoletti, Roberto

    2015-01-01

    A 55-year-old man with a history of acute myeloid leukaemia treated with hematopoietic stem cell transplantation and with a 5-year history of bisphosphonate-related osteonecrosis of the jaws, following 12 cycles of intravenous zoledronic acid therapy, presented in December 2009 with a history of increasingly severe unilateral lower jaw pain. Oral examination revealed, as previously, exposed bone in the left mandible, but also a new exophytic mass on the lower-left buccal mucosa. Biopsy confirmed a diagnosis of oral squamous cell carcinoma. To the best of our knowledge, this is the first report of an oral squamous cell carcinoma that appeared adjacent to an area of osteochemonecrosis.

  15. A simple RP-HPLC method for related substances of zoledronic acid in pharmaceutical products

    Directory of Open Access Journals (Sweden)

    L. Maheswara Reddy

    2017-02-01

    Full Text Available A novel, selective and sensitive reverse phase-high performance liquid chromatography (RP-HPLC method has been developed for the validated estimation of imidazol-1-yl-acetic acid in zoledronic acid formulations. The separation was achieved on a 5 μ C18 column (250 × 4.6 mm using a mobile phase that consists of the buffer (4.5 g of di-potassium hydrogen phosphate anhydrous and 2.0 g of tetra butyl ammonium hydrogen sulphate (TBAHS in 1000 mL of water and methanol in the ratio of 900:100 v/v. The flow rate was maintained at 1.0 mL min−1. The detection of the constituents was done at 215 nm using a UV detector. The retention times of imidazol-1-yl-acetic acid and zoledronic acid were 7.2 and 10.2 min respectively. Recovery studies were satisfactory and the correlation coefficient, 0.999 indicates linearity of the method within the limits. The developed method can be applicable for regular qualitative analysis.

  16. Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay

    International Nuclear Information System (INIS)

    Fehm, Tanja; Zwirner, Manfred; Wallwiener, Diethelm; Seeger, Harald; Neubauer, Hans

    2012-01-01

    The NeoAzure study has demonstrated that the use of the bisphosphonate zoledronic acid (Zol) in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity. The purpose of this study was to compare the antitumor effect of Zol with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA). Breast cancer specimens were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Department of Obstetrics and Gynecology, Tübingen, Germany, between 2006 through 2009. Antitumor effects of Zol, TAC (Docetaxel, Adriamycin, Cyclophosphamide) and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50), for IC90 and for the sensitivity index (IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls. The median IndexSUM value was lower for Zol than for the combined regimen FEC (36.8%) and TAC (12.9%), respectively, indicating increased antitumor activity of Zol in primary breast cancer cells. The difference regarding Zol and FEC was significant (p < 0.05). The median IC50 value for Zol (8.03% TDC) was significantly lower than the IC50 values for FEC (33.5% TDC) and TAC (19.3% TDC) treatment (p < 0.05). However, the median IC90 value for Zol (152.5% TDC) was significantly higher than the IC90 value obtained with TAC (49.5% TDC; p < 0.05), but similar to the IC90 value for FEC (180.9% TDC). In addition a significant positive correlation was observed for the IndexSum of Zol and the ER status

  17. Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment

    Directory of Open Access Journals (Sweden)

    Vessella Robert L

    2006-01-01

    Full Text Available Abstract Background After development of hormone-refractory metastatic disease, prostate cancer is incurable. The recent history of chemotherapy has shown that with difficult disease targets, combinatorial therapy frequently offers the best chance of a cure. In this study we have examined the effects of a combination of zoledronic acid (ZOL, a new-generation bisphosphonate, and docetaxel on LuCaP 23.1, a prostate cancer xenograft that stimulates the osteoblastic reaction when grown in the bone environment. Methods Intra-tibial injections of LuCaP 23.1 cells were used to generate tumors in the bone environment, and animals were treated with ZOL, docetaxel, or a combination of these. Effects on bone and tumor were evaluated by measurements of bone mineral density and histomorphometrical analysis. Results ZOL decreased proliferation of LuCaP 23.1 in the bone environment, while docetaxel at a dose that effectively inhibited growth of subcutaneous tumors did not show any effects in the bone environment. The combination of the drugs significantly inhibited the growth of LuCaP 23.1 tumors in the bone. Conclusion In conclusion, the use of the osteolysis-inhibitory agent ZOL in combination with docetaxel inhibits growth of prostate tumors in bone and represents a potential treatment option.

  18. The IL-6 receptor super-antagonist Sant7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma cells.

    Science.gov (United States)

    Tassone, Pierfrancesco; Galea, Eulalia; Forciniti, Samantha; Tagliaferri, Pierosandro; Venuta, Salvatore

    2002-10-01

    Interleukin-6 (IL-6) is the major growth and survival factor for multiple myeloma (MM), and has been shown to protect MM cells from apoptosis induced by a variety of agents. IL-6 receptor antagonists, which prevent the assembly of functional IL-6 receptor complexes, inhibit cell proliferation and induce apoptosis in MM cells. We have investigated whether the IL-6 receptor super-antagonist Sant7 might enhance the antiproliferative and apoptotic effects induced by the combination of dexamethasone (Dex) and zoledronic acid (Zln) on human MM cell lines and primary cells from MM patients. Here we show that each of these compounds individually induced detectable antiproliferative effects on MM cells. Sant7 significantly enhanced growth inhibition and apoptosis induced by Dex and Zln on both MM cell lines and primary MM cells. These results indicate that overcoming IL-6 mediated cell resistance by Sant7 potentiates the effect of glucocorticoides and bisphosphonates on MM cell growth and survival, providing a rationale for therapies including IL-6 antagonists in MM.

  19. Jaw osteonecrosis related to bisphosphonate therapy: a severe secondary disorder.

    Science.gov (United States)

    Dannemann, C; Grätz, K W; Riener, M O; Zwahlen, R A

    2007-04-01

    Bisphosphonate-related osteonecrosis of the jaws (BON), first described in 2003, is gaining importance due to the increasing indication spectrum of bisphosphonate therapy [S. Takeyama, M. Ito, H. Shinoda, A novel bisphosphonate, TRK-530, for periodontitis, Bone 38 (2006) 31-31; M. Tagil, A. W-Dahl, J. Astrand, D. Little, S. Toksvig-Larsen, Decreasing the catabolic response by a single bisphosphonate infusion shortens the healing time in hemicallotasis operations, Bone 38 (2006) 84-85; E. Rodriguez, M.C. Duran, L.M. Rodriguez, R. Ros, M.R. Aleman, M. Rodriguez-Gaspar, A.M. Lopez, E. Garcia-Valdecasas, F. Santolaria, Intravenous (IV) bisphosphonates for osteopenic cancer survivor women: an alternative treatment, Bone 38 (2006) 72-73; D.G. Little, K. Ward, P. Kiely, M.C. Bellemore, J. Briody, C.T. Cowell, Bisphosphonate rescue in distraction osteogenesis: a case series, Bone 38 (2006) 80-80; R. Marx, Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic, J. Oral Maxillofac. Surg. 61 (2003) 1115-1118]. BON patients suffering from varying bony defects and symptoms are extremely restricted in their quality of life. Due to a limited knowledge of the aetiology of BON efficient evidence-based treatment strategies are lacking. Until now 23 patients with bisphosphonate-related osteonecrosis have been admitted to the Department of Cranio-Maxillofacial Surgery of the University of Zurich. A complete history has been recorded. All patients underwent clinical and radiographic examination. CT scans and MRI have been performed in selected cases. All patients had in common that, before signs of BON were observed, a local traumatic incidence had occurred. All patients showed signs of infection which could be remarkably reduced by antibacterial treatment. Furthermore, the period of bisphosphonate treatment was found to be one of the significant factors causing bisphosphonate-related osteonecrosis of the jaws. The aetiology of BON

  20. Prediction of bioavailability of selected bisphosphonates using in silico methods towards categorization into a biopharmaceutical classification system.

    Science.gov (United States)

    Biernacka, Joanna; Betlejewska-Kielak, Katarzyna; Kłosińska-Szmurło, Ewa; Pluciński, Franciszek A; Mazurek, Aleksander P

    2013-01-01

    The physicochemical properties relevant to biological activity of selected bisphosphonates such as clodronate disodium salt, etidronate disodium salt, pamidronate disodium salt, alendronate sodium salt, ibandronate sodium salt, risedronate sodium salt and zoledronate disodium salt were determined using in silico methods. The main aim of our research was to investigate and propose molecular determinants thataffect bioavailability of above mentioned compounds. These determinants are: stabilization energy (deltaE), free energy of solvation (deltaG(solv)), electrostatic potential, dipole moment, as well as partition and distribution coefficients estimated by the log P and log D values. Presented values indicate that selected bisphosphonates a recharacterized by high solubility and low permeability. The calculated parameters describing both solubility and permeability through biological membranes seem to be a good bioavailability indicators of bisphosphonates examined and can be a useful tool to include into Biopharmaceutical Classification System (BCS) development.

  1. Early, middle, or late administration of zoledronate alleviates spontaneous nociceptive behavior and restores functional outcomes in a mouse model of CFA-induced arthritis.

    Science.gov (United States)

    Morado-Urbina, Carlos Eduardo; Alvarado-Vázquez, Perla Abigail; Montiel-Ruiz, Rosa Mariana; Acosta-González, Rosa Issel; Castañeda-Corral, Gabriela; Jiménez-Andrade, Juan Miguel

    2014-11-01

    This study was performed to evaluate whether early, middle, or late treatment of zoledronate, an approved bisphosphonate that blocks bone resorption, can reduce nociceptive behaviors in a mouse arthritis model. Arthritis was produced by repeated intra-articular knee injections of complete Freund's adjuvant (CFA). A dose-response curve with zoledronate (3, 30, 100, and 300 μg/kg, i.p., day 4 to day 25, twice weekly for 3 weeks) was performed, and the most effective dose of zoledronate (100 μg/kg, i.p.) was initially administered at different times of disease progression: day 4 (early), day 15 (middle), or day 21 (late) and continued until day 25 after the first CFA injection. Flinching of the injected extremity (spontaneous nociceptive behavior), vertical rearings and horizontal activity (functional outcomes), and knee edema were assessed. Zoledronate improved both functional outcomes and reduced flinching behavior. At day 25, the effect of zoledronate on flinching behavior and vertical rearings was greater in magnitude when it was given early or middle rather than late in the treatment regimen. Chronic zoledronate did not reduce knee edema in CFA-injected mice nor functional outcomes in naïve mice by itself. These results suggest that zoledronate may have a positive effect on arthritis-induced nociception and functional disabilities. © 2014 Wiley Periodicals, Inc.

  2. Reaction of 3-Amino-1,2,4-Triazole with Diethyl Phosphite and Triethyl Orthoformate: Acid-Base Properties and Antiosteoporotic Activities of the Products.

    Science.gov (United States)

    Miszczyk, Patrycja; Wieczorek, Dorota; Gałęzowska, Joanna; Dziuk, Błażej; Wietrzyk, Joanna; Chmielewska, Ewa

    2017-02-08

    The reaction of diethyl phosphite with triethyl orthoformate and a primary amine followed by hydrolysis is presented, and the reaction was suitable for the preparation of (aminomethylene)bisphosphonates. 3-Amino-1,2,4-triazole was chosen as an interesting substrate for this reaction because it possesses multiple groups that can serve as the amino component in the reaction-namely, the side-chain and triazole amines. This substrate readily forms 1,2,4-triazolyl-3-yl-aminomethylenebisphosphonic acid (compound 1 ) as a major product, along with N -ethylated bisphosphonates as side products. The in vitro antiproliferative effects of the synthesized aminomethylenebisphosphonic acids against J774E macrophages were determined. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid.

  3. The Pharmacological Profile of a Novel Highly Potent Bisphosphonate, OX14 (1‐Fluoro‐2‐(Imidazo‐[1,2‐α]Pyridin‐3‐yl)‐Ethyl‐Bisphosphonate)

    Science.gov (United States)

    Ebetino, Frank H; Mazur, Adam; Chantry, Andrew D; Paton‐Hough, Julia; Evans, Holly R; Lath, Darren; Tsoumpra, Maria K; Lundy, Mark W; Dobson, Roy LM; Quijano, Michael; Kwaasi, Aaron A; Dunford, James E; Duan, Xuchen; Triffitt, James T; Jeans, Gwyn; Russell, R Graham G

    2017-01-01

    ABSTRACT Bisphosphonates are widely used in the treatment of clinical disorders characterized by increased bone resorption, including osteoporosis, Paget's disease, and the skeletal complications of malignancy. The antiresorptive potency of the nitrogen‐containing bisphosphonates on bone in vivo is now recognized to depend upon two key properties, namely mineral binding affinity and inhibitory activity on farnesyl pyrophosphate synthase (FPPS), and these properties vary independently of each other in individual bisphosphonates. The better understanding of structure activity relationships among the bisphosphonates has enabled us to design a series of novel bisphosphonates with a range of mineral binding properties and antiresorptive potencies. Among these is a highly potent bisphosphonate, 1‐fluoro‐2‐(imidazo‐[1,2 alpha]pyridin‐3‐yl)‐ethyl‐bisphosphonate, also known as OX14, which is a strong inhibitor of FPPS, but has lower binding affinity for bone mineral than most of the commonly studied bisphosphonates. The aim of this work was to characterize OX14 pharmacologically in relation to several of the bisphosphonates currently used clinically. When OX14 was compared to zoledronate (ZOL), risedronate (RIS), and minodronate (MIN), it was as potent at inhibiting FPPS in vitro but had significantly lower binding affinity to hydroxyapatite (HAP) columns than ALN, ZOL, RIS, and MIN. When injected i.v. into growing Sprague Dawley rats, OX14 was excreted into the urine to a greater extent than the other bisphosphonates, indicating reduced short‐term skeletal uptake and retention. In studies in both Sprague Dawley rats and C57BL/6J mice, OX14 inhibited bone resorption, with an antiresorptive potency equivalent to or greater than the comparator bisphosphonates. In the JJN3‐NSG murine model of myeloma‐induced bone disease, OX14 significantly prevented the formation of osteolytic lesions (p < 0.05). In summary, OX14 is a new, highly potent

  4. Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels.

    Directory of Open Access Journals (Sweden)

    Shinya Okamoto

    Full Text Available We examined anti-tumor effects of zoledronic acid (ZOL, one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP, one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.

  5. Effect of low-level laser therapy on tissue repair after dental extraction in rats administered zoledronic acid and dexamethasone

    Science.gov (United States)

    Weber, João Batista Blessmann; Camilotti, Renata Stifelman; Jasper, Juliana; Casagrande, Liliane Cristina Onofre; Maito, Fábio Luiz Dal Moro

    2017-05-01

    Bisphosphonates (BPs) are being increasingly used for the treatment of metabolic and oncological pathologies involving the skeletal system. Because of the severity of the BP associated osteonecrosis of the jaws, the difficulties of treatment, and patient discomfort, additional support methods for their management are needed. Laser therapy has an easy handling, photobiostimulator effect on tissues healing, so it can be considered a preferred therapy. The aim of this study was to evaluate the influence of low-level laser therapy in the 685- and 830-nm wavelength in the healing process of the bone and soft tissues in rats under BP therapy [zoledronic acid (ZA)] and dexamethasone concomitantly that underwent a surgery for the extraction of upper molars. There were statistically significant differences in the clinical evaluation of the wound and the weight of the animals. Regarding the histological evaluation, it was possible to observe the different maturations of the healing stage between groups. The effect of drug therapy with ZA and dexamethasone in the bone tissue repair process induces osteonecrosis of the jaw in rats and slows down the healing process. In the laser groups, at the stipulated dosimetry, a positive influence on the bone and soft tissue repair process was observed.

  6. The impact of zoledronic acid on regenerate and native bone after consolidation and removal of the external fixator: an animal model study.

    Science.gov (United States)

    Saghieh, Said; Khoury, Nabil J; Tawil, Ayman; Masrouha, Karim Z; Musallam, Khaled M; Khalaf, Kinda; Dosh, Laura; Jaouhari, Rosemarie Reich; Birjawi, Ghina; El-Hajj-Fuleihan, Ghada

    2010-02-01

    We investigated the role of zoledronic acid on the regenerate and native bone after consolidation and removal of the external fixator in a rabbit model of distraction osteogenesis using 28 New Zealand white rabbits. The rabbits were randomly distributed into two groups. The first group received three doses of zoledronic acid (ZA) 0.1 mg/kg subcutaneously at weekly intervals while the second group received injections of sterile saline. Distraction started on day 7 at a rate of 0.8 mm/day for 12 days. At week 3 the average lengthening, regenerate density, and regenerate continuity were comparable between the two groups. At week 11 the regenerate in the treated group had a significant increase in Bone Mineral Density (BMD) and Bone Mineral Content (BMC) compared to the placebo group. On axial compression, the regenerate showed an increase in the peak load and a higher modulus of elasticity in the treated group. At 6 months, radiographs demonstrated signs of osteopenia of the proximal metaphysis in the control group, and failure of new bone formation around the pin sites in the treated group. BMC and BMD value differences between the two groups were not statistically significant. Histologically, there was persistence of more bone trabeculae in the medullary canal of the regenerate with the persistence of the pin-holes in the treated group. Mechanically, the regenerates in the treated group remain stronger in resisting the axial compression. The proximal fragment in the treated group exhibited a statistically significant decrease in the peak load, toughness and efail %. In conclusion, bisphosphonate-treated rabbits have a stronger regenerate during distraction, and directly after removal of the fixator. They do not develop disuse osteopenia in their lengthened tibia. This treatment may shorten the time in the external fixator and prevent fragility fractures in the treated extremity. However, its long-term safety has not yet been established. (c) 2009 Elsevier Inc. All

  7. Multicompartment vectors as novel drug delivery systems: selective activation of Tγδ lymphocytes after zoledronic acid delivery.

    Science.gov (United States)

    Agrati, Chiara; Marianecci, Carlotta; Sennato, Simona; Carafa, Maria; Bordoni, Veronica; Cimini, Eleonora; Tempestilli, Massimo; Pucillo, Leopoldo P; Turchi, Federica; Martini, Federico; Borioni, Giorgio; Bordi, Federico

    2011-04-01

    Multicompartment nanoscopic carriers can be easily assembled by inducing the aggregation of anionic "hybrid" niosomes by means of cationic biocompatible polyelectrolytes. The resulting vesicle clusters, whose size and overall net charge can be easily controlled by varying the polyelectrolyte-to-particle charge ratio, show an interesting potential for multidrug delivery. In this article we provide strong evidence for their effective use in vitro as multicompartment vectors selectively directed toward monocyte/macrophage cells, showing that the monocyte/macrophage-mediated activation of Tγδ lymphocytes induced by zoledronic acid is enhanced by a factor 10(3) when the zoledronic acid is intracellularly delivered through these carriers. Furthermore, the multicompartment ɛ-polylysine niosome clusters, with their intrinsic selectivity toward macrophages, appear particularly suitable for implementing therapeutic strategies against chronically infected macrophages. ɛ-polylysine niosome clusters, with their intrinsic selectivity toward macrophages, offer the potential for multidrug delivery. The effectiveness of aminobisphosphonate zoledronate is demonstrated to enhance the recruitment of Tγδ lymphocytes by macrophages by 2 orders of magnitude, suggesting a new therapeutic strategy for addressing pathologies featuring chronically infected macrophages. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial

    Science.gov (United States)

    García-Sanz, Ramón; Oriol, Albert; Moreno, María J.; de la Rubia, Javier; Payer, Angel R.; Hernández, Miguel T.; Palomera, Luis; Teruel, Ana I.; Blanchard, María J.; Gironella, Mercedes; Ribas, Paz; Bargay, Joan; Abellá, Eugenia; Granell, Miquel; Ocio, Enrique M.; Ribera, Josep M.; San Miguel, Jesús F.; Mateos, María V.

    2015-01-01

    This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P<0.001). In summary, zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma, but does reduce the risk of progression with symptomatic bone disease and skeletal complications. This trial was registered in the ClinicalTrials.gov database with code NCT01087008 PMID:26069291

  9. Long-term leukopenia in a lung transplanted patient with cystic fibrosis treated with zoledronic acid

    DEFF Research Database (Denmark)

    Karahasanovic, A; Thorsteinsson, A-L; Bjarnason, N H

    2016-01-01

    report a case of a young woman with CF, lung transplantation and low bone mass developing long-term leukopenia after treatment with zoledronic acid. The leukopenia, with a strong affection of the neutrocytes, lasted for 4 months and the condition only went into remission after granulocyte-colony...

  10. Effects of intravenous zoledronate and ibandronate on carotid intima-media thickness, lipids and FGF-23 in postmenopausal osteoporotic women.

    Science.gov (United States)

    Gonnelli, S; Caffarelli, C; Tanzilli, L; Pondrelli, C; Lucani, B; Franci, B M; Nuti, R

    2014-04-01

    Osteoporosis and atherosclerosis are interconnected entities and share also some pathophysiological mechanisms. Moreover, recent literature data have supported the hypothesis that bisphosphonates (BPs) may have some antiatherogenic actions. This study aimed to evaluate the effects of one year with zoledronate or ibandronate given intravenously on lipid profile and on carotid artery intima-media thickness (CA-IMT). Sixty postmenopausal osteoporotic women (mean age: 66.6±7.8years) were randomly assigned to 1-year treatment with zoledronate 5mg i.v. annually or ibandronate 3mg i.v. every 3 months. In all patients at baseline and after 12months we measured CA-IMT, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), 25-hydroxyvitamin D (25OHD), bone alkaline phosphatase (B-ALP), type I collagen β carboxy telopeptide (βCTX), osteocalcin (OC), fibroblast growth factor 23 (FGF-23) and sclerostin. The osteoporotic women treated with zoledronate showed a greater reduction in CA-IMT than those treated with ibandronate. HDL-C and HDL-C/LDL-C ratio showed a significant (pwomen treated with zoledronate and in those treated with ibandronate. At the end of the study period sclerostin serum levels showed a higher increase in the patients treated with zoledronate than in those treated with ibandronate. In osteoporotic women both zoledronate and ibandronate given intravenously resulted in an increase in HDL-C/LDL-C ratio and a reduction of CA-IMT which was significant only for zoledronate. Further prospective studies are needed to clarify whether the change in FGF-23 and sclerostin levels is a marker or a potential mechanism of the action of BPs at a vascular level. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Zoledronic acid at subtoxic dose extends osteoblastic stage span of primary human osteoblasts.

    Science.gov (United States)

    Zara, Susi; De Colli, Marianna; di Giacomo, Viviana; Zizzari, Vincenzo Luca; Di Nisio, Chiara; Di Tore, Umberto; Salini, Vincenzo; Gallorini, Marialucia; Tetè, Stefano; Cataldi, Amelia

    2015-04-01

    This study aimed to check the effect of zoledronic acid (ZA) at subtoxic dose on human osteoblasts (HOs) in terms of cell viability, apoptosis occurrence, and differentiation induction. ZA belongs to the family of bisphosphonates (BPs), largely used in the clinical practice for the treatment of bone diseases, often associated with jaw osteonecrosis onset. Their pharmacological action consists in the direct block of the osteoclast-mediated bone resorption along with indirect action on osteoblasts. HOs were treated choosing the highest limit concentration (10(-5) M) which does not induce toxic effects. Live/dead staining, flow cytometry, mitochondrial membrane potential assay, osteocalcin western blotting, gp38 RT-PCR, collagen type I, PGE2, and IL-6 ELISA assays were performed. Similar viability level between control and ZA-treated samples is found along with no significant increase of apoptotic and necrotic cells in ZA-treated sample. To establish if an early apoptotic pathway was triggered, Bax expression and mitochondrial membrane potential were evaluated finding a higher protein expression in control sample and a good integrity of mitochondrial membrane in both experimental points. Type I collagen secretion and alkaline phosphatase (ALP) activity appear increased in ZA-treated sample, osteocalcin expression level is reduced in ZA-treated cells, whereas no modifications of gp38 mRNA level are evidenced. No statistical differences are identified in PGE2 secretion level whereas IL-6 secretion is lower in ZA-treated HOs with respect to control ones. These results highlight that ZA, delaying the osteoblastic differentiation process versus the osteocytic lineage, strengthens its pharmacological activity enhancing bone density. The knowledge of ZA effects on osteoblasts at subtoxic dose allows to improve therapeutic protocols in order to strengthen drug pharmacological activity through a combined action on both osteoclastic and osteoblastic cells.

  12. The effect of a single infusion of zoledronic acid on early implant migration in total hip arthroplasty. A randomized, double-blind, controlled trial.

    Science.gov (United States)

    Friedl, Gerald; Radl, Roman; Stihsen, Christoph; Rehak, Peter; Aigner, Reingard; Windhager, Reinhard

    2009-02-01

    Aseptic loosening is the most frequent cause of implant failure in total hip arthroplasty. While a direct link between aseptic loosening and periprosthetic bone loss remains elusive, there is plentiful evidence for a close association with early implant migration. The present trial was primarily designed to evaluate whether a single infusion of 4 mg of zoledronic acid prevented early implant migration in patients with osteonecrosis of the femoral head. Fifty patients were consecutively enrolled to receive either zoledronic acid or saline solution after cementless total hip arthroplasty. Radiographs, biochemical parameters of bone turnover, and the Harris hip-rating score were determined preoperatively and at each follow-up examination at seven weeks, six months, one year, and yearly thereafter. The median follow-up period was 2.8 years. We found a significant subsidence of the stem of up to a mean (and standard deviation) of -1.2 +/- 0.6 mm at two years within the control group, and the cups had a mean medialization of 0.6 +/- 1.0 mm and a mean cranialization of 0.6 +/- 0.8 mm (p < 0.001). Treatment with zoledronic acid effectively minimized the migration of the cups in both the transverse and the vertical direction (mean, 0.15 +/- 0.6 mm and 0.06 +/- 0.6 mm, respectively; p < 0.05), while only a trend to decreased subsidence of the stem was detected. Finally, the Harris hip score rapidly increased over time in both treatment groups, although this increase was significantly more pronounced in the zoledronate-treated group than in the control group (analysis of variance, p = 0.008). A single infusion of zoledronic acid shows promise in improving initial fixation of a cementless implant, which may improve the clinical outcome of total hip arthroplasty in patients with osteonecrosis of the femoral head.

  13. A Biphasic Calcium Sulphate/Hydroxyapatite Carrier Containing Bone Morphogenic Protein-2 and Zoledronic Acid Generates Bone

    DEFF Research Database (Denmark)

    Raina, Deepak Bushan; Isaksson, Hanna; Hettwer, Werner

    2016-01-01

    -the-shelf osteoinductive bone substitutes that can replace bone grafts are required. We tested the carrier properties of a biphasic, calcium sulphate and hydroxyapatite ceramic material, containing a combination of recombinant human bone morphogenic protein-2 (rhBMP-2) to induce bone, and zoledronic acid (ZA) to delay...

  14. Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

    International Nuclear Information System (INIS)

    Knight, Louise A; Kurbacher, Christian M; Glaysher, Sharon; Fernando, Augusta; Reichelt, Ralf; Dexel, Susanne; Reinhold, Uwe; Cree, Ian A

    2009-01-01

    Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation

  15. Role of the nurse in preserving patients' independence.

    Science.gov (United States)

    Maxwell, Cathy

    2007-01-01

    Patients with metastatic bone disease may be treated with bisphosphonates to reduce or delay skeletal complications including pathologic fracture, radiotherapy to bone, and hypercalcemia of malignancy. Nurses can provide important education to patients and support or encourage the use of bisphosphonates throughout therapy. Literature and congress reports were reviewed for relevant efficacy information on bisphosphonates and adverse events that may occur during bisphosphonate therapy. Bisphosphonates can provide meaningful benefits to patients, and zoledronic acid is now approved for the treatment of bone metastases secondary to any solid tumor. To optimize care, nurses can monitor pain scores, changes in mobility, adverse events, and serum creatinine levels. A useful tool for recording these parameters is a patient diary. The nurse should fill out the diary at each patient visit and compare it with baseline information before treatment is administered. Patients should also be counseled on the importance of adequate hydration, good dental hygiene, the need for calcium and vitamin D supplements, and how to best manage potential side effects. Bisphosphonates are effective in reducing and delaying skeletal complications, and zoledronic acid has demonstrated significant efficacy in preventing skeletal complications across a wide range of solid tumors and multiple myeloma. Nurses play an important role in enabling patients to optimize bisphosphonate therapy and in supporting patients to continue treatment to preserve their functional independence.

  16. Determination of rat vertebral bone compressive fatigue properties in untreated intact rats and zoledronic-acid-treated, ovariectomized rats

    NARCIS (Netherlands)

    Brouwers, J.E.M.; Ruchselman, M.; Rietbergen, van B.; Bouxsein, M.L.

    2009-01-01

    Summary Compressive fatigue properties of whole vertebrae, which may be clinically relevant for osteoporotic vertebral fractures, were determined in untreated, intact rats and zoledronic-acid-treated, ovariectomized rats. Typical fatigue behavior was found and was similar to that seen in other

  17. Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study.

    Directory of Open Access Journals (Sweden)

    Yoshie Hasegawa

    Full Text Available Zoledronic acid (ZOL is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT.Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95 or the CTZ group (n = 93 from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2, followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug.This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8% was doubled to CT group (7.7%, respectively (one-sided chi-square test, p = 0.068, though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.071, and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.112. Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and

  18. Extracellular Ca(2+)-dependent enhancement of cytocidal potency of zoledronic acid in human oral cancer cells.

    Science.gov (United States)

    Inoue, Sayaka; Arai, Naoya; Tomihara, Kei; Takashina, Michinori; Hattori, Yuichi; Noguchi, Makoto

    2015-08-15

    Direct antitumor effects of bisphosphonates (BPs) have been demonstrated in various cancer cells in vitro. However, the effective concentrations of BPs are typically much higher than their clinically relevant concentrations. Oral cancers frequently invade jawbone and may lead to the release of Ca(2+) in primary lesions. We investigated the effects of the combined application of zoledronic acid (ZA) and Ca(2+) on proliferation and apoptosis of oral cancer cells. Human oral cancer cells, breast cancer cells, and colon cancer cells were treated with ZA at a wide range of concentrations in different Ca(2+) concentration environments. Under a standard Ca(2+) concentration (0.6mM), micromolar concentrations of ZA were required to inhibit oral cancer cell proliferation. Increasing extracellular Ca(2+) concentrations greatly enhanced the potency of the ZA cytocidal effect. The ability of Ca(2+) to enhance the cytocidal effects of ZA was negated by the Ca(2+)-selective chelator EGTA. In contrast, the cytocidal effect of ZA was less pronounced in breast and colon cancer cells regardless of whether extracellular Ca(2+) was elevated. In oral cancer cells incubated with 1.6mM Ca(2+), ZA up-regulated mitochondrial Bax expression and increased mitochondrial Ca(2+) uptake. This was associated with decreased mitochondrial membrane potential and increased release of cytochrome c. We suggest that ZA can specifically produce potent cytocidal activity in oral cancer cells in an extracellular Ca(2+)-dependent manner, implying that BPs may be useful for treatment of oral squamous cell carcinoma with jawbone invasion leading to the hypercalcemic state. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Bisphosphonates Inhibit Pain, Bone Loss, and Inflammation in a Rat Tibia Fracture Model of Complex Regional Pain Syndrome.

    Science.gov (United States)

    Wang, Liping; Guo, Tian-Zhi; Hou, Saiyun; Wei, Tzuping; Li, Wen-Wu; Shi, Xiaoyou; Clark, J David; Kingery, Wade S

    2016-10-01

    Bisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenesis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that antiresorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously, we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS, and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, postfracture cutaneous cytokine upregulation, and adaptive immune responses in this CRPS model. Rats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by microcomputed tomography, and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed, and skin cytokine (tumor necrosis factor, interleukin [IL]-1, IL-6) and nerve growth factor (NGF) levels were determined by enzyme immunoassay. Skin and sciatic nerve immunoglobulin levels were determined by enzyme immunoassay. Rats with tibia fractures developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression and trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by microcomputed tomography, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression, and elevated immunocomplex deposition in skin and nerve

  20. Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen.

    Science.gov (United States)

    Biggin, Andrew; Briody, Julie N; Ormshaw, Elizabeth; Wong, Karen K Y; Bennetts, Bruce H; Munns, Craig F

    2014-01-01

    Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.

  1. Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta.

    Science.gov (United States)

    Little, David G; Peacock, Lauren; Mikulec, Kathy; Kneissel, Michaela; Kramer, Ina; Cheng, Tegan L; Schindeler, Aaron; Munns, Craig

    2017-08-01

    In this study, we examined the therapeutic potential of anti-Sclerostin Antibody (Scl-Ab) and bisphosphonate treatments for the bone fragility disorder Osteogenesis Imperfecta (OI). Mice with the Amish OI mutation (Col1a2 G610C mice) and control wild type littermates (WT) were treated from week 5 to week 9 of life with (1) saline (control), (2) zoledronic acid given 0.025mg/kg s.c. weekly (ZA), (3) Scl-Ab given 50mg/kg IV weekly (Scl-Ab), or (4) a combination of both (Scl-Ab/ZA). Functional outcomes were prioritized and included bone mineral density (BMD), bone microarchitecture, long bone bending strength, and vertebral compression strength. By dual-energy absorptiometry, Scl-Ab treatment alone had no effect on tibial BMD, while ZA and Scl-Ab/ZA significantly enhanced BMD by week 4 (+16% and +27% respectively, P<0.05). Scl-Ab/ZA treatment also led to increases in cortical thickness and tissue mineral density, and restored the tibial 4-point bending strength to that of control WT mice. In the spine, all treatments increased compression strength over controls, but only the combined group reached the strength of WT controls. Scl-Ab showed greater anabolic effects in the trabecular bone than in cortical bone. In summary, the Scl-Ab/ZA intervention was superior to either treatment alone in this OI mouse model, however further studies are required to establish its efficacy in other preclinical and clinical scenarios. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  2. Antifracture efficacy and reduction of mortality in relation to timing of the first dose of zoledronic acid after hip fracture

    DEFF Research Database (Denmark)

    Eriksen, Erik Fink; Lyles, Kenneth W; Colón-Emeric, Cathleen S

    2009-01-01

    undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062...... was approximately 6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response......Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently...

  3. Comparative pharmacoeconomic analysis of the use of Bonviva® (ibandronat to prevent fractures in postmenopausal osteoporosis

    Directory of Open Access Journals (Sweden)

    E A Pyadushkina

    2012-01-01

    Full Text Available Objective: to make a pharmacoeconomic analysis of the use of oral (a 150-mg tablet once a month and injectable (a solution for intravenous bolus injection of 3 mg in 3 ml once every 3 months ibandronate in patients with postmenopausal osteoporosis (OP. Material and methods. The cost minimization method was used to calculate differences in the cost of using oral ibandronate, alendronate, and strontium ranelate in patients with postmenopausal OP for a year. The budgetary impact of administration of intravenous bisphosphonates (ibandronate and zoledronic acid was analyzed in patients with OP in a hospital context. A model calculator based on the Microsoft Excel software was applied to estimate how the expenditures of a health care facility were changing when different shares of drugs (ibandronate and zoledronic acid were used in purchase patterns. The cost of therapy with bisphosphonates (ibandronate and zoledronic acid, concomitant therapy (calcium and vitamin D, expendable materials, and therapy for adverse reactions (ARs due to the use of bisphophonates was considered in terms of the incidence of these ARs. Results. Among the oral drugs, ibandronate is more economically sound than alendronate: the difference in annual treatment costs was 7090.02 and 7334.31 rubles per patient, respectively, in favor of ibandronate. The inpatient use of only intravenous ibandronate versus the real administration practice determined on the basis of the data of the Farmekspert Marketing Researches Center on purchases in the hospital segment (30% for ibandronate and 70% for zoledronic acid considerably reduces the expenditures of a hospital, the saving will be 185416.06 rubles per year (if injections will be made in 20 patients. With 100% use of ibandronate, one can additionally provide 39 inpatients with bisphosphonate injections without additional expenditures.

  4. An Unpredicted Side Effect of Bisphosphonates in a Patient with Chronic Renal Failure Due to Multiple Myeloma: Reversible Parkinsonism

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    Barış İşak

    2010-09-01

    Full Text Available In this report, we present a unique case in which the chemotherapeutic agent, i.e., zoledronic acid, deepened the hypocalcemia on the basis of chronic renal failure secondary to multiple myeloma and caused parkinsonism episodes. An 80-year-old female patient, who had been diagnosed as multiple myeloma and had been administered bisphosphonate therapy monthly for six months, was ad¬mitted to our emergency room with two parkinsonism episodes. Low serum calcium levels accompanied parkinsonism symptoms, which subsided with calcium replacement therapy in both episodes. Imaging did not reveal any pathology in the basal ganglia. The fact that the patient was cured both times with calcium replacement suggests that hypocalcemia was the actual cause. This can be interpreted as a unique case, reflecting the reversible functional impairment due to metabolic side effects of a chemotherapeutic agent rather than destructive changes in the basal ganglia.

  5. An Unpredicted Side Effect of Bisphosphonates in a Patient with Chronic Renal Failure Due to Multiple Myeloma: Reversible Parkinsonism

    Directory of Open Access Journals (Sweden)

    Barış İşak

    2010-09-01

    Full Text Available In this report, we present a unique case in which the chemotherapeutic agent, i.e., zoledronic acid, deepened the hypocalcemia on the basis of chronic renal failure secondary to multiple myeloma and caused parkinsonism episodes. An 80-year-old female patient, who had been diagnosed as multiple myeloma and had been administered bisphosphonate therapy monthly for six months, was ad¬mitted to our emergency room with two parkinsonism episodes. Low serum calcium levels accompanied parkinsonism symptoms, which subsided with calcium replacement therapy in both episodes. Imaging did not reveal any pathology in the basal ganglia. The fact that the patient was cured both times with calcium replacement suggests that hypocalcemia was the actual cause. This can be interpreted as a unique case, reflecting the reversible functional impairment due to metabolic side effects of a chemotherapeutic agent rather than destructive changes in the basal ganglia

  6. [Efficacy of zoledronic acid combined with chemotherapy in treatment of skeletal metastases of non-small cell lung cancer and the bone metabolic markers].

    Science.gov (United States)

    Hu, Xiao-ye; Zou, Qing-feng; Jin, Chuan; Li, Wei-dong; Chen, Wen-sheng; Ma, Lei

    2010-06-01

    To evaluate the clinical efficacy of zoledronic acid combined with chemotherapy in the management of skeletal metastasis of non-small cell lung cancer (NSCLC) and investigate the value in urine amino-terminal telopeptide of type I collagen (uNTX) and serum bone specific alkaline phosphatase (sBALP) in monitoring skeletal metastasis of NSCLC. From February, 2007 to January, 2009, 32 NSCLC patients with bone metastases received treatment with zoledronic acid at the dose of 4 mg given every 3 weeks and platinum-based chemotherapy (each cycle lasting for 3 weeks). Before and during the treatments, uNTX and sBALP were measured in these patients using ELISA and precipitation with wheat germ lectin, respectively. The patients were followed up for skeletal-related events (SREs) and status of survival. A significant decrease occurred in the pain scores and analgesic use in the patients after the therapy. SREs were not observed during the treatment. Serum creatinine and calcium levels underwent no significant variation during the treatment. Eleven patients reported 14 possible zoledronic acid-related adverse events. The concentration of uNTX and sBALP in patients with bone metastases was above the upper limit of the normal range. A positive correlation was observed between the levels of the markers and the extent of bone metastases. At the third month, uNTX and sBALP were significantly lowered, but radionuclide whole-body bone imaging showed no obvious changes. Of the 32 patients, 24 had elevated uNTX values, which became normal after the treatment in 15 patients and remained elevated in the other 9 patients. SREs occurred in these two subgroups at the rates of 53% and 89% (P=0.039), respectively. Twenty-six patients had elevated sBALP level, and 16 of them exhibited normal sBALP level after the treatment. The incidences of SREs in the patients with elevated and normal sBALP level were 50% and 90% (P=0.038), respectively. The levels of uNTX/Cr and sBALP were not correlated

  7. The Efficacy of Bisphosphonates in Preventing Aromatase Inhibitor Induced Bone Loss for Postmenopausal Women with Early Breast Cancer: A Systematic Review and Meta-Analysis

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    Pooleriveetil Padikkal Anagha

    2014-01-01

    Full Text Available Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates. Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed. Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329–21.959, P value = 0.018 and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249–7.143, P value = 0.0002. Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group. Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR’s than patients with delayed ZOL.

  8. Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine.

    Science.gov (United States)

    Sun, Shuting; Błażewska, Katarzyna M; Kadina, Anastasia P; Kashemirov, Boris A; Duan, Xuchen; Triffitt, James T; Dunford, James E; Russell, R Graham G; Ebetino, Frank H; Roelofs, Anke J; Coxon, Fraser P; Lundy, Mark W; McKenna, Charles E

    2016-02-17

    A bone imaging toolkit of 21 fluorescent probes with variable spectroscopic properties, bone mineral binding affinities, and antiprenylation activities has been created, including a novel linking strategy. The linking chemistry allows attachment of a diverse selection of dyes fluorescent in the visible to near-infrared range to any of the three clinically important heterocyclic bisphosphonate bone drugs (risedronate, zoledronate, and minodronate or their analogues). The resultant suite of conjugates offers multiple options to "mix and match" parent drug structure, fluorescence emission wavelength, relative bone affinity, and presence or absence of antiprenylation activity, for bone-related imaging applications.

  9. Home-based zoledronic acid infusion therapy in patients with solid tumours: compliance and patient-nurse satisfaction.

    Science.gov (United States)

    Lebret, Thierry; Mouysset, Jean-Loup; Lortholary, Alain; El Kouri, Claude; Bastit, Laurent; Ktiouet, Meryem; Slimane, Khemaies; Murraciole, Xavier; Guérif, Stéphane

    2013-06-01

    This study aimed to explore patient and nurse satisfaction, compliance with best practice, technical feasibility and safety of home infusion of the bisphosphonate zoledronic acid (ZOL). This was a prospective 1-year survey of home ZOL therapy (4 mg Zometa, 15-min i.v., every 3-4 weeks) in patients with bone metastases secondary to a solid malignancy. A physician questionnaire, nurse satisfaction/feasibility questionnaire and patient satisfaction questionnaire were administered at several time-points. Physician participation rate was 56.5% (87/154). Physicians enrolled 818 patients visited by 381 predominantly community nurses. Of the 788 case report forms received, 763 met inclusion criteria. Patient characteristics were as follows: median age, 68 years (30-95); M/F, 40/60; ECOG-PS 0 or 1, 78.6%; and primary tumour site, breast (55.2%), prostate (28.4%), lung (7.2%) or other (9.4%). Nurse satisfaction rates were high: organisation of home ZOL therapy, 90.9%; ease of infusion, 96.7%; patient-nurse relationship, 97.5%; and relationship with hospital staff, 73%. Patient satisfaction was also very high (95.3%). The main reasons were quality of the nurse-patient relationship (57.6%), less travel/waiting (68.8%), home environment (52.9%) and less disruption to daily routine (36.6%). ZOL therapy was well tolerated, the discontinuation rate due to adverse events (including deaths whether related to diseases progression or not) was 33.6%. The incidence of osteonecrosis of the jaw was 0.6% and of fractures, 0.2%. Practitioner compliance with best practice was 76.7-83.7% for recommended and/or tolerated dosage, 73% for dental hygiene checks at inclusion and 48-56% thereafter, 66% for pre-infusion hydration, and often undocumented for calcium/vitamin D supplementation. Home ZOL therapy was well tolerated. Both patient and nurse satisfaction were very high. However, better compliance with best practice should be encouraged.

  10. A comparative study of zoledronic acid and once weekly Alendronate in the management of acute Charcot arthropathy of foot in patients with diabetes mellitus

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    R Bharath

    2013-01-01

    Full Text Available Aim: The aim of this study was to assess and compare the response to two forms of treatment-immobilization with zoledronic acid injection and immobilization with oral weekly Alendronate, in patients with diabetes mellitus and acute Charcot arthropathy (CA of foot in terms of clinical and radiological parameters. Material and Methods: Patients attending the endocrinology and podiatry clinic with history of diabetes mellitus and Acute CA were taken for study. The patients were randomized into two treatment groups. Group Z-zoledronic acid injection along with total contact cast (TCC. Group A-Tab. Alendronate 70 mg. once a week till the complete clinical resolution of acute CA along with TCC. Forty-five patients were randomized and 40 of them completed the study. The primary end point was complete clinical resolution of acute CA-defined as temperature difference between normal and affected foot <1oF. Results: Among the 40 patients, 30 (75% had complete clinical resolution. The mean number of days taken for complete clinical resolution since the initiation of treatment (either Zoledronic acid or Alendronate was approximately 122 days. There was no significant difference in a number of days required for complete clinical resolution, between the two forms of therapy. There was more than 50% reduction in the visual score between the baseline and the final scan. The target to non-target ratio in the skeletal phase also showed an average of 40% reduction from the baseline to the final skeletal scintigraphy. Conclusion: Both Intravenous Zoledronic acid and oral alendronate had comparable efficacy with respect to the time taken for attaining complete clinical resolution of acute CA of foot. However, Alendronate therapy was cost effective among the two. 99m Tc MDP bone scan can be used as an adjuvant to the clinical parameters in assessing the response to therapy.

  11. A systematic review of the role of bisphosphonates in metastatic disease.

    Science.gov (United States)

    Ross, J R; Saunders, Y; Edmonds, P M; Patel, S; Wonderling, D; Normand, C; Broadley, K

    2004-01-01

    significant in studies that lasted over a year 0.59 [0.39-0.88]. Bisphosphonates significantly increased the time to first SRE but did not affect survival. Subanalyses were performed for disease groups, drugs and route of administration. Most evidence supports the use of intravenous aminobisphosphonates. For adjuvant use of bisphosphonates, Clodronate, given to patients with primary operable breast cancer and no metastatic disease, significantly reduced the number of patients developing bone metastases. This benefit was not maintained once regular administration had been discontinued. Two trials reported significant survival advantages in the treated groups. Bisphosphonates reduce the number of bone metastases in patients with both early and advanced breast cancer. Bisphosphonates are well tolerated with a low incidence of side-effects. Economic modelling showed that for acute hypercalcaemia, drugs with the longest cumulative duration of normocalcaemia were most cost-effective. Zoledronate 4 mg was the most costly, but most cost-effective treatment. For skeletal morbidity, Markov models estimated that the overall cost of bisphosphonate therapy to prevent an SRE was GBP250 and GBP1500 per event for patients with breast cancer and multiple myeloma, respectively. Bisphosphonate treatment is sometimes cost-saving in breast cancer patients where fractures are prevented. High dose aminobisphosphonates are most effective for the treatment of acute hypercalcaemia and delay time to relapse. Bisphosphonates significantly reduce SREs and delay the time to first SRE in patients with bony metastatic disease but do not affect survival. Benefit is demonstrated after administration for at least 6-12 months. The greatest body of evidence supports the use of intravenous aminobisphosphonates. Further evidence is required to support use in the adjuvant setting.

  12. The role of vitamin E in the prevention of zoledronic acid-induced nephrotoxicity in rats: a light and electron microscopy study.

    Science.gov (United States)

    Sert, İbrahim Unal; Kilic, Ozcan; Akand, Murat; Saglik, Lutfi; Avunduk, Mustafa Cihat; Erdemli, Esra

    2018-03-01

    Bisphosphonates are widely used in metastatic cancer such as prostate and breast cancer, and their nephrotoxic effects have been established previously. In this study we aimed to evaluate both the nephrotoxic effects of zoledronic acid (ZA) and the protective effects of vitamin E (Vit-E) on this process under light and electron microscopy. A total of 30 male Sprague-Dawley rats were divided into 3 groups. The first group constituted the control group. The second group was given i.v. ZA of 3 mg/kg once every 3 weeks for 12 weeks from the tail vein. The third group received the same dosage of ZA with an additional i.m . injection of 15 mg Vit-E every week for 12 weeks. Tissues were taken 4 days after the last dose of ZA for histopathological and ultrastructural evaluation. Paller score, tubular epithelial thickness and basal membrane thickness were calculated for each group. For group 2, the p -values are all < 0.001 for Paller score, epitelial thickness, and basal membrane thickness. For group 3 (ZA + Vit. E), the p -values are < 0.001 for Paller score, 0.996 for epitelial thickness, and < 0.001 basal membrane thickness. Significant differences were also observed in ultrastructural changes for group 2. However, adding Vit-E to ZA administration reversed all the histopathological changes to some degree, with statistical significance. Administration of ZA had nephrotoxic effects on rat kidney observed under both light and electron microscopy. Concomitant administration of Vit-E significantly reduces toxic histopathological effects of ZA.

  13. Percutaneous kyphoplasty combined with zoledronic acid infusion in the treatment of osteoporotic thoracolumbar fractures in the elderly

    OpenAIRE

    Shi,Chen; Zhang,Mi; Cheng,An-Yuan; Huang,Zi-Feng

    2018-01-01

    Chen Shi,1,* Mi Zhang,2,* An-Yuan Cheng,1 Zi-Feng Huang1 1Department of Trauma Surgery, Wuhan No 1 Hospital, Wuhan, China; 2Department of Orthopedics, Wuhan No 5 Hospital, Wuhan, China *These authors contributed equally to this work Objective: We studied the efficacy of zoledronic acid (ZOL) infusion on radiographic and clinical outcomes after percutaneous kyphoplasty (PKP) for elderly patients with osteoporotic thoracolumbar fractures (osteoporotic vertebral compression fractures...

  14. Percutaneous kyphoplasty combined with zoledronic acid infusion in the treatment of osteoporotic thoracolumbar fractures in the elderly

    OpenAIRE

    Shi C; Zhang M; Cheng AY; Huang ZF

    2018-01-01

    Chen Shi,1,* Mi Zhang,2,* An-Yuan Cheng,1 Zi-Feng Huang1 1Department of Trauma Surgery, Wuhan No 1 Hospital, Wuhan, China; 2Department of Orthopedics, Wuhan No 5 Hospital, Wuhan, China *These authors contributed equally to this work Objective: We studied the efficacy of zoledronic acid (ZOL) infusion on radiographic and clinical outcomes after percutaneous kyphoplasty (PKP) for elderly patients with osteoporotic thoracolumbar fractures (osteoporotic vertebral compression fractures [OV...

  15. Local vs. systemic administration of bisphosphonates in rat cleft bone graft: A comparative study.

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    Christine Hong

    Full Text Available A majority of patients with orofacial cleft deformity requires cleft repair through a bone graft. However, elevated amount of bone resorption and subsequent bone graft failure remains a significant clinical challenge. Bisphosphonates (BPs, a class of anti-resorptive drugs, may offer great promise in enhancing the clinical success of bone grafting. In this study, we compared the effects of systemic and local delivery of BPs in an intraoral bone graft model in rats. We randomly divided 34 female 20-week-old Fischer F344 Inbred rats into four groups to repair an intraoral critical-sized defect (CSD: (1 Control: CSD without graft (n = 4; (2 Graft/Saline: bone graft with systemic administration of saline 1 week post-operatively (n = 10; (3 Graft/Systemic: bone graft with systemic administration of zoledronic acid 1 week post-operatively (n = 10; and (4 Graft/Local: bone graft pre-treated with zoledronic acid (n = 10. At 6-weeks post-operatively, microCT volumetric analysis showed a significant increase in bone fraction volume (BV/TV in the Graft/Systemic (62.99 ±14.31% and Graft/Local (69.35 ±13.18% groups compared to the Graft/Saline (39.18±10.18%. Similarly, histological analysis demonstrated a significant increase in bone volume in the Graft/Systemic (78.76 ±18.00% and Graft/Local (89.95 ±4.93% groups compared to the Graft/Saline (19.74±18.89%. The local delivery approach resulted in the clinical success of bone grafts, with reduced graft resorption and enhanced osteogenesis and bony integration with defect margins while avoiding the effects of BPs on peripheral osteoclastic function. In addition, local delivery of BPs may be superior to systemic delivery with its ease of procedure as it involves simple soaking of bone graft materials in BP solution prior to graft placement into the defect. This new approach may provide convenient and promising clinical applications towards effectively managing cleft patients.

  16. Reaction of 3-Amino-1,2,4-Triazole with Diethyl Phosphite and Triethyl Orthoformate: Acid-Base Properties and Antiosteoporotic Activities of the Products

    Directory of Open Access Journals (Sweden)

    Patrycja Miszczyk

    2017-02-01

    Full Text Available The reaction of diethyl phosphite with triethyl orthoformate and a primary amine followed by hydrolysis is presented, and the reaction was suitable for the preparation of (aminomethylenebisphosphonates. 3-Amino-1,2,4-triazole was chosen as an interesting substrate for this reaction because it possesses multiple groups that can serve as the amino component in the reaction—namely, the side-chain and triazole amines. This substrate readily forms 1,2,4-triazolyl-3-yl-aminomethylenebisphosphonic acid (compound 1 as a major product, along with N-ethylated bisphosphonates as side products. The in vitro antiproliferative effects of the synthesized aminomethylenebisphosphonic acids against J774E macrophages were determined. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid.

  17. Dental extraction following zoledronate, induces osteonecrosis in rat's jaw.

    Science.gov (United States)

    Vidal-Gutiérrez, X; Gómez-Clavel, J-F; Gaitán-Cepeda, L-A

    2017-03-01

    Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is clinically characterized by the presence of exposed bone in the oral cavity that persists for more than eight weeks. Previous attempts to establish an animal model have not sufficiently considered disease features. Our aim was to establish an inexpensive and replicable animal model that develops BRONJ in a short time. Thirty-two male Wistar rats were randomly divided into two groups: control and experimental. In the experimental group, we administered 0.06mg/kg intraperitoneal dose of zoledronic acid (ZA) 7 and 14 days prior to maxillary second molar extraction. At two, four and six weeks after tooth extraction, the animals were euthanized, and we dissected the maxilla following histological procedures. We stained serial slides with hematoxylin and eosin and Masson's trichrome. The samples were harvested for macroscopic, radiologic and histological evaluation of bone changes. At two weeks postextraction, we observed exposed necrotic bone in dental socket areas in experimental groups. Radiological analysis revealed osteolytic lesions accompanied by extensive destruction and sequestrum formation in the same group. Histological examination confirmed the absence of necrotic bone in control groups in contrast with the experimental groups. The percentage of empty lacunae and the number of osteoclasts and the necrotic bone area were significantly increased (p<0.05) in the experimental groups. The animal model using ZA administration to prior dental extraction successfully mimicked human BRONJ lesions. Also, the model was easily replicated, inexpensive and showed different features than other previous BRONJ models.

  18. Zoledronic acid enhances antitumor efficacy of liposomal doxorubicin.

    Science.gov (United States)

    Hattori, Yoshiyuki; Shibuya, Kazuhiko; Kojima, Kaori; Miatmoko, Andang; Kawano, Kumi; Ozaki, Kei-Ichi; Yonemochi, Etsuo

    2015-07-01

    Previously, we found that the injection of zoledronic acid (ZOL) into mice bearing tumor induced changes of the vascular structure in the tumor. In this study, we examined whether ZOL treatment could decrease interstitial fluid pressure (IFP) via change of tumor vasculature, and enhance the antitumor efficacy of liposomal doxorubicin (Doxil®). When ZOL solution was injected at 40 µg/mouse per day for three consecutive days into mice bearing murine Lewis lung carcinoma LLC tumor, depletion of macrophages in tumor tissue and decreased density of tumor vasculature were observed. Furthermore, ZOL treatments induced inflammatory cytokines such as interleukin (IL)-10 and -12, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α in serum of LLC tumor-bearing mice, but not in normal mice, indicating that ZOL treatments might induce an inflammatory response in tumor tissue. Furthermore, ZOL treatments increased antitumor activity by Doxil in mice bearing a subcutaneous LLC tumor, although they did not significantly increase the tumor accumulation of doxorubicin (DXR). These results suggest that ZOL treatments might increase the therapeutic efficacy of Doxil via improvement of DXR distribution in a tumor by changing the tumor vasculature. ZOL treatment can be an alternative approach to increase the antitumor effect of liposomal drugs.

  19. Monitoring changes in quality of life in patients with lung cancer under treatment with chemotherapy and co administration of zoledronic acid by using specialized questionnaires.

    Science.gov (United States)

    Tremmas, Ioannis; Petsatodis, George; Potoupnis, Michael; Laskou, Stella; Giannakidis, Dimitrios; Mantalovas, Stylianos; Koulouris, Charilaos; Katsaounis, Athanasios; Pavlidis, Efstathios; Amaniti, Aikaterini; Huang, Haidong; Bai, Chong; Shi, Dongchen; Dardas, Athanasios; Zarogoulidis, Paul; Sardeli, Chrisanthi; Konstantinou, Fotis; Katsikogiannis, Nikolaos; Zarogoulidis, Konstantinos; Karapantzos, Ilias; Karapantzou, Chrysanthi; Shen, Xiaping; Kesisoglou, Isaak; Sapalidis, Konstantinos

    2018-01-01

    Background: Due to the severity of the primary disease in patients with lung cancer, quality of life (QoL) is often overlooked. Factors that form QoL should be taken in consideration when planning the appropriate treatment and determining therapy targets, because of the increasing frequency of bone metastasis leading to high levels of pain. Purpose of this study is to assess quality of life in patients with lung cancer, before and after treatment combined with zoledronic acid. Methods and materials: QoL was assessed in 80 patients (49 males-31 females), of which 45 developed bone metastasis. Prior and post treatment (with co administration of zoledronic acid) seven reliable scales: Pittsburgh Sleep Quality index (PSQI), Epworth Sleeping Scale (ess), Dyspnea Scale (ds), Fatigue Severity Scale (FSS), Brief Pain Inventory (BPI), Fact-G scale for sleep quality and EQ-5D for general health condition. Results: Statistically positive correlations were verified between PSQI-DS, PSQI-FSS, BPI-ESS, DS-FSS, DS-BPI and BPI-FSS (pbetterment in quality of life was marked (p<0,001). Although significant decrease in fatigue levels was observed (p<0,001) there has been an increase in dyspnea symptoms (p<0,001). Conclusions: Significant improvement was apparent when zoledronic acid was co administered in any treatment in patients with lung cancer. Sleep quality, fatigue and pain parameters also improved, with no positive impact on the symptoms of dyspnea.

  20. New bisphosphonate labeled with Iodine-131 for the palliative therapy for bone metastases pain

    International Nuclear Information System (INIS)

    Prats Capote, Anaís; Perera Pintado, Alejandro; León, Mariela; Hernández González, Ignacio; Leyva Montaña, René; Mocelo Castell, Raúl; O'Reilly, Beatriz; Calderón, Osmar; Griffith Pérez, Yoel; García Batle, Marisé; Rodríguez Tanty, Chryslaine

    2016-01-01

    The aim of this work was to obtain new bisphosphonate marked with 131I suitable for palliative treatment of bone metastases pain characteristics. Materials and Methods: It started with aromatic amino acids and the synthesis consisted of three stages: 1) Protection of amino groups by acetylation; 2) phosphonation protected amino acids with a mixture of phosphorous acid and phosphorus pentachloride; 3) Lack of protection of the amino groups by basic hydrolysis. The compounds obtained were characterized by IR, 1H NMR, RMN13-C mass. Los spectrometry bisphosphonic acids obtained were labeled with 131I using chloramine T and iodogen as oxidants. Stability of labeled compounds in aqueous solution was studied serum. 3 mg of 2-amino-3- (4-hydroxyphenyl) -1-hydroxypropyl-1,1-bisphosphonic acid labeled of 131I were administered to male wistar rats (170-190 g) through a lateral tail vein. The scintigraphic study was conducted at 2, 6 and 12 hours. Results: The yield of the reactions of the amino group protection four compounds ranged from 75 to 80%, while the phosphonation was between 50 and 60%. The radiochemical purity of 2-amino-3- (4-hydroxyphenyl) -1-hydroxypropyl-1,1- bisphosphonic acid labeled with 131I was (91.5 ± 1.4)% and its stability was satisfactory for 72h. Scintigraphic images suggest excretion by the kidneys of the compound and from 12 h post-administration begin to visualize bone structures of the animal, suggesting that the compound exhibits affinity for these tissues. Conclusions: A novel synthesis method with modifications that yielded the sodium salts of bisphosphonic acids starting from the respective aromatic amino acids was developed. 2-amino-3- (4-hydroxyphenyl) -1-hydroxypropyl-1,1-bisphosphonic acid 131I labeled was stable up to 72h and showed affinity for bone tissue. (author)

  1. Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis.

    Science.gov (United States)

    Serrano, Ana Julissa; Begoña, Leire; Anitua, Eduardo; Cobos, Raquel; Orive, Gorka

    2013-12-01

    The aim of this meta-analysis was to evaluate the efficacy and safety of two bisphosphonates (alendronate and zoledronate) in the treatment of postmenopausal osteoporosis. The incidence of fractures was considered as primary endpoint. Only randomized trials with a follow-up period of 1 year or more were included in this systematic review and meta-analysis. We excluded studies that included patients with secondary osteoporosis especially in relation to therapy with corticosteroids or other drugs or diseases known to affect bone mineral density. Studies published as subgroup analysis, extension studies, economic evaluations, and comparisons with active control were excluded. The methodological quality of controlled clinical trials that met these inclusion criteria was evaluated. No studies were excluded from analysis due to lack of quality. The risk ratio of hip, vertebral and wrist fractures for alendronate were 0.61 [95% confidence interval (CI) 0.40-0.93], 0.54 (95% CI 0.44-0.66) and 0.65 (95% CI 0.33-1.25), respectively. Zoledronate risk ratio was 0.62 (95% CI 0.46-0.82) and 0.38 (95% CI 0.22-0.67) for hip and vertebral fractures, respectively.

  2. Zoledronate complexes. III. Two zoledronate complexes with alkaline earth metals: [Mg(C(5)H(9)N(2)O(7)P(2))(2)(H(2)O)(2)] and [Ca(C(5)H(8)N(2)O(7)P(2))(H(2)O)](n).

    Science.gov (United States)

    Freire, Eleonora; Vega, Daniel R; Baggio, Ricardo

    2010-06-01

    Diaquabis[dihydrogen 1-hydroxy-2-(imidazol-3-ium-1-yl)ethylidene-1,1-diphosphonato-kappa(2)O,O']magnesium(II), [Mg(C(5)H(9)N(2)O(7)P(2))(2)(H(2)O)(2)], consists of isolated dimeric units built up around an inversion centre and tightly interconnected by hydrogen bonding. The Mg(II) cation resides at the symmetry centre, surrounded in a rather regular octahedral geometry by two chelating zwitterionic zoledronate(1-) [or dihydrogen 1-hydroxy-2-(imidazol-3-ium-1-yl)ethylidene-1,1-diphosphonate] anions and two water molecules, in a pattern already found in a few reported isologues where the anion is bound to transition metals (Co, Zn and Ni). catena-Poly[[aquacalcium(II)]-mu(3)-[hydrogen 1-hydroxy-2-(imidazol-3-ium-1-yl)ethylidene-1,1-diphosphonato]-kappa(5)O:O,O':O',O''], [Ca(C(5)H(8)N(2)O(7)P(2))(H(2)O)](n), consists instead of a Ca(II) cation in a general position, a zwitterionic zoledronate(2-) anion and a coordinated water molecule. The geometry around the Ca(II) atom, provided by six bisphosphonate O atoms and one water ligand, is that of a pentagonal bipyramid with the Ca(II) atom displaced by 0.19 A out of the equatorial plane. These Ca(II) coordination polyhedra are ;threaded' by the 2(1) axis so that successive polyhedra share edges of their pentagonal basal planes. This results in a strongly coupled rhomboidal Ca(2)-O(2) chain which runs along [010]. These chains are in turn linked by an apical O atom from a -PO(3) group in a neighbouring chain. This O-atom, shared between chains, generates strong covalently bonded planar arrays parallel to (100). Finally, these sheets are linked by hydrogen bonds into a three-dimensional structure. Owing to the extreme affinity of zoledronic acid for bone tissue, in general, and with calcium as one of the major constituents of bone, it is expected that this structure will be useful in modelling some of the biologically interesting processes in which the drug takes part.

  3. Calixarene methylene bisphosphonic acids as promising effectors of biochemical processes

    Directory of Open Access Journals (Sweden)

    S. V. Komisarenko

    2013-12-01

    Full Text Available This interdisciplinary study, performed with participation of research workers of Palladin Institute of Biochemistry and Institute of Organic Chemist­ry of NAS of Ukraine, is devoted to analysis of biochemical effects of some calixarene methylene bisphosphonic acids (cyclic phenol oligomers on two well-known biological phenomenons – Mg2+-dependent ATP hydrolysis (myosin subfragment-1 of myometrium smooth muscle was used as an example and fibrin polymerization. Calix[4]arene С-97 (calix[4]arene methylene bisphosphonic acids is a macrocyclic substance, which contains intramolecular highly ordered lipophilic cavity formed by four aromatic rings, one of which is functionalized at the upper rim with methylene bisphosphonic group. At concentration of 100 µM, this substance was shown to effectively inhibit ATPase activity of pig myometrium myosin subfragment-1 (inhibition coefficient І0.5 = 83 ± 7 µM. At the same time, this calix[4]arene causes significant (vs. control increase of myosin subfragment-1 hydrodynamic diameter, which may indicate formation of an intermolecular complex between calixa­rene and myosin head. Computer simulation methods (docking and molecular dynamics with addition of grid technologies enabled to elucidate the grounds of intermolecular interactions between calix[4]arene С-97 and myometrium myosin subfragment-1, that involve hydrophobic, electrostatic and π-π-stacking interactions, some of which are close to the ATPase active centre. In view of the ability of calixarenes to penetrate into the cell and their low toxicity, the results obtained may be used as a basis for further development of a new generation of supramolecular effectors (starting from the above mentioned substances, in particular calix[4]arene С-97 for regulation of smooth muscle contractile activity at the level of ATP dependent actin-myosin interaction. Calix[4]arenes bearing two or four methylenebisphosphonic acid groups at the macrocyclic upper

  4. Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk.

    Science.gov (United States)

    Mignot, M A; Taisne, N; Legroux, I; Cortet, B; Paccou, J

    2017-12-01

    A cohort of 183 postmenopausal women, who had either discontinued or continued bisphosphonates (BPs) after first-line therapy, was used to investigate the relationships between "drug holiday" and clinical fracture. The risk of new clinical fractures was found to be 40% higher in women who had taken a BP "drug holiday." BPs are the most widely used treatment for postmenopausal osteoporosis. The optimal treatment duration, however, remains unclear. The purpose of this study was to evaluate the fracture risk in postmenopausal women with osteoporosis after discontinuing BP treatment (BP "drug holiday"). A retrospective analysis was performed at Lille University Hospital (LUH) on postmenopausal women with osteoporosis who had taken a "drug holiday" or continued treatment after first-line BP therapy (3 to 5 years). The occurrence of new clinical fractures during follow-up was also explored. Cox proportional hazards models were used to investigate the relationships between BP "drug holiday" and the occurrence of clinical fractures, while controlling for confounding factors. Survival without new clinical fractures was analyzed using Kaplan-Meier curves and log-rank tests. One hundred eighty-three women (mean age: 61.8 years; SD: 8.7) who had previously undergone BP treatment for 3 to 5 years were enrolled in our study. The patients had received alendronate (n = 81), risedronate (n = 73), zoledronic acid (n = 20), and ibandronate (n = 9). In 166 patients ("drug holiday" group: n = 31; continuous-treatment group: n = 135), follow-up ranged from 6 to 36 months (mean duration: 31.8 months; SD: 8.2). The incidences of new clinical fractures during follow-up were 16.1% (5/31) and 11.9% (16/135). After full adjustment, the hazard ratio of new clinical fractures among "drug holiday" patients was 1.40 (95% CI: 1.12-1.60; p = 0.0095). After first-line BP therapy in postmenopausal women with osteoporosis, the risk of new clinical fractures was 40% higher in

  5. Effect of local injection of Zolena, zoledronic acid made in Iran, on orthodontic tooth movement and root and bone resorption in rats.

    Science.gov (United States)

    Seifi, Massoud; Asefi, Sohrab; Hatamifard, Ghazal; Lotfi, Ali

    2017-01-01

    Background. Anchorage control is an essential part of orthodontic treatment planning, especially in adult patients who demand a more convenient treatment. Zoledronic acid (ZA) is an effective choice to address this problem. It is the most potent member of the bisphosphonates family that has an inhibitory effect on bone resorption by suppressing osteoclast function. Therefore, ZA might be a good option for orthodontic anchorage control. The current study evaluated the effect of local administration of Zolena (ZA made in Iran) on orthodontic tooth movement (OTM) and root and bone resorption. Methods. The experimental group consisted of 30 rats in 3 subgroups (n=10). Anesthesia was induced, and one closed NiTi coil spring was installed between the first molar and central incisor unilaterally, except for the negative control group. The positive control group received vestibular injection of 0.01 mL of saline next to the maxillary first molar, and 0.01 mL of the solution was injected at the same site in the ZA group. After 21 days, the rats were sacrificed and the distance between the first and second molars was measured with a leaf gauge. Histological analysis was conducted by a blind pathologist for the number of Howship's lacunae, blood vessels, osteoclast-like cells and root resorption lacunae. Data were analyzed with ANOVA, Tukey test and t-test. Results. There were no significant differences in OTM between the force-applied groups. ZA significantly inhibited bone/root resorption and angiogenesis compared to the positive control group. Conclusion. Zolena did not decrease OTM but significantly inhibited bone and root resorption. Zolena might be less potent than its foreign counterparts.

  6. Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model.

    Directory of Open Access Journals (Sweden)

    Tzong-Tyng Hung

    Full Text Available BACKGROUND: The bisphosphonate, zoledronic acid (ZOL, can inhibit osteoclasts leading to decreased osteoclastogenesis and osteoclast activity in bone. Here, we used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM, to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice. METHODS: The model involves intracardiac injection for arterial dissemination of the RM1(BM cells in C57BL/6 mice. ZOL treatment was given via subcutaneous injections on days 0, 4, 8 and 12, at 20 and 100 µg/kg doses. Bone integrity was assessed by micro-computed tomography and histology with comparison to untreated mice. The osteoclast and osteoblast activity was determined by measuring serum tartrate-resistant acid phosphatase 5b (TRAP 5b and osteocalcin, respectively. Mice were euthanased according to predetermined criteria and survival was assessed using Kaplan Meier plots. FINDINGS: Micro-CT and histological analysis showed that treatment of mice with ZOL from the day of intracardiac injection of RM1(BM cells inhibited tumour-induced bone lysis, maintained bone volume and reduced the calcification of tumour-induced endochondral osteoid material. ZOL treatment also led to a decreased serum osteocalcin and TRAP 5b levels. Additionally, treated mice showed increased survival compared to vehicle treated controls. However, ZOL treatment did not inhibit the cells ability to metastasise to bone as the number of bone-metastases was similar in both treated and untreated mice. CONCLUSIONS: ZOL treatment provided significant benefits for maintaining the integrity of tumour-bearing bones and increased the survival of tumour bearing mice, though it did not prevent establishment of bone-metastases in this model. From the mechanistic view, these observations confirm that tumour-induced bone lysis is not a

  7. Oroantral fistula from bisphosphonate induced osteonecrosis of the jaw

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    Henry Sharp

    2010-07-01

    Full Text Available Bisphosphonates like alendronic acid, disodium etidronate, and risedronate are effective for preventing postmenopausal and corticosteroid induced osteoporosis. They are also useful in the treatment of Paget’s disease, hypercalcaemia of malignancy and in bony metastases. However osteonecrosis of the jaw has been reported following intravenous bisphosphonate use and rarely in those taking them orally.Increasingly, oroantral fistulae have been shown to occur as sequelae of bisphosphonate-induced osteonecrosis of the jaw and this case report highlights a patient that presented to our ENT department and required sinus surgery in collaboration with maxillofacial surgeons.This case report aims to raise awareness among ENT surgeons to these patients on bisphosphonates that could present to them with sinus disease from oroantral fistulae. There is an on-going audit in the maxillofacial community on this emerging trend.

  8. Risk factors influencing the duration of treatment with bisphosphonates until occurrence of an osteonecrosis of the jaw in 963 cancer patients.

    Science.gov (United States)

    Gabbert, Tatjana I; Hoffmeister, Bodo; Felsenberg, Dieter

    2015-04-01

    Osteonecrosis of the jaw (ONJ) is an adverse effect that is associated with bisphosphonate (BP) use. Little data are available on risk factors influencing the time of treatment until an osteonecrosis occurs. From 1 Dec 2004 until 21 Sep 2012, the German Register collected all patients with validated diagnoses of ONJ (N = 1,229) that were reported to the national pharmaco-vigilance system or to the Register directly. We analysed 963 patients with cancerous disease and an ONJ during i.v. BP treatment. Duration of BP treatment until first diagnosis of ONJ and Kaplan-Meier curves of ONJ-free survival were analysed stratified by gender, type of BP and type of cancer. Main indications for BP treatment were breast cancer (36%), multiple myeloma (24%), prostate cancer (16%) and kidney cancer (4%). Men suffered from their ONJ earlier than women. A total of 780 patients (81%) had their ONJ during zoledronate treatment, 93 (10%) under pamidronate and 90 (9%) under ibandronate treatment. ONJ-free survival in single BP users was significantly longer in pamidronate-treated patients than in zoledronate or ibandronate users. Ibandronate users had the shortest median duration of treatment (17 months), similar to that of zoledronate users (21.5 months). Sequential prescription of two different BPs prolonged the period of overall BP treatment until an ONJ occurred. Time of BP treatment was shortest in patients with kidney cancer. Age or a concomitant osteoporosis did not influence the time to event of an ONJ. Systemic risk factors such as gender play a significant role in certain subgroups only. Comparative analysis of different cancer patients helps the treating oncologist/dentist to identify patients with a more imminent risk to develop an ONJ (i.e. kidney cancer, ibandronate/zoledronate use).

  9. Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

    Czech Academy of Sciences Publication Activity Database

    Borghese, C.; Casagrande, N.; Pivetta, E.; Colombatti, A.; Boccellino, M.; Amler, Evžen; Normanno, N.; Caraglia, M.; de Rosa, G.; Aldinucci, D.

    2017-01-01

    Roč. 8, č. 26 (2017), s. 42926-42938 ISSN 1949-2553 Institutional support: RVO:68378041 Keywords : zoledronic acid * self-assembling nanoparticles * mesenchymal stromal cells * prostate cancer * tumor microenvironment Subject RIV: FP - Other Medical Disciplines OBOR OECD: Technologies involving the manipulation of cells, tissues, organs or the whole organism (assisted reproduction) Impact factor: 5.168, year: 2016

  10. Pain and quality of life of children and adolescents with osteogenesis imperfecta over a bisphosphonate treatment cycle.

    Science.gov (United States)

    Tsimicalis, Argerie; Boitor, Madalina; Ferland, Catherine E; Rauch, Frank; Le May, Sylvie; Carrier, Jaimie Isabel; Ngheim, Tracy; Bilodeau, Claudette

    2018-06-01

    The objective was to describe the pain and quality of life among children and adolescents with any osteogenesis imperfecta (OI) type over one intravenous bisphosphonate treatment cycle from a child and parental perspective. A prospective, observational study was conducted, where children and adolescents evaluated their pain intensity, location, and quality, as well as quality of life before, 1 week after treatment, and 6 months later. Quality of life was also evaluated from the parental perspective at the same three time points. Thirty-three child/parent dyads participated. The results showed that pain intensity on the 0-10 self-report scale after the Zoledronate infusion (median = 0, range = 0-6) was not different from pre (median = 2, range = 0-10) and 6-months post-scores (median = 2, range = 0-8) (p = 0.170). Children and adolescents with OI reported experiencing pain mainly in the ankles and the anterior and posterior shoulders. They selected evaluative pain descriptors such as uncomfortable (n = 16, 48%) and annoying (n = 13, 39%). Children and adolescents' functioning and quality of life did not change significantly across the bisphosphonate treatment cycle (p = 0.326), parents perceived an improvement immediately after the treatment compared to before (p = 0.016). Children and adolescents with OI experience mild, yet complex pain localized across several body areas. There is little fluctuation in the pain intensity and functioning of children with OI undergoing bisphosphonate treatment. What is Known: • Acute and chronic musculoskeletal pain remains a major issue in OI. • Pain has a negative impact on quality of life. What is New: • New and unpublished methods and findings describing the pain and quality of life of children and adolescents with OI over one intravenous bisphosphonate treatment cycle from a child- and parental-proxy perspective. • Children and adolescents with OI experience pain intensity that is mild, yet

  11. [Osteonecrosis of the jaws and bisphosphonates].

    Science.gov (United States)

    Junod, A F; Carrel, J-P; Richter, M; Vogt-Ferrier, N

    2005-11-02

    Widely prescribed, bisphosphonates inhibit bone resorption. They are not metabolised and have long half-lives. Two cases of osteonecrosis of the jaws have recently been attributed to bisphosphonates at the University Hospital of Geneva. The recent literature reveals more than a hundred similar cases throughout the world. Bone exposure appears spontaneously or after dental care. Treatment of the osteonecrosis is controversial and cure very difficult. This pathology is usually seen in patients on chemotherapy, steroids and i.v. bisphosphonates, but is sometimes seen with low-dose p.o. bisphosphonates. In view of the strong association between bisphosphonate therapy and osteonecrosis of the jaw, specialists have recommended dental and oral evaluation during bisphosphonate therapy as well as for several years after drug discontinuation.

  12. Evidence for the prevention of bone loss in elderly and old early non-metastatic breast cancer patients treated with aromatase inhibitors

    DEFF Research Database (Denmark)

    Gunmalm, V.; Jørgensen, N. R.; Abrahamsen, B.

    2017-01-01

    Breast cancer (BC) is the most common cancer amongst women worldwide. Bone health is emerging as an important issue for BC survivors. In this literature study, we focus on agents for preventing bone loss in early non-metastatic estrogen receptor positive BC in treatment with aromatase inhibitors...... (AI) and to assess the evidence for antiresorptive treatment of bone loss in early non-metastatic breast cancer. We included randomized controlled trials (RCT's) comparing: (a) bisphosphonates and control; (b) different bisphosphonates; (c) denosumab and control and (d) bisphosphonates vs. denosumab...... in early non-metastatic BC women in AI treatment. Among antiresorptives, zoledronic acid currently has the highest evidence for prevention of AI associated bone loss in early non-metastatic BC. Data on fracture prevention among all patients, elderly and old is sparse. More randomized controlled studies...

  13. Eliminating the need for fasting with oral administration of bisphosphonates

    DEFF Research Database (Denmark)

    Pazianas, Michael; Abrahamsen, Bo; Ferrari, Serge

    2013-01-01

    or beverages create complexes that cannot be absorbed. For this reason, they must be taken on an empty stomach, and a period of up to 2 hours must elapse before the consumption of any food or drink other than plain water. This routine is not only inconvenient but can lead to discontinuation of treatment......Bisphosphonates are the major treatment of choice for osteoporosis, given that they are attached preferentially by bone and significantly reduce the risk of fractures. Oral bisphosphonates are poorly absorbed (usually less than 1% for nitrogen-containing bisphosphonates) and when taken with food......, and when mistakenly taken with food, may result in misdiagnosis of resistance to or failure of treatment. The development of an enteric-coated delayed-release formulation of risedronate with the addition of the calcium chelator, ethylenediaminetetraacetic acid (EDTA), a widely used food stabilizer...

  14. Complexes of DOTA-bisphosphonate conjugates: probes for determination of adsorption capacity and affinity constants of hydroxyapatite.

    Science.gov (United States)

    Vitha, Tomas; Kubícek, Vojtech; Hermann, Petr; Kolar, Zvonimir I; Wolterbeek, Hubert Th; Peters, Joop A; Lukes, Ivan

    2008-03-04

    The adsorption on hydroxyapatite of three conjugates of a bisphosphonate and a macrocycle having C1, C2, and C3 spacers and their terbium complexes was studied by the radiotracer method using 160Tb as the label. The radiotracer-containing complex of the conjugate with the C3 spacer was used as a probe for the determination of the adsorption parameters of other bisphosphonates that lack a DOTA unit. A physicochemical model describing the competitive adsorption was successfully applied in the fitting of the obtained data. The maximum adsorption capacity of bisphosphonates containing bulky substituents is determined mainly by their size. For bisphosphonates having no DOTA moiety, the maximum adsorption capacity is determined by the electrostatic repulsion between negatively charged bisphosphonate groups. Compounds with a hydroxy or amino group attached to the alpha-carbon atom show higher affinities. Macrocyclic compounds containing a short spacer between the different bisphosphonic acid groups and the macrocyclic unit exhibit high affinities, indicating a synergic effect of the bisphosphonic and the macrocyclic groups during adsorption. The competition method described uses a well-characterized complex and allows a simple evaluation of the adsorption behavior of bisphosphonates. The application of the macrocycle-bisphosphonate conjugates allows easy radiolabeling via complexation of a suitable metal isotope.

  15. Zoledronic acid inhibits vasculogenic mimicry in murine osteosarcoma cell line in vitro.

    Science.gov (United States)

    Fu, Dehao; He, Xianfeng; Yang, Shuhua; Xu, Weihua; Lin, Tao; Feng, Xiaobo

    2011-06-30

    To study the effects of zoledronic acid (ZA) on the vasculogenic mimicry of osteosarcoma cells in vitro. A Three-dimensional culture of LM8 osteosarcoma cells on a type I collagen matrix was used to investigate whether osteosarcoma cells can develop vasculogenic mimicry, and to determine the effects of ZA on this process. In addition, the cellular ultrastructural changes were observed using scanning electron microscopy and laser confocal microscopy. The effects of ZA on the translocation of RhoA protein from the cytosol to the membrane in LM8 cells were measured via immunoblotting. ZA inhibited the development of vasculogenic mimicry by the LM8 osteosarcoma cells, decreased microvilli formation on the cell surface, and disrupted the F-actin cytoskeleton. ZA prevented translocation of RhoA protein from the cytosol to the membrane in LM8 cells. ZA can impair RhoA membrane localization in LM8 cells, causing obvious changes in the ultrastructure of osteosarcoma cells and induce cell apoptosis, which may be one of the underlying mechanisms by which the agent inhibits the development of vasculogenic mimicry by the LM8 cells.

  16. Zoledronic acid inhibits vasculogenic mimicry in murine osteosarcoma cell line in vitro

    Directory of Open Access Journals (Sweden)

    Lin Tao

    2011-06-01

    Full Text Available Abstract Background To study the effects of zoledronic acid (ZA on the vasculogenic mimicry of osteosarcoma cells in vitro. Methods A Three-dimensional culture of LM8 osteosarcoma cells on a type I collagen matrix was used to investigate whether osteosarcoma cells can develop vasculogenic mimicry, and to determine the effects of ZA on this process. In addition, the cellular ultrastructural changes were observed using scanning electron microscopy and laser confocal microscopy. The effects of ZA on the translocation of RhoA protein from the cytosol to the membrane in LM8 cells were measured via immunoblotting. Results ZA inhibited the development of vasculogenic mimicry by the LM8 osteosarcoma cells, decreased microvilli formation on the cell surface, and disrupted the F-actin cytoskeleton. ZA prevented translocation of RhoA protein from the cytosol to the membrane in LM8 cells. Conclusions ZA can impair RhoA membrane localization in LM8 cells, causing obvious changes in the ultrastructure of osteosarcoma cells and induce cell apoptosis, which may be one of the underlying mechanisms by which the agent inhibits the development of vasculogenic mimicry by the LM8 cells.

  17. New 68Ga-PhenA bisphosphonates as potential bone imaging agents

    International Nuclear Information System (INIS)

    Wu, Zehui; Zha, Zhihao; Choi, Seok Rye; Plössl, Karl; Zhu, Lin; Kung, Hank F.

    2016-01-01

    Introduction: In vivo positron emission tomography (PET) imaging of the bone using [ 68 Ga]bisphosphonates may be a valuable tool for cancer diagnosis and monitoring therapeutic treatment. We have developed new [ 68 Ga]bisphosphonates based on the chelating group, AAZTA (6-[bis(hydroxycarbonyl-methyl)amino]-1,4-bis(hydroxycarbonyl methyl)-6-methylperhydro-1,4-diazepine). Method: Phenoxy derivative of AAZTA (2,2′-(6-(bis(carboxymethyl)amino)-6-((4-(2-carboxyethyl)phenoxy) methyl)-1,4-diazepane-1,4-diyl)diacetic acid), PhenA, 2, containing a bisphosphonate group (PhenA-BPAMD, 3, and PhenA-HBP, 4) was prepared. Labeling of these chelating agents with 68 Ga was evaluated. Results: The ligands reacted rapidly in a sodium acetate buffer with [ 68 Ga]GaCl 3 eluted from a commercially available 68 Ge/ 68 Ga generator (pH 4, > 95% labeling at room temperature in 5 min) to form [ 68 Ga]PhenA-BPAMD, 3, and [ 68 Ga]PhenA-HBP, 4. The improved labeling condition negates the need for further purification. The 68 Ga bisphosphonate biodistribution and autoradiography of bone sections in normal mice after an iv injection showed excellent bone uptake. Conclusion: New 68 Ga labeled bisphosphonates may be useful as in vivo bone imaging agents in conjunction with positron emission tomography (PET).

  18. Evaluation of the efficacy of zoledronic acid and amifostine on radiation induced bone loss in mice

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Wook; Lee, Sueum; Kang, Sohi; Moon, Cahng Jong; Kim, Jong Choon; Kim, Sung Ho [College of Veterinary Medicine, Chonnam National University, Gwangju (Korea, Republic of); Jung, Uhee; Jo, Sung Kee [Advanced Radiation Technology Institute, Jeungeup (Korea, Republic of); Jang, Jong Sik [College of Ecology and Environmental Science, Kyungpook National University, Sangju (Korea, Republic of)

    2016-09-15

    This study investigated the effects of zoledronic acid (ZA) on radiation-induced bone loss in C3H/HeN mice. C3H/HeN mice were divided into sham control and three irradiated groups (3 Gy, gamma ray). The irradiated mice were treated for 12 weeks with vehicle, amifostine (intraperitoneal injection), or ZA (subcutaneous injection). Grip strength, uterus weight, and serum alkaline phosphatase (ALP), and tartrate-resistant acid phosphatase (TRAP) levels were measured. Tibiae were analyzed using micro-computed tomography. Treatment of ZA (100 μg·kg{sup -1}·week{sup -1}) significantly preserved trabecular bone volume, trabecular thickness, trabecular number, trabecular separation, bone mineral density of proximal tibia metaphysic, and cortical bone volume, but did not alter the uterus weight of the mice. The administration of ZA for 12 weeks lowered serum ALP and TRAP levels in irradiated mice, suggesting that ZA can reduce the bone turnover rate in mice. No differences were apparent between the amifostine-treated group and the irradiation control group. The results indicate that ZA can prevent radiation-induced bone loss in mice.

  19. Thermodynamic study of the interaction between calcium and zoledronic acid by calorimetry

    International Nuclear Information System (INIS)

    Mostefa Side Larbi, Mohamed A.; Sauzet, Christophe; Piccerelle, Philippe; Cau, Pierre

    2016-01-01

    Bisphosphonates (BPs) are widely used to treat calcium disorders because of their structural and functional similarities with the organic pyrophosphates present in plasma and urine. BPs are well known for their strong interactions with calcium, and they have been shown to bind to hydroxyapatite or bone; however, no model exists for studying in greater detail how BPs and particularly amino-bisphosphonates (N-BPs) such as zolendronate (Zol) bind to free calcium. The aim of this work was to determine the effect of pH on Ca 2+ /Zol complex formation using isothermal titration calorimetry (ITC) because these effects might have important implications for the future development of a solid dosage form. In this study, using a predictive model, we can observe, the existence of three Ca 2+ /Zol complexes. Knowledge of the binding constant for each complex is helpful for predicting the predominance of the different species at different Ca 2+ /Zol ratios. Binding is due to ionic interaction between Ca 2+ and the negative charges formed by dissociated Zol as a function of the pKa. Ca 2+ fixation induces a strong rearrangement of the surrounding water molecules and causes proton release or uptake. The pH-dependent affinity of calcium for each site based on the model used in this work is proposed in detail, which might facilitate the development of new bisphosphonates and enable further elucidation of their mode of action.

  20. Diminished Progression of Periapical Lesions with Zoledronic Acid in Ovariectomized Rats.

    Science.gov (United States)

    Wayama, Marcelo Tadahiro; Yoshimura, Hitoshi; Ohba, Seigo; Yoshida, Hisato; Matsuda, Shinpei; Kobayashi, Junichi; Kobayashi, Motohiro; Gomes Filho, João Eduardo; Sano, Kazuo

    2015-12-01

    The aim of this study was to investigate the effects of systemically administered zoledronic acid (ZOL) on the progression of periapical lesions in estrogen-deficient rats. Female Wistar rats were divided into the following groups: SHAM-veh, sham surgery treated with vehicle (physiological saline); OVX-veh, ovariectomy treated with vehicle; SHAM-ZOL, sham surgery treated with ZOL; and OVX-ZOL, ovariectomy treated with ZOL. Vehicle or ZOL was administered intravenously once a week for 4 weeks. The pulp of the mandibular first molar of all rats was exposed to the oral environment to induce a periapical lesion, and the lesions were analyzed after 7 and 30 days. The mandibles were examined by micro-computed tomographic imaging and histopathologic, histometric, and immunohistochemical analyses. Histopathologically, the OVX-veh group had more severe inflammation and bone loss and a larger number of cells that were positive for tartrate-resistant acid phosphatase compared with the SHAM-veh and OVX-ZOL groups; the SHAM-veh and OVX-ZOL groups were similar to each other. The SHAM-ZOL group had the lowest magnitude of these conditions. Tomographically, the OVX-veh group had greater bone loss than the other groups at both time points. The SHAM-veh, SHAM-ZOL, and OVX-ZOL groups had similar bone loss at both time points. In the sagittal section on day 30, the SHAM-ZOL group had lower bone loss compared with the SHAM-veh and OVX-ZOL groups. The hypoestrogenic condition aggravates the progression of periapical lesions. ZOL therapy may help contain bone destruction of periapical lesions. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  1. Osteoporosebehandling kan pauseres efter individuel vurdering

    DEFF Research Database (Denmark)

    Eiken, Pia A; Abrahamsen, Bo

    2017-01-01

    In most patients, treatment of osteoporosis is a long-term challenge. Because alendronate and zoledronic acid accumulate in bone with some persistent antifracture efficacy after therapy, it is reasonable to consider a "drug holiday" for low-risk patients. It is recommended that the duration...... and length of drug holiday should be individualized for each patient. For all other bisphosphonates data are limited. For other antiresorptive and anabolic agents "drug holiday" is not recommended....

  2. The rabbit biodistribution of a therapeutic dose of zoledronic acid labeled with Tc-99m

    International Nuclear Information System (INIS)

    Asikoglu, Makbule; Gamze Durak, Funda

    2009-01-01

    The aim of the present study was to label a therapeutic dose of zoledronic acid (ZOL) with Tc-99m, evaluate its in vitro stability and compare its biodistribution to 99m Tc-methylene biphosphonate ( 99m Tc-MDP) in normal rabbits. Preparation of 0.50 mg of 99m Tc-ZOL was carried out by the reduction of 99m Tc-pertechnetate in the presence of stannous chloride. The radiolabeling efficiency was found to be greater than 99%. The labeled complex was stable at least up to 6 h at room temperature determined by paper chromatography. 99m Tc-ZOL and 99m Tc-MDP were administered intravenously to the rabbits for scintigraphic studies. Between 99m Tc-ZOL and 99m Tc-MDP, there were no significant differences in the ratios of femur/BG and lumbar vertebrae/BG, whereas epiphysis/BG and the kidney/BG ratios of 99m Tc-MDP were higher than 99m Tc-ZOL at the static studies.

  3. Antiparasitic Activity of Sulfur- and Fluorine-Containing Bisphosphonates against Trypanosomatids and Apicomplexan Parasites

    Directory of Open Access Journals (Sweden)

    Tamila Galaka

    2017-01-01

    Full Text Available Based on crystallographic data of the complexes 2-alkyl(aminoethyl-1,1-bisphosphonates–Trypanosoma cruzi farnesyl diphosphate synthase, some linear 1,1-bisphosphonic acids and other closely related derivatives were designed, synthesized and biologically evaluated against T. cruzi, the responsible agent of Chagas disease and against Toxoplasma gondii, the etiologic agent of toxoplasmosis and also towards the target enzymes farnesyl pyrophosphate synthase of T. cruzi (TcFPPS and T gondii (TgFPPS, respectively. The isoprenoid-containing 1,1-bisphosphonates exhibited modest antiparasitic activity, whereas the linear α-fluoro-2-alkyl(aminoethyl-1,1-bisphosphonates were unexpectedly devoid of antiparasitic activity. In spite of not presenting efficient antiparasitic activity, these data turned out to be very important to establish a structural activity relationship.

  4. How much we know about bisphosphonate lesions

    Directory of Open Access Journals (Sweden)

    Pešić Zoran

    2016-01-01

    Full Text Available Introduction: Bisphosphonate drugs are used in the treatment of the osteoporosis and malignant processes in the bone tissue. As a result of this use bisphosphonate lesions are formed in bone tissue and oral mucosis, which representing a remarkable therapeutic problem. The aim of this study was to determine how many dentists in general practice are familiar with the character, diagnosis and therapy bisphosphonate lesions. Material and Methods: An anonymous questionnaire of 13 questions was conducted in dental practices in Nis County in the period from October 2015 to December 2015. The obtained data were statistically analyzed. Results: A total of 60% dentists knew what drugs are used in the treatment of osteoporosis and malignant processes in the bones. 25% knew what the bisphosphonate bone lesions are . 66, 6% of dentists knewn what is the prevention of bisphosphonate lesions. 63.3% of dentists are aware of the complications bisphosphonate lesions. Conclusion: Dentists in general practices are insufficiently familiar with the character, diagnosis and treatment of bisphosphonate lesions. We should activate all entities that participate in more continuous medical education, in order to achieve a higher level of prevention of these therapeutic ungrateful lesions.

  5. Inhibition of Zoledronic Acid on Cell Proliferation and Invasion of Lung Cancer Cell Line 95D

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    Mingming LI

    2009-03-01

    Full Text Available Background and objective Abnormal proliferation and metastasis is the basic characteristic of malignant tumors. The aim of this work is to explore the effects of zoledronic acid on cell proliferation and invasion in lung cancer cell line 95D. Methods The effect of zoledrnic acid (ZOL on proliferation of lung cancer cell line 95D was detected by MTT. The expression of proliferation and invasion-relation genes and proteins were detected by Western blot, RT-PCR and immunofluorescence. Changes of invasion of lung cancer cell numbers were measured by polycarbonates coated with Matrigel. Results ZOL could inhibit the proliferation of lung cancer cell line 95D in vitro in a time-dependant and a dose-dependant manner. With time extending after ZOL treated, the mRNA expresion of VEGF, MMP9, MMP2 and protein expression of VEGF, MMP9, ERK1/ ERK2 were decreased. The results of Tanswell invasion showed the numbers of invasive cells were significantly reduced in 95D cells treated with ZOL 4 d and 6 d later. Conclusion ZOL could inhibit cell proliferation and invasion of lung cancer cell line 95D.

  6. BISPHOSPHONATE - RELATED MUCOSITIS (BRM: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Pavel Stanimirov

    2017-03-01

    Full Text Available Bisphosphonates (BPs are the most widely used and effective antiresorptive agents for the treatment of diseases in which there is an increase in osteoclastic resorption, including post-menopausal osteoporosis, Paget’s disease, and tumor-associated osteolysis. Oral and maxillofacial surgeons are well aware of the side effects of bisphosphonates and mainly with bisphosphonate-related osteonecrosis of the jaws (BRONJ. Less known are the mucosal lesions associated with the use of these agents. In the scientific literature, there are only few reports of mucosal lesions due to the direct contact of the oral form of BPs with the mucosa (bisphosphonate-related mucositis. They are mostly related to improper use of bisphosphonate tablets that are chewed, sucked or allowed to melt in the mouth before swallowing. Lesions are atypical and need to be differentiated from other mucosal erosions. We present a case of bisphosphonate-related mucositis due to the improper use of alendronate.

  7. Discovery, clinical development, and therapeutic uses of bisphosphonates.

    Science.gov (United States)

    Licata, Angelo A

    2005-04-01

    To review the literature concerning the history, development, and therapeutic uses of bisphosphonates. English-language articles were identified through a search of MEDLINE (through December 2004) using the key word bisphosphonate. Reference lists of pivotal studies, reviews, and full prescribing information for the approved agents were also examined. Selected studies included those that discussed the discovery and initial applications of bisphosphonates, as well as their historical development, pharmacokinetic and pharmacodynamic properties, and current therapeutic uses. Bisphosphonates structurally resemble pyrophosphates (naturally occurring polyphosphates) and have demonstrated similar physicochemical effects to pyrophosphates. In addition, bisphosphonates reduce bone turnover and resist hydrolysis when administered orally. The information gained from initial work with etidronate generated a considerable scientific effort to design new and more effective bisphosphonates. The PCP moiety in the general bisphosphonate structure is essential for binding to hydroxyapatite and allows for a number of chemical variations by changing the 2 lateral side chains (designated R(1) and R(2)). The R(1) side chain determines binding affinity to hydroxyapatite, and the R(2) side chain determines antiresorptive potency. Accordingly, each bisphosphonate has its own characteristic profile of activity. The bisphosphonates reduce bone turnover, increase bone mass, and decrease fracture risk and therefore have a significant place in the management of skeletal disorders including osteoporosis, Paget's disease, bone metastases, osteogenesis imperfecta, and heterotopic ossification.

  8. Effect of zoledronic acid on reducing femoral bone mineral density loss following total hip arthroplasty: A meta-analysis from randomized controlled trails.

    Science.gov (United States)

    Gao, Jian; Gao, Chong; Li, Hui; Wang, Guo-Sheng; Xu, Chang; Ran, Jian

    2017-11-01

    This meta-analysis aimed to assess the efficiency of intravenous administration of zoledronic acid on reducing femoral periprosthetic bone mineral density loss in patients undergoing primary total hip arthroplasty (THA). A systematic search was performed in Medline (1966-2017.07.31), PubMed (1966-2017.07.31), Embase (1980-2017.07.31), ScienceDirect (1985-2017.07.31) and the Cochrane Library (1966-2017.07.31). Fixed/random effect model was used according to the heterogeneity tested by I 2 statistic. Sensitivity analysis was conducted and publication bias was assessed. Meta-analysis was performed using Stata 11.0 software. Four studies including 185 patients met the inclusion criteria. The present meta-analysis indicated that there were significant differences between groups in terms of periprosthetic bone mineral density in Gruen zone 1 (SMD = 0.752, 95% CI: 0.454 to 1.051, P = 0.000), 2 (SMD = 0.524, 95% CI: 0.230 to 0.819, P = 0.000), 4 (SMD = 0.400, 95% CI: 0.107 to 0.693, P = 0.008), 6 (SMD = 0.893, 95% CI: 0.588 to 1.198, P = 0.000) and 7 (SMD = 0.988, 95% CI: 0.677 to 1.300, P = 0.000). Intravenous administration of zoledronic acid could significantly reduce periprosthetic bone mineral density loss (Gruen zone 1, 2, 4, 6 and 7) after THA. In addition, no severe adverse events were identified. High-quality RCTs with large sample size were still required. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

  9. Zoledronic acid use in patients with bone metastases from renal cell carcinoma or bladder cancer.

    Science.gov (United States)

    Saad, Fred; Eastham, James A

    2010-06-01

    Approximately 30% of patients with renal cell carcinoma (RCC) and 40% of patients with bladder cancer develop bone metastases that can disrupt normal bone homeostasis and place patients at risk for potentially life-limiting skeletal-related events (SREs). In the absence of bone-directed therapies, patients with RCC may experience up to four SREs per year. In patients with bone metastases from RCC or bladder cancer, zoledronic acid (ZOL) significantly reduced the risk of SREs compared with placebo. In addition to its bone-protective effects, preclinical and early clinical evidence indicates that ZOL prevents tumor progression. For example, retrospective subset analysis in patients with RCC indicated that ZOL extended time to disease progression and demonstrated a trend toward improved overall survival compared with placebo. Additionally, a study in patients with bone metastases from bladder cancer demonstrated that ZOL improved 1-year overall survival compared with placebo. Bone metastases place a heavy burden on patients with RCC or bladder cancer, and early, continuous treatment with ZOL may provide anticancer benefits in addition to important patient quality of life. 2010. Published by Elsevier Inc.

  10. Modulation of Tumor Cell Metabolism by Laser Photochemotherapy with Cisplatin or Zoledronic Acid In Vitro.

    Science.gov (United States)

    Heymann, Paul Günther Baptist; Henkenius, Katharina Sabine Elisabeth; Ziebart, Thomas; Braun, Andreas; Hirthammer, Klara; Halling, Frank; Neff, Andreas; Mandic, Robert

    2018-03-01

    Laser photochemotherapy is a new approach in cancer treatment using low-level laser therapy (LLLT) to enhance the effect of chemotherapy. In order to evaluate the effect of LLLT on tumor cells, HeLa cells were treated with cisplatin or zoledronic acid (ZA) followed by LLLT. Cell viability was evaluated with 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Oxidative phosphorylation and glycolysis were measured using extracellular flux analysis. Immunocytochemistry of heat-shock protein 70 (HSP70) and western blot analysis were performed. LLLT alone increased viability and was associated with lower oxidative phosphorylation but higher glycolysis rates. Cisplatin and ZA alone lowered cell viability, glycolysis and oxidative phosphorylation. This effect was significantly enhanced in conjunction with LLLT and was accompanied by reduced oxidative phosphorylation and collapse of glycolysis. Our observations indicate that LLLT may raise the cytotoxicity of cisplatin and ZA by modulating cellular metabolism, pointing to a possible application in cancer treatment. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  11. Adjuvant bisphosphonates in early breast cancer

    DEFF Research Database (Denmark)

    Hadji, P; Coleman, R E; Wilson, C

    2016-01-01

    Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have...... regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature...... was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus...

  12. Radiographic features of bisphosphonate therapy in pediatric patients

    Energy Technology Data Exchange (ETDEWEB)

    Grissom, L.E.; Theodore Harcke, H. [Dept. of Medical Imaging, Alfred I. duPont Hospital for Children, Nemours Children' s Clinic, Wilmington, DE (United States)

    2003-04-01

    Background: Pediatric patients are being treated with bisphosphonates for low bone mineral density. Skeletal radiographic findings have been described with bisphosphonates given orally and intravenously. Objective: To determine and describe the radiographic findings of cyclic intravenous bisphosphonate therapy in the growing skeleton. Materials and methods: Retrospective review of radiographs of 32 patients with osteogenesis imperfecta or cerebral palsy treated with intravenous bisphosphonates on a quarterly schedule. Results: Principal observations were metaphyseal bands and increased bone mineral density. The bands varied in spacing according to the age of the patient, rate of growth, and the location of the metaphysis. Fractures continued to be seen in patients with osteogenesis imperfecta. Conclusion: Cyclic bisphosphonate therapy results in distinctive radiographic findings in the growing skeleton. (orig.)

  13. Radiographic features of bisphosphonate therapy in pediatric patients

    International Nuclear Information System (INIS)

    Grissom, L.E.; Theodore Harcke, H.

    2003-01-01

    Background: Pediatric patients are being treated with bisphosphonates for low bone mineral density. Skeletal radiographic findings have been described with bisphosphonates given orally and intravenously. Objective: To determine and describe the radiographic findings of cyclic intravenous bisphosphonate therapy in the growing skeleton. Materials and methods: Retrospective review of radiographs of 32 patients with osteogenesis imperfecta or cerebral palsy treated with intravenous bisphosphonates on a quarterly schedule. Results: Principal observations were metaphyseal bands and increased bone mineral density. The bands varied in spacing according to the age of the patient, rate of growth, and the location of the metaphysis. Fractures continued to be seen in patients with osteogenesis imperfecta. Conclusion: Cyclic bisphosphonate therapy results in distinctive radiographic findings in the growing skeleton. (orig.)

  14. Amorphous, Smart, and Bioinspired Polyphosphate Nano/Microparticles: A Biomaterial for Regeneration and Repair of Osteo-Articular Impairments In-Situ

    Directory of Open Access Journals (Sweden)

    Werner E. G. Müller

    2018-01-01

    Full Text Available Using femur explants from mice as an in vitro model, we investigated the effect of the physiological polymer, inorganic polyphosphate (polyP, on differentiation of the cells of the bone marrow in their natural microenvironment into the osteogenic and chondrogenic lineages. In the form of amorphous Ca-polyP nano/microparticles, polyP retains its function to act as both an intra- and extracellular metabolic fuel and a stimulus eliciting morphogenetic signals. The method for synthesis of the nano/microparticles with the polyanionic polyP also allowed the fabrication of hybrid particles with the bisphosphonate zoledronic acid, a drug used in therapy of bone metastases in cancer patients. The results revealed that the amorphous Ca-polyP particles promote the growth/viability of mesenchymal stem cells, as well as the osteogenic and chondrogenic differentiation of the bone marrow cells in rat femur explants, as revealed by an upregulation of the expression of the transcription factors SOX9 (differentiation towards osteoblasts and RUNX2 (chondrocyte differentiation. In parallel to this bone anabolic effect, incubation of the femur explants with these particles significantly reduced the expression of the gene encoding the osteoclast bone-catabolic enzyme, cathepsin-K, while the expression of the tartrate-resistant acid phosphatase remained unaffected. The gene expression data were supported by the finding of an increased mineralization of the cells in the femur explants in response to the Ca-polyP particles. Finally, we show that the hybrid particles of polyP complexed with zoledronic acid exhibit both the cytotoxic effect of the bisphosphonate and the morphogenetic and mineralization inducing activity of polyP. Our results suggest that the Ca-polyP nano/microparticles are not only a promising scaffold material for repairing long bone osteo-articular damages but can also be applied, as a hybrid with zoledronic acid, as a drug delivery system for

  15. A review of the clinical implications of bisphosphonates in dentistry.

    Science.gov (United States)

    Borromeo, G L; Tsao, C E; Darby, I B; Ebeling, P R

    2011-03-01

    Bisphosphonates are drugs that suppress bone turnover and are commonly prescribed to prevent skeletal related events in malignancy and for benign bone diseases such as osteoporosis. Bisphosphonate associated jaw osteonecrosis (ONJ) is a potentially debilitating, yet poorly understood condition. A literature review was undertaken to review the dental clinical implications of bisphosphonates. The present paper briefly describes the postulated pathophysiology of ONJ and conditions with similar clinical presentations. The implications of bisphosphonates for implantology, periodontology, orthodontics and endodontics are reviewed. Whilst bisphosphonates have potential positive applications in some clinical settings, periodontology particularly, further clinical research is limited by the risk of ONJ. Prevention and management are reviewed, including guidelines for reducing cumulative intravenous bisphosphonate dose, cessation of bisphosphonates prior to invasive dental treatment or after ONJ development, and the use of serum beta-CTX-1 in assessing risk. In the context of substantial uncertainty, the implications of bisphosphonate use in the dental clinical setting are still being determined. © 2010 Australian Dental Association.

  16. Bisphosphonate-related osteonecrosis of the jaw: specificities

    Directory of Open Access Journals (Sweden)

    Siri Paulo

    2014-09-01

    Full Text Available Bisphosphonate-related osteonecrosis of the jaws (BRONJ is a severe complication that has recently emerged in patients treated with intravenous bisphosphonates for malignant diseases. This complication usually presents after a minor local trauma during a dental treatment. Several etiopathogenic mechanisms of this pathological condition have been proposed, but no model can explain all morphological changes observed at the macroscopic and microscopic level. BRONJ is likely to be related to direct toxicity in the bone and soft tissue cells, due to nitrogen-containing bisphosphonates. This review elucidates the clinical indications and mechanism of action of bisphosphonates, reports some clinical diagnostic criteria for BRONJ, describe the histopathological criteria for BRONJ diagnosis, the potential triggering pathways and the available treatment strategies.

  17. Effects of Zoledronate and Mechanical Loading during Simulated Weightlessness on Bone Structure and Mechanical Properties

    Science.gov (United States)

    Scott, R. T.; Nalavadi, M. O.; Shirazi-Fard, Y.; Castillo, A. B.; Alwood, J. S.

    2016-01-01

    Space flight modulates bone remodeling to favor bone resorption. Current countermeasures include an anti-resorptive drug class, bisphosphonates (BP), and high-force loading regimens. Does the combination of anti-resorptives and high-force exercise during weightlessness have negative effects on the mechanical and structural properties of bone? In this study, we implemented an integrated model to mimic mechanical strain of exercise via cyclical loading (CL) in mice treated with the BP Zoledronate (ZOL) combined with hindlimb unloading (HU). Our working hypothesis is that CL combined with ZOL in the HU model induces additive structural and mechanical changes. Thirty-two C57BL6 mice (male,16 weeks old, n8group) were exposed to 3 weeks of either HU or normal ambulation (NA). Cohorts of mice received one subcutaneous injection of ZOL (45gkg), or saline vehicle, prior to experiment. The right tibia was axially loaded in vivo, 60xday to 9N in compression, repeated 3xweek during HU. During the application of compression, secant stiffness (SEC), a linear estimate of slope of the force displacement curve from rest (0.5N) to max load (9.0N), was calculated for each cycle once per week. Ex vivo CT was conducted on all subjects. For ex vivo mechanical properties, non-CL left femurs underwent 3-point bending. In the proximal tibial metaphysis, HU decreased, CL increased, and ZOL increased the cancellous bone volume to total volume ratio by -26, +21, and +33, respectively. Similar trends held for trabecular thickness and number. Ex vivo left femur mechanical properties revealed HU decreased stiffness (-37),and ZOL mitigated the HU stiffness losses (+78). Data on the ex vivo Ultimate Force followed similar trends. After 3 weeks, HU decreased in vivo SEC (-16). The combination of CL+HU appeared additive in bone structure and mechanical properties. However, when HU + CL + ZOL were combined, ZOL had no additional effect (p0.05) on in vivo SEC. Structural data followed this trend with

  18. Bisphosphonates and osteonecrosis of the jaw.

    Science.gov (United States)

    Shannon, Jodi; Shannon, John; Modelevsky, Steven; Grippo, Anne A

    2011-12-01

    Bisphosphonates are used worldwide as a successful treatment for people with osteoporosis, which is the major underlying cause of fractures in postmenopausal women and older adults. These agents are successful at increasing bone mass and bone trabecular thickness, decreasing the risk of fracture, and decreasing bone pain, enabling individuals to have better quality of life. Bisphosphonates are also used to treat multiple myeloma, bone metastasis, and Paget's disease; however, bisphosphonate treatment may result in negative side effects, including osteonecrosis of the jaw (ONJ). ONJ involves necrotic, exposed bone in the jaw, pain, possible secondary infection, swelling, painful lesions, and various dysesthesias, although less-severe cases may be asymptomatic. First-generation bisphosphonates, which do not contain nitrogen, are metabolized into a nonfunctional, cytotoxic analogue of adenosine triphosphate and cause osteoclast death by starvation. Second-generation bisphosphonates are nitrogen-containing agents; these inhibit osteoclast vesicular trafficking, membrane ruffling, morphology, and cytoskeletal arrangement by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. Physicians treating older adults with osteoporosis and cancer should work together with dental practitioners, pharmacists, and other clinicians to inform individuals receiving bisphosphonates of their possible side effects and to suggest precautionary steps that may minimize the risk of osteonecrosis, particularly of the jaw. These include practicing good oral hygiene; scheduling regular dental examinations and cleanings; and cautioning people who are scheduling treatment for periodontal disease, oral and maxillofacial therapy, endodontics, implant placement, restorative dentistry, and prosthodontics. Recommendations for management of people with ONJ include an oral rinse, such as chlorhexidine, and antibiotics. © 2011, Copyright the Authors Journal compilation © 2011, The American

  19. Pregnancy and Lactation-Associated Osteoporosis: Bone Histomorphometric Analysis and Response to Treatment with Zoledronic Acid.

    Science.gov (United States)

    Grizzo, Felipe Merchan Ferraz; da Silva Martins, Janaina; Pinheiro, Marcelo M; Jorgetti, Vanda; Carvalho, Maria Dalva Barros; Pelloso, Sandra Marisa

    2015-10-01

    Pregnancy and lactation-associated osteoporosis (PAO) is a rare condition with little known pathophysiology. Most cases are diagnosed in the third trimester of pregnancy or in the first weeks postpartum, particularly in first pregnancies. Vertebral fractures are most commonly observed and characterised by prolonged severe pain, functional limitations and a loss of height. Measurements of bone mineral density and biochemical markers of bone remodelling are the clinical methods most commonly used for the management of these patients. However, a bone biopsy with histomorphometric analysis has been considered to be the gold-standard. Few studies have evaluated the histomorphometry in patients with this clinical condition and none of them performed the procedure at the beginning of the clinical assessment. In this study, we report a case of PAO in a 31-year-old postpartum patient who had undergone a twin pregnancy. We describe the clinical, laboratory tests and imaging features. Bone histomorphometry showed a high resorption rate and excellent evolution after 1 year of treatment with intravenous zoledronic acid. Our data suggest that osteoclastogenesis plays a central role in the pathophysiological processes of this disease.

  20. Heart failure in patients treated with bisphosphonates

    DEFF Research Database (Denmark)

    Grove, E L; Abrahamsen, B; Vestergaard, P

    2013-01-01

    The aim of this study was to investigate the occurrence of heart failure in patients treated with bisphosphonates.......The aim of this study was to investigate the occurrence of heart failure in patients treated with bisphosphonates....

  1. Superparamagnetic Bifunctional Bisphosphonates Nanoparticles: A Potential MRI Contrast Agent for Osteoporosis Therapy and Diagnostic

    Directory of Open Access Journals (Sweden)

    Y. Lalatonne

    2010-01-01

    Full Text Available A bone targeting nanosystem is reported here which combined magnetic contrast agent for Magnetic Resonance Imaging (MRI and a therapeutic agent (bisphosphonates into one drug delivery system. This new targeting nanoplatform consists of superparamagnetic γFe2O3 nanoparticles conjugated to 1,5-dihydroxy-1,5,5-tris-phosphono-pentyl-phosphonic acid (di-HMBPs molecules with a bisphosphonate function at the outer of the nanoparticle surface for bone targeting. The as-synthesized nanoparticles were evaluated as a specific MRI contrast agent by adsorption study onto hydroxyapatite and MRI measurment. The strong adsorption of the bisphosphonates nanoparticles to hydroxyapatite and their use as MRI T2∗ contrast agent were demonstrated. Cellular tests performed on human osteosarcoma cells (MG63 show that γFe2O3@di-HMBP hybrid nanomaterial has no citoxity effect in cell viability and may act as a diagnostic and therapeutic system.

  2. Development of superior bone scintigraphic agent from a series of {sup 99m}Tc-labeled zoledronic acid derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Lin Jianguo [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063 (China); Qiu Ling, E-mail: qiulingwx@gmail.com [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063 (China); Cheng Wen [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063 (China); Luo Shineng, E-mail: shineng914@yahoo.com.cn [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063 (China); Xue Li; Zhang Shu [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063 (China)

    2012-05-15

    Two novel zoledronic acid (ZL) derivatives, 1-hydroxy-4-(1H-imidazol-1-yl)butane-1,1-diyldiphosphonic acid (IBDP) and 1-hydroxy-5-(1H-imidazol-1-yl)pentane-1,1-diyldiphosphonic acid (IPeDP), were prepared and labeled with the radionuclide technetium-99m in a high labeling yield. In vitro stabilities of these radiolabeled complexes were measured by the radio-HPLC analysis as a function of time, which showed excellent stability with the radiochemical purity of over 95% at 6 h post preparation. Their in vivo biological performances were evaluated and compared with those of {sup 99m}Tc-ZL and {sup 99m}Tc-MDP (methylenediphosphonic acid). The biodistribution in mice and scintigraphic images of the rabbit showed that the tracer agent {sup 99m}Tc-IPeDP had highly selective uptake in the skeletal system and rapid clearance from the blood and soft tissues and an excellent scintigraphic image can be obtained in a shorter time post injection with clear visualization of the skeleton and low soft tissue activity. These preclinical studies suggest that {sup 99m}Tc-IPeDP would be a novel superior bone scintigraphic agent. - Highlights: Black-Right-Pointing-Pointer Two novel diphosphonic acids were labeled with the {sup 99m}Tc in high labeling yield. Black-Right-Pointing-Pointer {sup 99m}Tc-IPeDP had high uptake in skeletal system and rapid clearance from blood. Black-Right-Pointing-Pointer {sup 99m}Tc-IPeDP reveals attractive biological features as superior bone scanning agent.

  3. Downregulation of CXCR4 Expression and Functionality After Zoledronate Exposure in Canine Osteosarcoma.

    Science.gov (United States)

    Byrum, M L; Pondenis, H C; Fredrickson, R L; Wycislo, K L; Fan, T M

    2016-07-01

    The establishment and progression of metastases remains the life-limiting factor for dogs diagnosed with osteosarcoma (OS). The pattern of metastases is likely regulated through interactions between chemokine receptors and chemokines, and perturbations in these signaling cascades responsible for cytoskeletal organization and directional migration have the potential to alter metastatic cell trafficking behaviors. Zoledronate will impair directional migration of OS cells through downregulation of chemokine (C-X-C motif) receptor 4 (CXCR4) expression and functionality. Nineteen archived tumor specimens and plasma from 20 dogs with OS. Prospectively, the expressions of CXCR4 were studied in OS cell lines and spontaneous tumor samples. The effect of zoledronate on CXCR4 expression and functionality was investigated by characterizing responses in 3 OS cell lines. In 19 OS specimens and 20 dogs with OS, changes in CXCR4 expression and circulating CXCR4 concentrations were characterized in response to zoledronate therapy respectively. All canine OS cells express CXCR4, and zoledronate reduces CXCR4 expression and functionality by 27.7% (P < .0001), through augmented proteasome degradation and reduced prenylation of heterotrimeric G-proteins in 33% of tumor cell lines evaluated. In OS-bearing dogs, zoledronate reduces CXCR4 expressions by 40% within the primary tumor compared to untreated controls (P = .03) and also decreases the circulating concentrations of CXCR4 in 18 of 20 dogs with OS. Zoledronate can alter CXCR4 expression and functionality in OS cells, and consequent perturbations in CXCR4 intracellular signaling cascades might influence patterns of metastases. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  4. Bisphosphonates for osteoporosis in primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Rudic, Jelena; Giljaca, Vanja; Krstic, Miodrag N

    2011-01-01

    Bisphosphonates are widely used for treatment of postmenopausal osteoporosis. Patients with primary biliary cirrhosis often have osteoporosis - either postmenopausal or secondary to the liver disease. No systematic review or meta-analysis has assessed the effects of bisphosphonates for osteoporosis...

  5. Bisphosphonate adverse effects, lessons from large databases

    DEFF Research Database (Denmark)

    Abrahamsen, Bo

    2010-01-01

    To review the latest findings on bisphosphonate safety from health databases, in particular sources that can provide incidence rates for stress fractures, osteonecrosis of the jaw (ONJ), atrial fibrillation and gastrointestinal lesions including esophageal cancer. The main focus is on bisphosphon...

  6. Atypical fractures on long term bisphosphonates therapy.

    LENUS (Irish Health Repository)

    Hussein, W

    2011-01-01

    Bisphosphonates reduce fractures risk in patients with osteoporosis. A new pattern of fractures is now being noted in patients on prolonged bisphosphonate therapy. We report a case of an atypical femoral fracture with preceding pain and highlight the characteristics of these fractures.

  7. EFFECTIVENESS OF NITROGEN-CONTAINING BISPHOSPHONATES IN THE REGULATION OF MINERAL METABOLISM DISTURBANCES ASSOCIATED WITH ALIMENTARY OSTEOPOROSIS IN RATS

    Directory of Open Access Journals (Sweden)

    Komisarenko S. V.

    2015-08-01

    Full Text Available The aim of the study was to investigate the effectiveness of nitrogen-containing bisphosphonates synthesized as promising substances for correction of mineral metabolism in osteoporosis. The study was carried out on a model of alimentary osteoporosis that was characterized by hypocalcaemia, hypophosphatemia, decreased 25-Hydroxyvitamin D3 content in blood serum and severe bone tissue demineralization (reduced ash content and mineral components. It was found that synthesized novel nitrogen bisphosphonates (pyrazole-containing analogues, like reference drugs — metylene bisphosphonate (disodium salt of metylene bisphosphonic acid and alendronate (4-amino-1-hidroxybutyliden bisphosphonate, inhibit with the different efficiency demineralization of the bone tissue and increase the mineral metabolism in rats with alimentary (nutritional osteoporosis that was assessed by the marker parameters of bone formation. In particular, drug administration (bisphosphonates І-12, І-40, І-42 resulted in elevation of calcium and phosphate levels and decreased the total activity of alkaline phosphatase and its isoenzymes in blood serum. The ash content and the levels of calcium and phosphorus in the ash of tibia and femur bones were shown to be markedly elevated. Bisphosphonate І-12 has shown more profound antiresorbtive activity and ability to correct mineral metabolism in alimentary osteoporosis, including such of reference drugs. It was found a significant decrease of 25-Hydroxyvitamin D3 content in the serum that is considered as a profound vitamin D3 deficiency associated with nutritional osteoporosis. As it was not compensated by bisphosphonates, we suggest that further investigations should be directed to the combined use of both: bisphosphonates as inhibitors of osteoclast activity that diminish bone resorption and vitamin D3 as a key regulator of bone remodeling process and osteosynthesis activator.

  8. Efeito do ácido zoledrônico em tíbias de ratas ooforectomizadas: estudo prospectivo e randomizado Effects of zoledronic acid on ooforectomized rats' tibiae: a prospective and randomized study

    Directory of Open Access Journals (Sweden)

    Fernando Roberto Alves Pereira

    2009-02-01

    Full Text Available OBJETIVO: Investigar as repercussões clínicas, biomecânicas e histomorfométricas do ácido zoledrônico em tíbias de ratas osteoporóticas, após ooforectomia bilateral. MÉTODOS: Foram estudadas, prospectivamente, 40 ratas da linhagem Wistar (Rattus novergicus albinus. Com 60 dias de vida, os animais foram aleatorizados em dois grupos de acordo com o procedimento cirúrgico: ooforectomia bilateral (O (n=20 e pseudo-cirurgia ("sham" (P (n=20. Após 30 dias, os animais foram divididos em quatro subgrupos, de acordo com a administração de 0,1mg/kg de ácido zoledrônico (AZ ou água destilada (AD: OAZ (n=10, OAD (n=10, PAZ (n=10 e PAD (n=10. Após 12 meses, os animais foram eutanasiados e suas tíbias analisadas. No estudo clínico foi considerado o peso dos animais; no estudo biomecânico foram realizados ensaios compressivos e na análise histomorfométrica foi determinada a área trabecular óssea. RESULTADOS: Os grupos "O" tiveram aumento de peso significativamente maior que os grupos "P" (p=0,005. Os grupos OAZ e PAZ tiveram aumento, não significativo, de peso quando comparados aos grupos OAD (p=0,47 e PAD (p=0,68. Os grupos com ácido zoledrônico e com água destilada suportaram carga máxima, semelhante (p=0,2, no momento em que ocorreu fratura. Nos grupos com ácido zoledrônico verificou-se o aumento não significante da área trabecular óssea quando comparados aos grupos com água destilada (p=0,21. Houve correlação positiva entre a área trabecular e a carga máxima (p=0,04; r=0,95. CONCLUSÃO: O ácido zoledrônico não influiu significativamente no peso dos animais. Os resultados mostraram aumento, não significante, tanto da resistência óssea diafisária tibial, como da área trabecular óssea.OBJECTIVE: To investigate clinical, biomechanic and histomorphometric effects of zoledronic acid on osteoporotic rats'tibiae after bilateral ooforectomy. METHODS: 40 female Wistar (Rattus novergicus albinus rats were prospectively

  9. Relative binding affinity of carboxylate-, phosphonate-, and bisphosphonate-functionalized gold nanoparticles targeted to damaged bone tissue

    Energy Technology Data Exchange (ETDEWEB)

    Ross, Ryan D. [Rush University Medical Center, Department of Anatomy and Cell Biology (United States); Cole, Lisa E.; Roeder, Ryan K., E-mail: rroeder@nd.edu [University of Notre Dame, Department of Aerospace and Mechanical Engineering Bioengineering Graduate Program (United States)

    2012-10-15

    Functionalized Au NPs have received considerable recent interest for targeting and labeling cells and tissues. Damaged bone tissue can be targeted by functionalizing Au NPs with molecules exhibiting affinity for calcium. Therefore, the relative binding affinity of Au NPs surface functionalized with either carboxylate (l-glutamic acid), phosphonate (2-aminoethylphosphonic acid), or bisphosphonate (alendronate) was investigated for targeted labeling of damaged bone tissue in vitro. Targeted labeling of damaged bone tissue was qualitatively verified by visual observation and backscattered electron microscopy, and quantitatively measured by the surface density of Au NPs using field-emission scanning electron microscopy. The surface density of functionalized Au NPs was significantly greater within damaged tissue compared to undamaged tissue for each functional group. Bisphosphonate-functionalized Au NPs exhibited a greater surface density labeling damaged tissue compared to glutamic acid- and phosphonic acid-functionalized Au NPs, which was consistent with the results of previous work comparing the binding affinity of the same functionalized Au NPs to synthetic hydroxyapatite crystals. Targeted labeling was enabled not only by the functional groups but also by the colloidal stability in solution. Functionalized Au NPs were stabilized by the presence of the functional groups, and were shown to remain well dispersed in ionic (phosphate buffered saline) and serum (fetal bovine serum) solutions for up to 1 week. Therefore, the results of this study suggest that bisphosphonate-functionalized Au NPs have potential for targeted delivery to damaged bone tissue in vitro and provide motivation for in vivo investigation.

  10. BISPHOSPHONATE INDUCED STRESS FRACTURE OF BILATERAL FEMUR: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Saidapur

    2015-08-01

    Full Text Available Osteoporosis is a common problem affecting people after 4 - 5 decade of life. There are various treatment options available for Osteoporosis and Bisphosphonates are widely used. Bisphosphonates work by blocking osteoclast mediated bone resorption and can be given in oral and injectable forms. R ecent studies have brought to light the risk of sub trochanteric stress fracture secondary to bisphosphonate therapy. Here we are presenting a case with bilateral sub trochanteric fracture following prolonged bisphosphonate therapy

  11. Bisphosphonate adverse effects, lessons from large databases

    DEFF Research Database (Denmark)

    Abrahamsen, Bo

    2010-01-01

    is on bisphosphonates used for osteoporosis. RECENT FINDINGS: Register studies have so far not confirmed a shift from classical to nonclassical femur fractures with bisphosphonates. However, studies were either small or without X-ray adjudication. Two new studies found no increase in jaw surgery for inflammatory...

  12. Are long-term bisphosphonate users a reality?

    DEFF Research Database (Denmark)

    Abrahamsen, B

    2012-01-01

    The prevalence of long-term bisphosphonate use may be low due to low refill compliance and gaps in treatment. An analysis of the prescription history of 58,674 bisphosphonate users in Denmark found that only 2.8 % had received ten dose years of treatment or above. INTRODUCTION: This study aims...... to describe the demographics of present bisphosphonate (BP) users, to determine the prevalence of long-term BP use, and to establish if long-term use (a 10-year history of osteoporosis treatment) translated to ten dose years of bisphosphonate prescriptions filled, given the propensity for treatment gaps...... more than ten dose years of a BP. For any osteoporosis drug, 3.0 % had received ten dose years or more, while 23.2 % had received between 5 and 10 years of treatment. CONCLUSION: Long-term users with ten dose years or more of a BP are rare due to periods of low compliance and gaps, with a discrepancy...

  13. The dental implications of bisphosphonates and bone disease.

    Science.gov (United States)

    Cheng, A; Mavrokokki, A; Carter, G; Stein, B; Fazzalari, N L; Wilson, D F; Goss, A N

    2005-12-01

    In 2002/2003 a number of patients presented to the South Australian Oral and Maxillofacial Surgery Unit with unusual non-healing extraction wounds of the jaws. All were middle-aged to elderly, medically compromised and on bisphosphonates for bone pathology. Review of the literature showed similar cases being reported in the North American oral and maxillofacial surgery literature. This paper reviews the role of bisphosphonates in the management of bone disease. There were 2.3 million prescriptions for bisphosphonates in Australia in 2003. This group of drugs is very useful in controlling bone pain and preventing pathologic fractures. However, in a small number of patients on bisphosphonates, intractable, painful, non-healing exposed bone occurs following dental extractions or denture irritation. Affected patients are usually, but not always, over 55 years, medically compromised and on the potent nitrogen containing bisphosphonates pamidronate (Aredia/Pamisol), alendronate (Fosamax) and zolendronate (Zometa) for non-osteoporotic bone disease. Currently, there is no simple, effective treatment and the painful exposed bone may persist for years. The main complications are marked weight loss from difficulty in eating and severe jaw and neck infections. Possible preventive and therapeutic strategies are presented although at this time there is no evidence of their effectiveness. Dentists must ask about bisphosphonate usage for bone disease when recording medical histories and take appropriate actions to avoid the development of this debilitating condition in their patients.

  14. Technetium-99 conjugated with methylene diphosphonate ameliorates ovariectomy-induced osteoporotic phenotype without causing osteonecrosis in the jaw.

    Science.gov (United States)

    Zhao, Yinghua; Wang, Lei; Liu, Yi; Akiyama, Kentaro; Chen, Chider; Atsuta, Ikiru; Zhou, Tao; Duan, Xiaohong; Jin, Yan; Shi, Songtao

    2012-12-01

    Technetium-99 conjugated with methylene diphosphonate ((99)Tc-MDP) is a novel bisphosphonate derivative without radioactivity and has been successfully used to treat arthritis in China for years. Since bisphosphonate therapy has the potential to induce bisphosphonate-related osteonecrosis of the jaw (BRONJ), we examined whether (99)Tc-MDP represents a new class of bisphosphonate for antiresorptive therapy to ameliorate estrogen deficiency-induced bone resorption with less risk of causing BRONJ. We showed that (99)Tc-MDP-treated, ovariectomized (OVX) mice had significantly improved bone mineral density and trabecular bone volume in comparison to the untreated OVX group by inhibiting osteoclasts and enhancing osteogenic differentiation of bone marrow mesenchymal stem cells. To determine the potential of inducing BRONJ, (99)Tc-MDP/dexamethasone (Dex) or zoledronate/Dex was administered into C57BL/6J mice via the tail vein, followed by extraction of maxillary first molars. Interestingly, (99)Tc-MDP treatment showed less risk to induce osteonecrosis in the maxillary bones compared to zoledronate treatment group, partially because (99)Tc-MDP neither suppressed adaptive regulatory T cells nor activated the inflammatory T-helper-producing interleukin-17 cells. Taken together, our findings demonstrate that (99)Tc-MDP therapy may be a promising approach in the treatment of osteoporosis with less risk of causing BRONJ.

  15. [gammadelta T cells stimulated by zoledronate kill osteosarcoma cells].

    Science.gov (United States)

    Jiang, Hui; Xu, Qiang; Yang, Chao; Cao, Zhen-Guo; Li, Zhao-Xu; Ye, Zhao-Ming

    2010-12-01

    To investigate the cytotoxicity of human γδT cells from PBMCs stimulated by zoledronate against osteosarcoma cell line HOS in vitro and in vivo and evaluate the relavent pathways. The peripheral blood mononuclear cells (PBMCs)of healthy donors were stimulated by single dose zoledronate and cultured in the present of IL-2 for two weeks, analysising the percentage of γδT cells on a FACSCalibur cytometer.Study the cytotoxicity of γδT cells against the osteosarcoma line HOS using LDH release assay kit. Pre-treatment of γδT cells with anti-human γδTCR antibody, anti-human NKG2D antibody and concanamycin A to bolck the relavent pathways for evaluating the mechenisms of its cytotoxicity. In vivo, BALB/c mice were inoculated subcutaneously osteosarcoma cell HOS for developing hypodermal tumors. And they were randomized into two groups: unteated group, γδT cell therapy group. Tumor volume and weight of the two groups were compared. After two weeks of culture, γδT cells from zoledronate-stimulated PBMCs could reach (95±3)%. When the E:T as 6:1, 12:1, 25:1, 50:1, the percentage of osteosarcoma cell HOS killed by γδT cells was 26.8%, 31.5%, 37.8%, 40.9%, respectively.When anti-huma γδTCR antibody, anti-human NKG2D antibody and concanamycin A blocked the relavent pathways, the percentage was 32.3%, 4.7%, 16.7% ( E:T as 25:1), respectively. In vivo, the tumor inhibition rate of the group of γδT cell therapy was 42.78%. γδT cells derived from PBMCs stimulated by zoledronate can acquired pure γδT cells. And they show strong cytoxicity against osteosarcoma cell line HOS in vitro and in vivo.

  16. Bisphosphonates and oral pathology II. Osteonecrosis of the jaws: review of the literature before 2005.

    Science.gov (United States)

    Estefanía Fresco, Ruth; Ponte Fernández, Ruth; Aguirre Urizar, José Manuel

    2006-11-01

    Bisphosphonates are bone-turnover modulating drugs which are used in the management of a number of bone diseases ranging from osteoporosis to neoplasic pathology-associated osteolysis. In the last years a number of cases of osteonecrosis of the jaws associated with these drugs have been reported. In this review we analyze the cases published in the literature indexed from 2003 to December 2005. During this period 246 cases were reported, being more frequently associated with women in the sixth decade of life. More frequently associated bisphosphonates were the nitrogenated bisphosphonates (pamidronate, zolendronic acid) and the most common oral antecedent was a dental extraction. Nevertheless more than 25% of the cases were spontaneous. The most frequent site was the mandible and most of the cases presented clinical evidence of bone exposure and pain. Different treatments have been proposed with different antibiotic therapies with or without surgery, showing in general terms an uncertain prognosis with low healing rates.

  17. Design and methods for a Scandinavian pharmacovigilance study of osteonecrosis of the jaw and serious infections among cancer patients treated with antiresorptive agents for the prevention of skeletal-related events

    DEFF Research Database (Denmark)

    Acquavella, John; Ehrenstein, Vera; Schiødt, Morten

    2016-01-01

    OBJECTIVE: Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authoriza......OBJECTIVE: Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post...... (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function). Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Followup will extend from the first administration of antiresorptive treatment...... to the earliest of death, loss-to-follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naïve patients, zoledronic acid-naïve patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly...

  18. Use of bis phosphonates in prostate cancer

    International Nuclear Information System (INIS)

    Della Valle, A.

    2004-01-01

    Prostate cancer is the second leading cause of cancer death in men in the world, meaning a real public health problem. The prevalence of Bone metastases may reach 100% of those who die from this disease printing a serious decline in the quality of life especially in the occurrence of skeletal-related events. Since three decades we try to find an inhibitor bone resorption which might prevent or treat bone metastases develop bisphosphonates (BF). These can not only inhibit the recruitment and differentiation osteoclast but decrease its half-life leading to early apoptosis. All BF have similar physicochemical properties and pharmacokinetics, but they differ in their anti-resorptive potency, ibandronate and zoledronic acid are BF generation that have been successful in the treatment of pain and decreased bone events in several works, however only one study randomized was conducted to show significant therapeutic advantages bone metastasis of prostate cancer. Although most authors indicate a therapeutic benefit, the evidence is weak and higher costs. Urges the implementation of new studies assessing both ibandronate and zoledronic acid in order to assert its virtues

  19. The “CROMa” Project: A Care Pathway for Clinical Management of Patients with Bisphosphonate Exposure

    Directory of Open Access Journals (Sweden)

    Mauro Capocci

    2014-01-01

    Full Text Available Aim. To describe 7 years of activity of “CROMa” (Coordination of Research on Osteonecrosis of the Jaws project of “Sapienza” University of Rome. Materials and Methods. A preventive and therapeutic care pathway was created for patients with bisphosphonates (BPs exposure. Demographic, social, behavioural, pharmacological, and clinical variables were registered in a dedicated database. Results. In the project, 502 patients, 403 females and 99 males, were observed. Bone pathologies were 79% osteometabolic diseases (OMD and 21% metastatic cancer (CA. Females were 90% in OMD group and 41% in CA. BP administration was 54% oral, 31% IV, and 11% IM; 89% of BPs were amino-BP and 11% non-amino-BP. Consistently with bone pathology (OMD/CA, alendronate appears to be prevalent for OMD (40% relative, while zoledronate was indicated in 92% of CA patients. Out of 502 cases collected, 28 BRONJ were detected: 17 of them were related to IV BP treatment. Preventive oral assessment was required for 50% of CA patients and by 4% of OMD patients. Conclusions. The proposed care pathway protocols for BP exposed patients appeared to be useful to meet treatment and preventive needs, in both oncological and osteometabolic diseases patients. Patients’ and physicians’ prevention awareness can be the starting point of a multilevel prevention system.

  20. Toxicity of a dental adhesive compared with ionizing radiation and zoledronic acid.

    Science.gov (United States)

    Alcaraz, Miguel; Olivares, Amparo; Achel, Daniel-Giyngiri; García-Cruz, Emilio; Fondevilla-Soler, Adriana; Canteras-Jordana, Manuel

    2015-07-01

    To determine the toxicity of aqueous dilutions of a universal self-priming dental adhesive (DA) and comparing these with those elicited by exposure to ionizing radiation (IR), Zoledronic acid (Z) treatment and the synergic effects of the combined treatment with IR+Z. The genotoxic effect of DA was determined by the increase in the frequency of micronuclei in cytokinesis-blocked in cultured human lymphocytes before and after exposure to 2Gy of X-rays. The cytotoxic effect was studied by using the MTT cell viability test in normal prostate cell lines (PNT2) after exposure to different X-ray doses (0Gy-20Gy). The cell lines divided into different groups and treated with different test substances: DA in presence of O2, DA in absence of O2, Z-treated and control. An in vitro dose-dependent and time-dependent cytotoxic effect of DA, Z and IR on PNT2 cells (p>0.001) was demonstrated. DA without-O2, following the recommendations of manufacturers, had a more pronounced effect of increasing cell death than DA with-O2 (p<0.001). In the genotoxicity assay, DA at 25% of its original concentration significantly increased chromosome damage (p<0.001). The samples studied were found to be toxic, and the samples photo-polymerized in absence of O2 showed a bigger cytotoxic effect comparable to the additive toxic effect showed by the combined treatment of IR+Z. Additional effort should be carried out to develop adhesives, which would reduce the release of hazardous substances; since toxic effects are similar to that reported by other agents whose clinical use is controlled by the health authorities.

  1. Inflammatory eye reactions with bisphosphonates and other osteoporosis medications

    DEFF Research Database (Denmark)

    Clark, Emma M; Durup, Darshana

    2015-01-01

    Inflammatory eye reactions (IERs) are rare but have been associated with medications to treat osteoporosis. The aim of this review is to summarize the current literature on the association between IERs and specific medications to treat osteoporosis (bisphosphonates, selective estrogen receptor...... of the information available is from spontaneous case reports and case series reporting associations between bisphosphonates and IERs. No case reports describe IERs after other anti-osteoporosis medications. Importantly, some case reports describe recurrence of the IER after affected patients were rechallenged...... with the same or another bisphosphonate, and that no reported cases resolved without discontinuation of the bisphosphonate. However, three large population-based cohort studies have shown conflicting results between osteoporosis treatments and IERs, but overall these studies suggest that IERs may actually...

  2. Bisphosphonate-Related Osteonecrosis of the Jaws. A Severe Side Effect of Bisphosphonate Therapy

    Directory of Open Access Journals (Sweden)

    Zuzana Janovská

    2012-01-01

    Full Text Available Bisphosphonates (BP are potent inhibitors of bone resorption used mainly in the treatment of metastatic bone disease and osteoporosis. By inhibiting bone resorption, they prevent complications as pathological fracture, pain, tumor-induced hypercalcemia. Even though patient’s benefit of BP therapy is huge, various side effects may develop. Bisphosphonate-related osteonecrosis of the jaws (BRONJ is among the most serious ones. Oncologic patients receiving high doses of BP intravenously are at high risk of BRONJ development. BPs impair bone turnover leading to compromised bone healing which may result in the exposure of necrotic bone in the oral cavity frequently following tooth extraction or trauma of the oral mucosa. Frank bone exposure may be complicated by secondary infection leading to osteomyelitis development with various symptoms and radiological findings. In the management of BRONJ, conservative therapy aiming to reduce the symptoms plays the main role. In patients with extensive bone involvement resective surgery may lead to complete recovery, provided that the procedure is correctly indicated. Since the treatment of BRONJ is difficult, prevention is the main goal. Therefore in high risk patients dental preventive measures should be taken prior to bisphosphonate administration. This requires adequate communication between the prescribing physician, the patient and the dentist.

  3. Bisphosphonate Treatment and Pregnancy

    Science.gov (United States)

    ... rats given bisphosphonates during pregnancy developed calcium deficiency (hypocalcemia), which led to abnormal bone development, and also slow, difficult labor and delivery. Effects related to low calcium are not expected in ...

  4. The bisphosphonates: risks and benefits of long term use

    DEFF Research Database (Denmark)

    Hermann, Anne Pernille; Abrahamsen, Bo

    2013-01-01

    Bisphosphonates are widely used globally as the main treatment for osteoporosis. Both safety and efficacy have only been rigorously evaluated in studies of relatively short duration (3-5 years), with smaller extension studies. The evidence for benefit beyond five years in intervention studies...... is limited and does not include proven efficacy against nonvertebral fractures. Observational studies suggest a sustained benefit against hip fractures. Bisphosphonates are stored in the skeleton for months to years, depending on the degree of bone turnover and the binding properties of the bisphosphonate...

  5. Characteristics of patients initiating raloxifene compared to those initiating bisphosphonates

    Directory of Open Access Journals (Sweden)

    Wang Sara

    2008-12-01

    Full Text Available Abstract Background Both raloxifene and bisphosphonates are indicated for the prevention and treatment of postmenopausal osteoporosis, however these medications have different efficacy and safety profiles. It is plausible that physicians would prescribe these agents to optimize the benefit/risk profile for individual patients. The objective of this study was to compare demographic and clinical characteristics of patients initiating raloxifene with those of patients initiating bisphosphonates for the prevention and treatment of osteoporosis. Methods This study was conducted using a retrospective cohort design. Female beneficiaries (45 years and older with at least one claim for raloxifene or a bisphosphonate in 2003 through 2005 and continuous enrollment in the previous 12 months and subsequent 6 months were identified using a collection of large national commercial, Medicare supplemental, and Medicaid administrative claims databases (MarketScan®. Patients were divided into two cohorts, a combined commercial/Medicare cohort and a Medicaid cohort. Within each cohort, characteristics (demographic, clinical, and resource utilization of patients initiating raloxifene were compared to those of patients initiating bisphosphonate therapy. Group comparisons were made using chi-square tests for proportions of categorical measures and Wilcoxon rank-sum tests for continuous variables. Logistic regression was used to simultaneously examine factors independently associated with initiation of raloxifene versus a bisphosphonate. Results Within both the commercial/Medicare and Medicaid cohorts, raloxifene patients were younger, had fewer comorbid conditions, and fewer pre-existing fractures than bisphosphonate patients. Raloxifene patients in both cohorts were less likely to have had a bone mineral density (BMD screening in the previous year than were bisphosphonate patients, and were also more likely to have used estrogen or estrogen/progestin therapy in the

  6. Determinants of change in bone mineral density and fracture risk during bisphosphonate holiday.

    Science.gov (United States)

    Xu, L H R; Adams-Huet, B; Poindexter, J R; Maalouf, N M

    2016-05-01

    In a retrospective analysis of 208 osteoporotic patients followed during a bisphosphonate holiday, lower body weight and risedronate use were associated with a more rapid decline in bone mineral density during the bisphosphonate holiday, while bone mineral density (BMD) trends were similar in patients who sustained vs. did not sustain a fracture. A drug holiday has been suggested for some bisphosphonate-treated patients with osteoporosis to minimize potential side effects from prolonged use. However, there is limited information on the evolution of BMD during a bisphosphonate holiday. Our study analyzed the longitudinal course of BMD following bisphosphonate discontinuation and assessed its determinants. Retrospective single-center cohort study of osteoporosis patients treated with alendronate or risedronate for at least 2 years and then discontinued their bisphosphonate for a drug holiday. Patients were stratified by bisphosphonate type and by fracture occurrence during drug holiday. A total of 208 patients were included in this analysis (87.5 % female). At the time of bisphosphonate cessation, mean ± SD age was 66.9 ± 8.9 years and BMI 24.5 ± 4.4 kg/m(2). Duration of bisphosphonate treatment was 5.2 ± 2.3 years, and follow-up during holiday was 3.3 ± 1.7 years. During the first 2 years of the holiday, BMD remained stable at the lumbar spine and femoral neck, but declined significantly at the total hip. BMD declined significantly at all sites thereafter. Significant predictors of BMD decline during bisphosphonate holiday included lower BMI at the start of the holiday and change in body weight during the holiday. BMD decline was more pronounced in former risedronate compared to former alendronate users. BMD trends were similar in patients who sustained vs. did not sustain a fracture during the holiday. BMD at the total hip declines significantly within 1 year of bisphosphonate discontinuation, particularly in lean patients

  7. Long-term radiographic follow-up of bisphosphonate-associated atypical femur fractures

    Energy Technology Data Exchange (ETDEWEB)

    Favinger, Jennifer L. [University of Washington, Department of Radiology, 1959 N.E. Pacific Street, Box 357115, Seattle, WA (United States); Hippe, Daniel [University of Washington, Department of Radiology, Seattle, WA (United States); Ha, Alice S. [University of Washington, Department of Radiology, 4245 Roosevelt Way NE, Box 354755, Seattle, WA (United States)

    2016-05-15

    To evaluate the appearance of bisphosphonate-related femur insufficiency fractures on long-term follow-up radiographic studies and to describe the rate of fracture line obscuration and cortical beak healing over time. In this retrospective study, bisphosphonate-related femur fracture radiographs were reviewed by two radiologists for the presence of a fracture line, callus, and the characteristic cortical beak. Kaplan-Meier curves were used to analyze the time to first indication of healing. Femurs were also subdivided into those who underwent early versus late surgical fixation and those who underwent early versus late discontinuation of bisphosphonate. Clinical data including pain level and medication history were collected. Forty-seven femurs with a bisphosphonate-related femur fracture were identified in 28 women. Eighty-five percent took a bisphosphonate for greater than 5 years and 59 % for greater than 10 years. The median time to beak healing was 265 weeks and the median time to fracture line healing was 56 weeks in the 31 femurs with a baseline fracture. No statistically significant difference was identified between surgical fixation and conservative management. Bisphosphonate-related fractures demonstrate notably prolonged healing time on long-term follow-up. (orig.)

  8. Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent

    International Nuclear Information System (INIS)

    Ogawa, Kazuma; Takai, Kenichiro; Kanbara, Hiroya; Kiwada, Tatsuto; Kitamura, Yoji; Shiba, Kazuhiro; Odani, Akira

    2011-01-01

    Introduction: 68 Ga is a radionuclide of great interest as a positron emitter for positron emission tomography (PET). To develop a new bone-imaging agent with radiogallium, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as a chelating site and Ga-DOTA complex-conjugated bisphosphonate, which has a high affinity for bone, was prepared and evaluated. Although we are interested in developing 68 Ga-labeled bone imaging agents for PET, in these initial studies 67 Ga was used because of its longer half-life. Methods: DOTA-conjugated bisphosphonate (DOTA-Bn-SCN-HBP) was synthesized by conjugation of 2-(4-isothiocyanatebenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). 67 Ga-DOTA-Bn-SCN-HBP was prepared by coordination with 67 Ga, and its in vitro and in vivo evaluations were performed. Results: 67 Ga-DOTA-Bn-SCN-HBP was prepared with a radiochemical purity of over 95% without purification. 67 Ga-DOTA-Bn-SCN-HBP had great affinity for hydroxyapatite in binding assay. In biodistribution experiments, 67 Ga-DOTA-Bn-SCN-HBP accumulated in bone rapidly but was hardly observed in tissues other than bone. Pretreatment of an excess amount of alendronate inhibited the bone accumulation of 67 Ga-DOTA-Bn-SCN-HBP. Conclusions: 67 Ga-DOTA-Bn-SCN-HBP showed ideal biodistribution characteristics as a bone-imaging agent. These findings should provide useful information on the drug design of bone imaging agents for PET with 68 Ga.

  9. Maintaining bone health in prostate cancer throughout the disease continuum.

    Science.gov (United States)

    Saad, Fred; Eastham, James

    2010-06-01

    Prostate cancer (PC) is the most prevalent malignancy in men, with 604,506 new cases diagnosed yearly worldwide. Maintaining bone health is important during all stages of PC, including patients who experience bone loss from androgen-deprivation therapy and patients who develop bone metastases. Patients with bone metastases often experience severe bone pain and are at increased risk for potentially debilitating skeletal-related events. Bisphosphonates are a well-established treatment option for patients with bone metastases from solid tumors and bone lesions from multiple myeloma. Zoledronic acid (ZOL) is the only bisphosphonate (BP) that has been extensively studied in patients with castration-recurrent PC and is indicated for treating patients with bone metastases from PC in conjunction with standard antineoplastic therapy. This review will examine the breadth of evidence supporting a role for ZOL and emerging therapies in managing patients with PC throughout the disease continuum. 2010 Elsevier Inc. All rights reserved.

  10. Atrial fibrillation in fracture patients treated with oral bisphosphonates

    DEFF Research Database (Denmark)

    Abrahamsen, B; Eiken, P; Brixen, K

    2009-01-01

    OBJECTIVES: To determine if patients receiving oral bisphosphonates are at excess risk of atrial fibrillation (AF), stroke and myocardial infarction. DESIGN: Register-based restricted cohort study. SETTING: National Hospital Discharge Register and National Prescriptions Database (1995-2005). SUBJ......OBJECTIVES: To determine if patients receiving oral bisphosphonates are at excess risk of atrial fibrillation (AF), stroke and myocardial infarction. DESIGN: Register-based restricted cohort study. SETTING: National Hospital Discharge Register and National Prescriptions Database (1995...... to adherence. There was no increased risk of ischaemic stroke and an increased risk of myocardial infarction was not significant after adjustment for comorbidity. CONCLUSIONS: The increased occurrence of AF in fracture patients who are users of oral bisphosphonates should be attributed to targeting...

  11. BISPHOSPHONATES IN LANGERHANS CELL HISTIOCYTOSIS: AN INTERNATIONAL RETROSPECTIVE CASE SERIES

    Directory of Open Access Journals (Sweden)

    Deepak Chellapandian

    2016-07-01

    Full Text Available Background: Bone is the most common organ of involvement in patients with Langerhans cell histiocytosis (LCH, which is often painful and associated with significant morbidity from pathological fractures. Current first-line treatments include chemotherapy and steroids that are effective but often associated with adverse effects, whereas the disease may reactivate despite an initial response to first-line agents. Bisphosphonates are osteoclast inhibitors that have shown to be helpful in treating bone lesions of LCH. To date, there are no large international studies to describe their role in treating bone lesions of LCH. Method: We conducted a multicenter retrospective review of 13 patients with histologically proven LCH, who had received bisphosphonates either at diagnosis or at disease reactivation. Results: Ten patients (77% had a single system bone disease, and 3 (23% had bone lesions as part of multisystem disease. Median follow-up time post-bisphosphonate therapy was 4.6 years (range, 0.8 to 8.2 years. Treatment with bisphosphonates was associated with significant pain relief in almost all patients. Twelve  (92% achieved resolution of active bone lesions, and 10 out of them had no active disease for a median of 3.5 years (range, 0.8 to 5 years. One patient did not respond. No major adverse effects were reported in this series.  Conclusion: Bisphosphonates are well-tolerated drugs that can significantly improve bone pain and induce remission in active bone LCH. Future prospective studies evaluating the role of bisphosphonates in LCH are warranted.

  12. Atypical Femur Fractures in Patients Treated with Bisphosphonates: Identification, Management, and Prevention

    Directory of Open Access Journals (Sweden)

    Judith Sarah Bubbear

    2016-10-01

    Full Text Available Osteoporosis is a common condition with significant health care costs. First-line therapy is with bisphosphonates, which have proven anti-fracture efficacy. Around 10 years after the introduction of bisphosphonates reports began to be published of atypical femoral fractures (AFFs that may be associated with this therapy. These fractures are associated with significant morbidity although lower mortality than the more common osteoporotic neck-of-femur fractures. A case definition has been described to allow identification of this class of fracture. Further work has established a high relative risk of AFFs in patients treated with bisphosphonates, but a low absolute risk in comparison to that of osteoporotic fractures. Proposed pathological mechanisms include low bone turnover states leading to stress/insufficiency fractures. Clinicians should be aware of the risk of AFFs and in particular the high rate of prodromal thigh/groin pain that warrants investigation in a patient receiving a bisphosphonate. If an incomplete fracture is diagnosed then bisphosphonate therapy needs to be stopped and prophylactic surgery may be considered. Due to these rare side effects patients on bisphosphonates require regular review, and this is particularly advised after 5 years of oral or 3 years of intravenous therapy.

  13. Exploring methods for comparing the real-world effectiveness of treatments for osteoporosis: adjusted direct comparisons versus using patients as their own control.

    Science.gov (United States)

    Karlsson, Linda; Mesterton, Johan; Tepie, Maurille Feudjo; Intorcia, Michele; Overbeek, Jetty; Ström, Oskar

    2017-09-21

    Using Swedish and Dutch registry data for women initiating bisphosphonates, we evaluated two methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for differences in patient baseline characteristics. Each method has advantages and disadvantages; both are potential complements to clinical trial analyses. We evaluated methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for both observed and unobserved confounding. Swedish and Dutch registry data for women initiating zoledronate or oral bisphosphonates (OBPs; alendronate/risedronate) were used; the primary outcome was fracture. In adjusted direct comparisons (ADCs), regression and matching techniques were used to account for baseline differences in known risk factors for fracture (e.g., age, previous fracture, comorbidities). In an own-control analysis (OCA), for each treatment, fracture incidence in the first 90 days following treatment initiation (the baseline risk period) was compared with fracture incidence in the 1-year period starting 91 days after treatment initiation (the treatment exposure period). In total, 1196 and 149 women initiating zoledronate and 14,764 and 25,058 initiating OBPs were eligible in the Swedish and Dutch registries, respectively. Owing to the small Dutch zoledronate sample, only the Swedish data were used to compare fracture incidences between treatment groups. ADCs showed a numerically higher fracture incidence in the zoledronate than in the OBPs group (hazard ratio 1.09-1.21; not statistically significant, p > 0.05). For both treatment groups, OCA showed a higher fracture incidence in the baseline risk period than in the treatment exposure period, indicating a treatment effect. OCA showed a similar or greater effect in the zoledronate group compared with the OBPs group. ADC and OCA each possesses advantages and disadvantages. Combining both methods may provide an estimate of real

  14. Bisphosphonates and osteonecrosis of jaws

    Directory of Open Access Journals (Sweden)

    Geetha Vijay

    2012-01-01

    The purpose of the present article is to enlighten the dental fraternity about this frequently prescribed class of drugs with regard to its types and mode of action, and the implication of bisphosphonates-induced ONJ.

  15. Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Kazuma, E-mail: kogawa@p.kanazawa-u.ac.jp [Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192 (Japan); Takai, Kenichiro; Kanbara, Hiroya; Kiwada, Tatsuto [Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192 (Japan); Kitamura, Yoji; Shiba, Kazuhiro [Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640 (Japan); Odani, Akira [Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192 (Japan)

    2011-07-15

    Introduction: {sup 68}Ga is a radionuclide of great interest as a positron emitter for positron emission tomography (PET). To develop a new bone-imaging agent with radiogallium, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as a chelating site and Ga-DOTA complex-conjugated bisphosphonate, which has a high affinity for bone, was prepared and evaluated. Although we are interested in developing {sup 68}Ga-labeled bone imaging agents for PET, in these initial studies {sup 67}Ga was used because of its longer half-life. Methods: DOTA-conjugated bisphosphonate (DOTA-Bn-SCN-HBP) was synthesized by conjugation of 2-(4-isothiocyanatebenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). {sup 67}Ga-DOTA-Bn-SCN-HBP was prepared by coordination with {sup 67}Ga, and its in vitro and in vivo evaluations were performed. Results: {sup 67}Ga-DOTA-Bn-SCN-HBP was prepared with a radiochemical purity of over 95% without purification. {sup 67}Ga-DOTA-Bn-SCN-HBP had great affinity for hydroxyapatite in binding assay. In biodistribution experiments, {sup 67}Ga-DOTA-Bn-SCN-HBP accumulated in bone rapidly but was hardly observed in tissues other than bone. Pretreatment of an excess amount of alendronate inhibited the bone accumulation of {sup 67}Ga-DOTA-Bn-SCN-HBP. Conclusions: {sup 67}Ga-DOTA-Bn-SCN-HBP showed ideal biodistribution characteristics as a bone-imaging agent. These findings should provide useful information on the drug design of bone imaging agents for PET with {sup 68}Ga.

  16. Use of bisphosphonate therapy for osteoporosis in childhood and adolescence.

    Science.gov (United States)

    Batch, J A; Couper, J J; Rodda, C; Cowell, C T; Zacharin, M

    2003-03-01

    Congenital and acquired forms of osteoporosis in childhood and adolescence can result in morbidity from fracture and pain in childhood, and place an individual at significant risk for problems in adult life. A range of therapies exist for the prevention and treatment of osteoporosis, including optimization of daily calcium intake, adequate vitamin D status, weight-bearing exercise, treatment with sex steroids where delayed puberty is a problem and, more recently, use of bisphosphonate therapy. Intravenous pamidronate therapy (a bisphosphonate) has been shown to reduce fractures and improve bone density in children with osteogenesis imperfecta, and might prove to be of benefit in other osteoporotic conditions in childhood. However, a number of issues regarding the optimal use of bisphosphonate therapy in children and adolescents remain to be resolved, including total annual dose and frequency and duration of administration. Bisphosphonate therapy should, therefore, be used only in the context of a well-run clinical programme with specialist knowledge in the management of osteopenic disorders in childhood.

  17. Dental complications and management of patients on bisphosphonate therapy: A review article

    OpenAIRE

    Kalra, Sandeep; Jain, Veena

    2012-01-01

    Bisphosphonates are group of drugs that inhibit bone resorption and are used to treat a range of pathologies including Paget's disease, osteoporosis, multiple myeloma and metastasis associated with breast or prostate cancer. The most common complication in patients on bisphosphonate therapy is osteonecrosis of jaw (ONJ) which can occur after any surgical dental procedure and the risk for the development of osteonecrosis of jaw is higher in patients receiving intravenous bisphosphonate therapy...

  18. Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw.

    Science.gov (United States)

    Khan, Aliya A; Sándor, George K B; Dore, Edward; Morrison, Archibald D; Alsahli, Mazen; Amin, Faizan; Peters, Edmund; Hanley, David A; Chaudry, Sultan R; Dempster, David W; Glorieux, Francis H; Neville, Alan J; Talwar, Reena M; Clokie, Cameron M; Al Mardini, Majd; Paul, Terri; Khosla, Sundeep; Josse, Robert G; Sutherland, Susan; Lam, David K; Carmichael, Robert P; Blanas, Nick; Kendler, David; Petak, Steven; St-Marie, Louis Georges; Brown, Jacques; Evans, A Wayne; Rios, Lorena; Compston, Juliet E

    2008-07-01

    Following publication of the first reports of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates in 2003, a call for national multidisciplinary guidelines based upon a systematic review of the current evidence was made by the Canadian Association of Oral and Maxillofacial Surgeons (CAOMS) in association with national and international societies concerned with ONJ. The purpose of the guidelines is to provide recommendations regarding diagnosis, identification of at-risk patients, and prevention and management strategies, based on current evidence and consensus. These guidelines were developed for medical and dental practitioners as well as for oral pathologists and related specialists. The multidisciplinary task force established by the CAOMS reviewed all relevant areas of research relating to ONJ associated with bisphosphonate use and completed a systematic review of current literature. These evidence-based guidelines were developed utilizing a structured development methodology. A modified Delphi consensus process enabled consensus among the multidisciplinary task force members. These guidelines have since been reviewed by external experts and endorsed by national and international medical, dental, oral surgery, and oral pathology societies. RECOMMENDATIONS regarding diagnosis, prevention, and management of ONJ were made following analysis of all current data pertaining to this condition. ONJ has many etiologic factors including head and neck irradiation, trauma, periodontal disease, local malignancy, chemotherapy, and glucocorticoid therapy. High-dose intravenous bisphosphonates have been identified as a risk factor for ONJ in the oncology patient population. Low-dose bisphosphonate use in patients with osteoporosis or other metabolic bone disease has not been causally linked to the development of ONJ. Prevention, staging, and treatment recommendations are based upon collective expert opinion and current data, which has been limited to case

  19. Osteonecrosis of the jaw: a rare and devastating side effect of bisphosphonates.

    LENUS (Irish Health Repository)

    Ryan, P

    2009-12-01

    Evidence has emerged that bisphosphonate use in cancer patients is associated with osteonecrosis of the jaw. This form of osteonecrosis has been termed bisphosphonate induced osteonecrosis of the jaw (BIONJ). BIONJ is commonly precipitated by a tooth extraction in patients treated with long term, potent, high dose intravenous bisphosphonates for the management of myeloma, breast or prostate cancer. The overall prevalence of BIONJ is about 5% in patients with these malignancies. Current evidence shows that the risk of BIONJ in non-cancerous patients, such as those with osteoporosis, is very low and appears to be comparable with that of the general population. Prescribing physicians need to encourage cancer patients to see their dentists before the initiation of bisphosphonate treatment, and regularly thereafter.

  20. Changes in the utilization of osteoporosis drugs after the 2010 FDA bisphosphonate drug safety communication

    Directory of Open Access Journals (Sweden)

    Bander Balkhi

    2018-02-01

    Conclusions: The 2010 FDA bisphosphonates safety communication appeared to have influenced Osteoporosis utilization in Medicaid recipients. The 2010 FDA bisphosphonates safety communication was associated with a significant reduction in the utilization of bisphosphonates in the Medicaid program.

  1. Bisphosphonates-induced osteonecrosis of the jaw: pharmacology and clinical procedures.

    Directory of Open Access Journals (Sweden)

    Candice Belchior Duplat

    2012-01-01

    Full Text Available Osteonecrosis of the jaw is a consequent condition of a variety of local and systemic factors that compromises the bone blood flow. Bisphosphonates are a class of compounds widely used for the treatment of disorders of bone metabolism, such as bone metastasis and osteoporosis. Bisphosphonates-induced osteonecrosis of the jaw is a new complication, published for the first time at 2003, and can be defined as an unexpected necrosis development on the oral cavity in patients who received bisphosphonates and were not being treated with head and neck radiotherapy. Radiographies show radiolucent zones or sclerotic bone and, in some cases, show areas with delayed or absent bone remodeling after extraction, remain the socket cavity. The treatment can be done in accordance with the condition stage, since management of 0,12% chlorhexidine and antibiotics until laser utilization, hyperbaric oxygen, surgical debridement and resection. It is important to promote more communication between physicians and dentists to guarantee dental attention during the bisphosphonate administration, establishing oral health and preventing complications, such as osteonecrosis induced by this medication.

  2. BISPHOSPHONATES-INDUCED OSTEONECROSIS OF THE JAW: PHARMACOLOGY AND CLINICAL PROCEDURES.

    Directory of Open Access Journals (Sweden)

    Candice Belchior Duplat

    2012-08-01

    Full Text Available Osteonecrosis of the jaw is a consequent condition of a variety of local and systemic factors that compromises the bone blood flow. Bisphosphonates are a class of compounds widely used for the treatment of disorders of bone metabolism, such as bone metastasis and osteoporosis. Bisphosphonates-induced osteonecrosis of the jaw is a new complication, published for the first time at 2003, and can be defined as an unexpected necrosis development on the oral cavity in patients who received bisphosphonates and were not being treated with head and neck radiotherapy. Radiographies show radiolucent zones or sclerotic bone and, in some cases, show areas with delayed or absent bone remodeling after extraction, remain the socket cavity. The treatment can be done in accordance with the condition stage, since management of 0,12% chlorhexidine and antibiotics until laser utilization, hyperbaric oxygen, surgical debridement and resection. It is important to promote more communication between physicians and dentists to guarantee dental attention during the bisphosphonate administration, establishing oral health and preventing complications, such as osteonecrosis induced by this medication.

  3. Bisphosphonates and Bone Fractures in Long-term Kidney Transplant Recipients

    Science.gov (United States)

    Conley, Emily; Muth, Brenda; Samaniego, Millie; Lotfi, Mary; Voss, Barbara; Armbrust, Mike; Pirsch, John; Djamali, Arjang

    2013-01-01

    Background There is little information on the role of bisphosphonates and bone mineral density (BMD) measurements for the follow-up and management of bone loss and fractures in long-term kidney transplant recipients. Methods To address this question, we retrospectively studied 554 patients who had two BMD measurements after the first year posttransplant and compared outcomes in patients treated, or not with bisphosphonates between the two BMD assessments. Kaplan-Meier survival and stepwise Cox regression analyses were performed to examine fracture-free survival rates and the risk-factors associated with fractures. Results The average time (±SE) between transplant and the first BMD was 1.2±0.05 years. The time interval between the two BMD measurements was 2.5±0.05 years. There were 239 and 315 patients in the no-bisphosphonate and bisphosphonate groups, respectively. Treatment was associated with significant preservation of bone loss at the femoral neck (HR 1.56, 95% CI 1.21-2.06, P=0.0007). However, there was no association between bone loss at the femoral neck and fractures regardless of bisphosphonate therapy. Stepwise Cox regression analyses showed that type-1 diabetes, baseline femoral neck T-score, interleukin-2 receptor blockade, and proteinuria (HR 2.02, 0.69, 0.4, 1.23 respectively, Pbone loss in long-term kidney transplant recipients. However, these data suggest a limited role for the initiation of therapy after the first posttransplant year to prevent fractures. PMID:18645484

  4. Comparison of raloxifene and bisphosphonates based on adherence and treatment satisfaction in postmenopausal Asian women.

    Science.gov (United States)

    Pasion, Ellewellyn G; Sivananthan, Shanmugam K; Kung, Annie Wai-Chee; Chen, Sung-Hsiung; Chen, Yen-Jen; Mirasol, Roberto; Tay, Boon Keng; Shah, Ghazanfar Ali; Khan, Mansoor Ali; Tam, Frances; Hall, Belinda J; Thiebaud, Daniel

    2007-01-01

    We evaluated adherence with raloxifene therapy compared with daily bisphosphonate in Asian postmenopausal women at increased risk of osteoporotic fractures. In this 12-month observational study conducted in Asia (Hong Kong, Malaysia, Pakistan, Philippines, Singapore, Taiwan), 984 postmenopausal women (aged 55 years or older) were treated with raloxifene 60 mg/day (n = 707; 72%) or daily bisphosphonate (alendronate 10 mg/day; n = 206; 21%, or risedronate 5 mg/day; n = 71; 7%) during their normal course of care. Patients were assessed at baseline, 6, and 12 months. Baseline characteristics (including age, race, education, menopausal status, and baseline fractures) were comparable between the raloxifene and bisphosphonate groups. More women on raloxifene completed the study compared with those on bisphosphonate (50.2% versus 37.5%; P < 0.001). Patients also took raloxifene for a longer period than bisphosphonate (median, 356 versus 348 days; P = 0.011). Compared with those taking bisphosphonate, significantly fewer patients taking raloxifene discontinued the study because of stopping treatment (5.7% versus 10.1%, P = 0.017) or changing treatment (2.8% versus 9.7%, P < 0.001). Inconvenient dosing was reported as a primary reason for discontinuation due to stopping or changing treatment in 19 (6.9%) bisphosphonate patients compared with 0 raloxifene patients. The percentage of patients who had consumed 80% or more of their study medication was similar for raloxifene patients (48-56 weeks; 95.2%) and bisphosphonate patients (48-56 weeks; 93.3%). More raloxifene patients responded that they were satisfied with their medication than bisphosphonate patients at 48-56 weeks (P = 0.002). We concluded that Asian postmenopausal women at increased risk of osteoporotic fractures showed a greater propensity to remain on raloxifene compared with bisphosphonate. The women on raloxifene exhibited lower discontinuation rates and higher treatment satisfaction.

  5. A retrospective clinical and radiographic study on healing of periradicular lesions in patients taking oral bisphosphonates.

    Science.gov (United States)

    Hsiao, Angela; Glickman, Gerald; He, Jianing

    2009-11-01

    Bisphosphonates have been related to impaired bone remodeling. The impact of oral bisphosphonates on periradicular healing has not been studied. The purpose of this study was to evaluate the healing of periradicular lesions in patients taking oral bisphosphonates after root canal therapy. Thirty-four teeth with preoperative periradicular radiolucencies were identified in patients undergoing oral bisphosphonate therapy. These cases were examined clinically and radiographically to determine treatment outcome. Thirty-eight control teeth were selected from a pool of patients not taking bisphosphonates. Nonsurgical root canal treatment and retreatment was performed by endodontic residents and undergraduate dental students at Baylor College of Dentistry using nonstandardized protocols. In the bisphosphonate group, 73.5% of the lesions healed, whereas the control cases had a healing rate of 81.6%. There was no statistically significant difference between the groups (p > 0.05). The results of this preliminary short-term study suggest that patients taking long-term oral bisphosphonates can expect a satisfactory outcome with evidence of periradicular healing after conventional root canal treatment. Thus, root canal treatment may be considered a safe and realistic alternative to extraction in patients on bisphosphonate therapy.

  6. The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT)

    Science.gov (United States)

    Black, Dennis M; Reid, Ian R; Boonen, Steven; Bucci-Rechtweg, Christina; Cauley, Jane A; Cosman, Felicia; Cummings, Steven R; Hue, Trisha F; Lippuner, Kurt; Lakatos, Peter; Leung, Ping Chung; Man, Zulema; Martinez, Ruvie Lou Maria; Tan, Monique; Ruzycky, Mary Ellen; Su, Guoqin; Eastell, Richard

    2012-01-01

    Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue

  7. Subtrochanteric stress fractures in patients on oral bisphosphonate therapy: an emerging problem.

    LENUS (Irish Health Repository)

    Murphy, Colin G

    2012-01-31

    The emergence of a new variant of subtrochanteric stress fractures of the femur, affecting patients on oral bisphosphonate therapy, has only recently been described. This fracture is often preceded by pain and distinctive radiographic changes (lateral cortical thickening), and associated with a characteristic fracture pattern (transverse fracture line and medial cortical spike). A retrospective review (2007-2009) was carried out for patients who were taking oral bisphosphonates and who sustained a subtrochanteric fracture after a low velocity injury. Eleven fractures were found in 10 patients matching the inclusion criteria outlined. All were females, and taking bisphosphonates for a mean of 43 years. Five of the 10 patients mentioned prodromal symptoms, for an average of 9.4 months before the fracture. Although all fractures were deemed low velocity, 5 of 11 were even atraumatic. Two patients had previously sustained contralateral subtrochanteric fractures. Plain radiographs of two patients showed lateral cortical thickening on the contralateral unfractured femur; the bisphosphonate therapy was stopped and close surveillance was started. Patients taking oral bisphosphonates may be at risk of a new variant of stress fracture of the proximal femur. Awareness of the symptoms is the key to ensure that appropriate investigations are undertaken.

  8. Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment?

    Directory of Open Access Journals (Sweden)

    Roger von Moos

    2013-08-01

    Full Text Available Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a vicious cycle of metastasis growth and bone destruction. The RANK-RANK ligand (RANKL pathway plays a key role in this cycle, and inhibition of RANKL using the fully-human monoclonal antibody denosumab, has demonstrated efficacy in delaying skeletal complications associated with bone metastases in three phase 3 trials. Preclinical studies suggest that the RANKL pathway also plays a role in breast cancer tumourigenesis and migration to bone. In a subgroup analysis of the negative Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE trial, the bisphosphonate zoledronic acid showed potential for improving survival in patients who were postmenopausal; however, a prospective study in this patient population is required to validate this observation. Ongoing trials are examining whether adjuvant blockade of the RANKL pathway using denosumab can prevent disease recurrence in patients with high-risk breast cancer. These are building on analogous studies that have shown that denosumab improves bone metastasis-free survival in prostate cancer and suggested that it confers an overall survival benefit in non-small-cell lung cancer.

  9. Msx-1 is suppressed in bisphosphonate-exposed jaw bone analysis of bone turnover-related cell signalling after bisphosphonate treatment.

    Science.gov (United States)

    Wehrhan, F; Hyckel, P; Amann, K; Ries, J; Stockmann, P; Schlegel, Ka; Neukam, Fw; Nkenke, E

    2011-05-01

    Bone-destructive disease treatments include bisphosphonates and antibodies against receptor activator for nuclear factor κB ligand (aRANKL). Osteonecrosis of the jaw (ONJ) is a side-effect. Aetiopathology models failed to explain their restriction to the jaw. The osteoproliferative transcription factor Msx-1 is expressed constitutively only in mature jaw bone. Msx-1 expression might be impaired in bisphosphonate-related ONJ. This study compared the expression of Msx-1, Bone Morphogenetic Protein (BMP)-2 and RANKL, in ONJ-affected and healthy jaw bone. An automated immunohistochemistry-based alkaline phosphatase-anti-alkaline phosphatase method was used on ONJ-affected and healthy jaw bone samples (n = 20 each): cell-number ratio (labelling index, Bonferroni adjustment). Real-time RT-PCR was performed to quantitatively compare Msx-1, BMP-2, RANKL and GAPDH mRNA levels. Labelling indices were significantly lower for Msx-1 (P Msx-1, 22-fold lower (P Msx-1, RANKL suppression and BMP-2 induction were consistent with the bisphosphonate-associated osteopetrosis and impaired bone remodelling in BP- and aRANKL-induced ONJ. Msx-1 suppression suggested a possible explanation of the exclusivity of ONJ in jaw bone. Functional analyses of Msx-1- RANKL interaction during bone remodelling should be performed in the future. © 2011 John Wiley & Sons A/S.

  10. Subtrochanteric fractures in bisphosphonate-naive patients

    DEFF Research Database (Denmark)

    Adachi, Jonathan D; Lyles, Kenneth; Boonen, Steven

    2011-01-01

    Our purpose was to characterize the risks of osteoporosis-related subtrochanteric fractures in bisphosphonate-naive individuals. Baseline characteristics of patients enrolled in the HORIZON-Recurrent Fracture Trial with a study-qualifying hip fracture were examined, comparing those who sustained ...

  11. Preparation and in vivo biological investigations on a novel radioligand for bone scanning: technetium-99m-labeled zoledronic acid derivative

    International Nuclear Information System (INIS)

    Lin Jianguo; Qiu Ling; Cheng Wen; Luo Shineng; Ye Wanzhong

    2011-01-01

    Introduction: To enable imaging at an earlier time after injection, a radiopharmaceutical with higher affinity for bone, larger ratio of bone-to-soft tissue uptake and more rapid clearance from blood is required. The nature of diphosphonic acid is a key factor to determine the advantages of the radiopharmaceuticals. The purpose of this study is to optimize the linker chain between the imidazolyl and geminal diphosphonate group in the zoledronic acid (ZL) to develop novel single photon emission computed tomography (SPECT) bone imaging agent. Methods: A novel ZL derivative, 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid (IPrDP), was successfully prepared and labeled with 99m Tc in a high labeling yield. Biodistribution of 99m Tc-IPrDP and 99m Tc-ZL in normal mice were studied and compared. SPECT bone scanning was performed on the rabbit and a series of dynamic and static images were recorded by Philips SKY Light emission computed tomography. Results: In the biodistribution studies, 99m Tc-IPrDP exhibits significant advantages on the bone resorption and the clearance from soft tissues compared with 99m Tc-ZL. Kinetics of blood clearance in mice showed that T 1/2α and T 1/2β of 99m Tc-IPrDP were 1.47 min and 46.47 min, while those of 99m Tc-ZL were 2.28 and 52.63 min respectively. Excellent images of the rabbit skeleton can be quickly obtained for 99m Tc-IPrDP, which was faster than 99m Tc-ZL and the clinically widely used bone imaging agent 99m Tc-MDP (technetium-99m labeled with methylenediphosphonate). Conclusions: 99m Tc-IPrDP possesses excellent characteristics for the potential application as a novel bone scanning agent.

  12. Atypical femur fractures associated with bisphosphonates: from prodrome to resolution

    Directory of Open Access Journals (Sweden)

    Braulio Sastre-Jala

    2015-10-01

    Full Text Available Atypical fractures related to the prolonged use of bisphosphonates are caused by low energy mechanisms and are characterized by oblique and transverse lines and frequent bilateralism. We present a clinical case of a patient who we believe illustrates, both in clinical and radiological aspects, the new definition of atypical femur fracture related to treatment using bisphosphonates treated conservatively and successfully with discharge and teriparatide 20 mcg/80 mcl s.c./24h. The appearance of painful symptoms in the upper thigh, especially if bilateral, in patients treated with bisphosphonates for long periods of time, makes it necessary to dismiss bone lesions that might otherwise suggest atypical fracture. In those cases where the fracture is incomplete, restoring bone metabolism through the administration of teriparatide 20 mcg/80 mcl s.c./24h could prevent displaced fractures.

  13. Current state of orthodontic patients under Bisphosphonate therapy

    Science.gov (United States)

    2013-01-01

    Background Bisphosphonates are a common medication for the prevention and therapy of osteoporosis, but are also applied for tumor diseases. They affect bone metabolism, and therefore also orthodontic treatments, but how it does has yet not been definitively clarified. Therefore, the aim of this research was to evaluate and demonstrate the reported effects and the current state of scientific research regarding orthodontic treatment and bisphosphonate medication exclusively in humans. Material and methods A systematic research of the literature for selected keywords in the Medline database (Pubmed) as well as a manual search was conducted. The following search terms were used: ‘Bisphosphonate’ in combination with: orthodontic, orthodontic treatment, tooth movement. Findings To date, only nine reported patients (case reports/series) and one original article (retrospective cohort study) regarding orthodontic treatment under bisphosphonate medication in humans have been published. Decelerated tooth movement with increased side effects (especially in high-risk patients) and longer treatment duration was reported in some articles. Patients with initial spacing or extraction cases had a higher risk of incomplete space closure and poor root parallelism. Conclusions Orthodontic tooth movement under bisphosphonate medication is possible, especially in low-risk patients (low dose and short period of intake). But the treatment is still not predictable, especially in high-risk patients. Therefore, the altered bone metabolism and higher extent of side effects should be considered in treatment planning, especially in extraction cases or high-risk patients. Regardless, longer treatment duration, decelerated tooth movement, and more side effects, e.g., incomplete space closure and poor root parallelism, should be expected, especially in extraction cases or space closure. PMID:23556517

  14. Bisphosphonates for the prevention of fractures in osteogenesis imperfecta: meta-analysis of placebo-controlled trials.

    Science.gov (United States)

    Hald, Jannie D; Evangelou, Evangelos; Langdahl, Bente L; Ralston, Stuart H

    2015-05-01

    Bisphosphonates are widely used off-label in the treatment of patients with osteogenesis imperfecta (OI) with the intention of reducing the risk of fracture. Although there is strong evidence that bisphosphonates increase bone mineral density in osteogenesis imperfecta, the effects on fracture occurrence have been inconsistent. The aim of this study was to gain a better insight into the effects of bisphosphonate therapy on fracture risk in patients with osteogenesis imperfecta by conducting a meta-analysis of randomized controlled trials in which fractures were a reported endpoint. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials in which the effects of bisphosphonates on fracture risk in osteogenesis imperfecta were compared with placebo and conducted a meta-analysis of these studies using standard methods. Heterogeneity was assessed using the I2 statistic. Six eligible studies were identified involving 424 subjects with 751 patient-years of follow-up. The proportion of patients who experienced a fracture was not significantly reduced by bisphosphonate therapy (Relative Risk [RR] = 0.83 [95% confidence interval 0.69-1.01], p = 0.06) with no heterogeneity between studies (I2  = 0). The fracture rate was reduced by bisphosphonate treatment when all studies were considered (RR = 0.71 [0.52-0.96], p = 0.02), but with considerable heterogeneity (I2  = 36%) explained by one study where a small number of patients in the placebo group experienced a large number of fractures. When this study was excluded, the effects of bisphosphonates on fracture rate was not significant (RR = 0.79 [0.61-1.02], p = 0.07, I2  = 0%). We conclude that the effects of bisphosphonates on fracture prevention in osteogenesis imperfecta are inconclusive. Adequately powered trials with a fracture endpoint are needed to further investigate the risks and benefits of bisphosphonates in this condition. © 2014 American Society for

  15. Risk of atrial fibrillation among bisphosphonate users: a multicenter, population-based, Italian study

    NARCIS (Netherlands)

    L. Herrera (Lizbeth); I. Leal (Ingrid); F. Lapi (Francesco); M.J. Schuemie (Martijn); V. Arcoraci (Vincenzo); F. Cipriani (Francesco); E. Sessa (E.); A. Vaccheri (Alberto); C. Piccinni (C.); T. Staniscia (Tommaso); A. Vestri (Annarita); M. Di Bari (M.); G. Corrao (Giovanni); A. Zambon (A.); D Gregori (Dario); F. Carle (F.); M.C.J.M. Sturkenboom (Miriam); G. Mazzaglia (Giampiero); G. Trifirò (Gianluca)

    2015-01-01

    textabstractSummary: Bisphosphonate treatment is used to prevent bone fractures. A controversial association of bisphosphonate use and risk of atrial fibrillation has been reported. In our study, current alendronate users were associated with a higher risk of atrial fibrillation as compared with

  16. Off-trial evaluation of bisphosphonates in patients with metastatic breast cancer

    International Nuclear Information System (INIS)

    Liauw, Winston; Segelov, Eva; Lih, Anna; Dunleavy, Ms Ruth; Links, Matthew; Ward, Robyn

    2005-01-01

    Bisphosphonate therapy has been readily accepted as standard of care for individuals with bone metastases from breast cancer. In this study we determined whether the proportion of patients experiencing a skeletal related event (SRE) in a clinical practice population was similar to that observed in phase III randomized controlled studies. A retrospective chart review was conducted of 110 patients receiving intravenous bisphosphonates for advanced breast cancer. The proportion of patients experiencing at least one SRE after 12 months of therapy was determined. SRE included vertebral or non-vertebral fracture, cord compression, surgery and/or radiotherapy to bone. The proportion of patients who had an SRE was 30% (28 individuals) and the median time to first event was greater than 350 days. Non-vertebral events and radiotherapy were the most frequent type of SRE, while cord compression and hypercalcaemia were rare (1%). Most patients in the study had bone-only disease (58.2%) and most had multiple bone lesions. In the first 12 months the mean duration of exposure to intravenous bisphosphonates was 261 days and most patients remained on treatment until just before death (median 27 days). This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. We attribute this lower rate to observational bias. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilisation of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice. Phase IV observational studies need to be conducted to determine the true benefits of bisphosphonate therapy in order to implement rationale use of bisphosphonates

  17. Intravenous aminohydroxypropylidene bisphosphonate does not modify 99mTc-hydroxymethylene bisphosphonate bone scintigraphy. A prospective study

    International Nuclear Information System (INIS)

    Macro, M.; Bouvard, G.; Le Gangneux, E.; Colin, T.; Loyau, G.

    1995-01-01

    Bisphosphonates have market affinity for bone that makes them useful in both the treatment and imaging of bone lesions. Bone scintigraphy is very sensitive for the detection of bone metastases, which can cause life-threatening hypercalcemia requiring emergency treatment. This prospective study was done to determine whether intravenous administration of pamidronate, a second-generation bisphophonate used to treat hypercalcemia, affects the affinity of the radiopharmaceutical 99m technetium-labeled hydroxymethylene bisphosphonate (99m Tc- HMDP) for bone and bone lesions. Six patients with metastatic bone disease and five with Paget's disease of bone had a 99m Tc-HMDP bone scan before and two to four days after an intravenous infusion of pamidronate. The number and activity of metastatic bone lesions were unchanged after pamidronate, even when the second bone scan was done only 24 hours after the pamidronate infusion. Our data suggest that emergency treatment of life-threatening hypercalcemia by intravenous pamidronate does not decrease the sensitivity of subsequent bone scanning done to detect bone metastases. (authors). 17 refs. 1 tab. 2 figs

  18. Gastrointestinal tolerability with ibandronate after previous weekly bisphosphonate treatment

    Directory of Open Access Journals (Sweden)

    Richard Derman

    2009-09-01

    Full Text Available Richard Derman1, Joseph D Kohles2, Ann Babbitt31Department of Obstetrics and Gynecology, Christiana Hospital, Newark, DE, USA; 2Roche, Nutley, NJ, USA; 3Greater Portland Bone and Joint Specialists, Portland, ME, USAAbstract: Data from two open-label trials (PRIOR and CURRENT of women with postmenopausal osteoporosis or osteopenia were evaluated to assess whether monthly oral and quarterly intravenous (IV ibandronate dosing improved self-reported gastrointestinal (GI tolerability for patients who had previously experienced GI irritation with bisphosphonate (BP use. In PRIOR, women who had discontinued daily or weekly BP treatment due to GI intolerance received monthly oral or quarterly IV ibandronate for 12 months. The CURRENT subanalysis included women receiving weekly BP treatment who switched to monthly oral ibandronate for six months. GI symptom severity and frequency were assessed using the Osteoporosis Patient Satisfaction Questionnaire™. In PRIOR, mean GI tolerability scores increased significantly at month 1 from screening for both treatment groups (oral: 79.3 versus 54.1; IV: 84.4 versus 51.0; p < 0.001 for both. Most patients reported improvement in GI symptom severity and frequency from baseline at all post-screening assessments (>90% at Month 10. In the CURRENT subanalysis >60% of patients reported improvements in heartburn or acid reflux and >70% indicated improvement in other stomach upset at month 6. Postmenopausal women with GI irritability with daily or weekly BPs experienced improvement in symptoms with extended dosing monthly or quarterly ibandronate compared with baseline.Keywords: ibandronate, osteoporosis, bisphosphonate, gastrointestinal

  19. Differences in In Vitro Disintegration Time among Canadian Brand and Generic Bisphosphonates.

    Science.gov (United States)

    Olszynski, Wojciech P; Adachi, Jonathan D; Davison, K Shawn

    2014-01-01

    The objective of this study was to compare the disintegration times among Canadian-marketed brand (alendronate 70 mg, alendronate 70 mg plus vitamin D 5600 IU, and risedronate 35 mg) and generic (Novo-alendronate 70 mg and Apo-alendronate 70 mg) once-weekly dosed bisphosphonates. All disintegration tests were performed with a Vanderkamp Disintegration Tester. Disintegration was deemed to have occurred when no residue of the tablet, except fragments of insoluble coating or capsule shell, was visible. Eighteen to 20 samples were tested for each bisphosphonate group. The mean (±standard deviation) disintegration times were significantly (P disintegration of the generic tablets as compared to the brand bisphosphonates may have concerning safety and effectiveness implications for patients administering these therapies.

  20. Bisphosphonate-associated Osteonecrosis of the jaws and endodontic treatment: two case reports.

    Science.gov (United States)

    Goodell, Gary

    2006-01-01

    Bisphosphonates are commonly used in the management of bone diseases, such as osteoporosis and Paget's disease, and to prevent bone complications and treat malignant hypercalcemia in certain types of cancer. Although this class of drugs has clear evidence of medical efficacy, there are an, increasing number of reports of bisphosphonate-associated osteonecrosis of the jaws that have substantial implications for the patient and for the treating dentist. This article reviews proposed possible mechanisms of bisphosphonate-associated osteonecrosis of the jaws and describes two case reports where non-surgical and surgical root canal treatment were precipitating factors. Recommendations for prevention and treatment of the disease follow. Thorough history-taking and timely consultation with the patient's oral surgeon and oncologist are emphasized.

  1. Safety issues with bisphosphonate therapy for osteoporosis

    DEFF Research Database (Denmark)

    Suresh, Ernest; Pazianas, Michael; Abrahamsen, Bo

    2014-01-01

    Randomized controlled trials have demonstrated the efficacy of bisphosphonates (BP) in improving BMD and reducing fracture risk. Various safety issues that were not noted in clinical trials have, however, now emerged with post-marketing surveillance and increasing clinical experience. The risk...

  2. Position Statement: Drug Holiday in Osteoporosis Treatment with Bisphosphonates in South Korea

    Science.gov (United States)

    Lee, Seung Hun; Gong, Hyun Sik; Kim, Tae-Hee; Park, Si Young; Shin, Jung-Ho; Cho, Sun Wook

    2015-01-01

    Bisphosphonates have been widely used in the treatment of osteoporosis with robust data from many placebo-controlled trials demonstrating its efficacy in fracture risk reduction over 3 to 5 years of treatment. Although bisphosphonates are generally safe and well tolerated, concerns have emerged about the adverse effects related to its long-term use, including osteonecrosis of the jaw and atypical femur fractures. Because bisphosphonates are incorporated into the skeleton and continue to exert an anti-resorptive effect for a period of time after the discontinuation of drugs, the concept of a "drug holiday" has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from anti-fracture efficacy. As randomized clinical trial evidence is not yet available on who may qualify for a drug holiday, there is considerable controversy regarding the selection of candidates for the drug holiday and monitoring during a drug holiday, both of which should be based on individual assessments of risk and benefit. This statement will provide suggestions for clinicians in South Korea on the identification of possible candidates and monitoring during a bisphosphonate drug holiday. PMID:26713307

  3. Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer.

    Science.gov (United States)

    Stachnik, Agnes; Yuen, Tony; Iqbal, Jameel; Sgobba, Miriam; Gupta, Yogesh; Lu, Ping; Colaianni, Graziana; Ji, Yaoting; Zhu, Ling-Ling; Kim, Se-Min; Li, Jianhua; Liu, Peng; Izadmehr, Sudeh; Sangodkar, Jaya; Scherer, Thomas; Mujtaba, Shiraz; Galsky, Matthew; Gomez, Jorge; Epstein, Solomon; Buettner, Christoph; Bian, Zhuan; Zallone, Alberta; Aggarwal, Aneel K; Haider, Shozeb; New, Maria I; Sun, Li; Narla, Goutham; Zaidi, Mone

    2014-12-16

    A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1(ΔE746-A750)-driven HCC827 NSCLCs and HER1(wt)-expressing MB231 triple negative breast cancers, but not by HER(low)-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HER(low) SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI-resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI-resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-driven cancers.

  4. Clinical strategies to address patients' concerns in osteoporosis management with bisphosphonates.

    Science.gov (United States)

    Cole, Raymond E

    2011-03-01

    Approximately 44 million Americans either have, or are at risk of developing, osteoporosis, a disease associated with an increased risk of fracture and, consequently, morbidity and mortality. Osteoporosis affects 20% to 30% of postmenopausal women, and resulting fractures pose a major economic burden, with estimated annual direct costs ranging from $17 billion to $19 billion. Hip fractures account for the majority of costs (~60%) because they often require costly long-term follow-up care in addition to the direct costs of initial treatment. Screening, diagnosis, and disease management are of paramount importance when treating patients at risk for osteoporosis. The National Osteoporosis Foundation recommends that all postmenopausal women be evaluated for osteoporosis risk factors and that all women aged ≥ 65 years undergo bone mineral density testing. Once the primary care physician has identified a patient at risk for osteoporosis-related fracture, the physician must decide whether and how to treat the patient (ie, nonpharmacologic or pharmacologic options). Bisphosphonates are the first-line pharmacologic treatment for women aged ≥ 50 years with postmenopausal osteoporosis. Bisphosphonates-which have a favorable safety and tolerability profile in clinical trials-have shown efficacy in reducing fractures. However, achieved real world effectiveness is very much dependent on good treatment adherence by the patient. Media attention to rare adverse events has motivated some patients to deliberate nonadherence. Physicians should screen patients for contraindications and adverse event risk factors, educate them on the risks of fracture and benefits and risks of treatment, and monitor them during therapy. To assist primary care physicians in clinical decision making for women at risk for or with confirmed osteoporosis, this article presents a review of the guidelines for the diagnosis and treatment of postmenopausal osteoporosis, recent long-term efficacy data for

  5. Zoledronic Acid improves clinical outcomes when administered before onset of bone pain in patients with prostate cancer.

    Science.gov (United States)

    Saad, Fred; Eastham, James

    2010-11-01

    To evaluate, in an exploratory analysis, the effect of zoledronic acid (ZOL) on skeletal-related event (SRE) incidence as determined by the bone pain levels at study entry. Bone metastases can undermine skeletal integrity long before the onset of symptoms. Treating patients before symptom onset might be more effective in preventing SREs and improving patients' quality of life. ZOL has shown significant reductions in SREs and pain compared with placebo in patients with bone metastases from advanced prostate cancer in a randomized placebo-controlled trial. Patients from a placebo-controlled, Phase III trial of men with castration-resistant prostate cancer, randomized to receive ZOL 4 mg (n = 214) or placebo (n = 208) for ≤ 24 months, were stratified by pain or no pain at baseline. Bone pain was assessed at baseline, week 3, and week 6 and at 6-week intervals thereafter. The primary endpoint was the proportion of patients with ≥ 1 SRE. ZOL significantly reduced the mean pain scores compared with placebo at 3, 9, 21, and 24 months (P ≤ .03 for each point) and reduced the annual incidence of SREs. Among patients without baseline pain, ZOL decreased the percentage of patients with ≥ 1 SRE by 39% and reduced the annual incidence of SREs by 49% compared with placebo. ZOL delayed the onset of bone pain in those patients without pain at baseline compared with placebo. ZOL reduced bone pain and SREs compared with placebo in patients with bone metastases from castration-resistant prostate cancer, irrespective of the baseline pain status, and appeared more efficacious when initiated before the onset of pain. Copyright © 2010 Elsevier Inc. All rights reserved.

  6. Efficacy and safety of bisphosphonates in management of low bone density in inflammatory bowel disease

    Science.gov (United States)

    Yao, Liwei; Wang, Haiqing; Dong, Wenwei; Liu, Zhenxin; Mao, Haijiao

    2017-01-01

    Abstract This study aims to determine whether bisphosphonates are safe, as well as effective against bone mineral loss in inflammatory bowel disease (IBD). A computerized search of electronic databases from 1966 to 2016 was performed. Randomized controlled trials (RCTs) were included in this review to evaluate the role of bisphosphonates in the management of osteoporosis in IBD patients. A revised 7-point Jadad scale was used to evaluate the quality of each study. Overall, 13 RCTs and 923 patients met the inclusion criteria of this meta-analysis. The result showed that bisphosphonates decreased bone mass density (BMD) loss at the lumbar spine (P = 0.0002), reduced the risk of new fractures (P = 0.01), and retained the similar adverse events (P = 0.86). Bisphosphonates may provide protection and safety against bone mineral loss in IBD patients. PMID:28099343

  7. Early effects of zoledronic acid and teriparatide on bone microarchitecture, remodeling and collagen crosslinks: comparison between iliac crest and lumbar vertebra in ewes.

    Science.gov (United States)

    Portero-Muzy, N R; Chavassieux, P M; Bouxsein, M L; Gineyts, E; Garnero, P; Chapurlat, R D

    2012-10-01

    Iliac crest bone biopsies are used to assess the mechanism of action of drug treatments, yet there are little data comparing this site to sites prone to fracture. The purpose of this study was to compare the delay and the amplitude of responses to treatment in two different bone sites. The short-term effects of zoledronic acid and teriparatide on microarchitecture, collagen crosslinks and bone remodeling were evaluated in iliac crest and lumbar vertebrae. Aged ewes (n=8/gr) received either vehicle (CTRL) or a single injection of zoledronic acid (ZOL, 10mg) or daily injections of teriparatide (TPTD, 20 μg/d) for 3 months. Blood samples were collected monthly for assessing bone turnover markers. At the end of the study, a transiliac bone biopsy (IC) and L1 lumbar vertebrae (LV1) were collected to assess bone microarchitecture; pyridinoline (PYD), deoxypyridinoline (DPD), pentosidine (PEN) content, static and dynamic parameters of bone remodeling. In CTRL, Tb-BV/TV was significantly higher in LV1 than IC (psALP (p<0.001) and sCTX (p<0.001) were observed in the ZOL-group whereas in TPTD-group, after transient increases, they returned to baseline values. When compared to their respective CTRL, ZOL induced significant increases in Tb.BV/TV, Conn.D, Tb.N and Tb.Sp, in IC but not in LV1. Regardless of the site, ZOL markedly depressed the bone turnover: The static parameters of bone formation significantly decreased and the diminution of MS/BS, BFR/BS and Ac.f varied from -94 to -98% vs CTRL (p<0.01 to 0.001). It was associated with a diminution of the DPD content and the PYD/DPD ratio mainly in IC cortices. In contrast, after 3 months, TPTD did not modify the 3D structure and microarchitecture in IC and LV1, except a trend of higher Conn.D in IC, compared to IC-CTRL. TPTD treatment induced a significant increase in cortical porosity in LV1 (p<0.05) when compared to LV1-CTRL. Static parameters of bone formation and resorption were augmented in both sites, significantly

  8. Acrylic injectable and self-curing formulations for the local release of bisphosphonates in bone tissue.

    Science.gov (United States)

    Rodríguez-Lorenzo, L M; Fernández, M; Parra, J; Vázquez, B; López-Bravo, A; Román, J San

    2007-11-01

    Two bisphosphonates (BPs), namely 1-hydroxy-2-[4-aminophenyl]ethane-1,1-diphosphonic acid (APBP) and 1-hydroxy-2-[3-indolyl]ethane-1,1-diphosphonic acid (IBP), have been synthesized and incorporated to acrylic injectable and self-curing formulations. Alendronic acid monosodium trihydrated salt (ALN) containing cement was formulated as control. These systems have potential applications in low density hard tissues affected by ailments characterized by a high osteoclastic resorption, i.e. osteoporosis and osteolysis. Values of curing parameters of APBP and IBP were acceptable to obtain pastes with enough fluency to be injected through a biopsy needle into the bone cavity. Working times ranged between 8 and 15 min and maximum temperature was around 50 degrees C. Cured systems stored for a month in synthetic body fluid had compressive strengths between 90 and 96 MPa and modulus between 1.2 and 1.3 GPa, which suggest mechanical stabilization after setting and in the short time. BPs were released in PBS at an initial rate depending on the corresponding chemical structure in the order ALN > APBP > IBP to give final concentrations in PBS of 2.21, 0.44, and 0.19 mol/mL for ALN, APBP, and IBP, respectively. Cytotoxicities of bisphosphonates were evaluated, IC(50) values being in the order APBP > ALN > IBP. Absence of cytotoxicity coming from leachables of the cured systems was observed in all cases independently of the BP. An improved cell growth and proliferation for the systems loaded with APBP and IBP compared with that loaded with ALN was observed, as assessed by measuring cell adhesion and proliferation, and total DNA content.

  9. Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss.

    Science.gov (United States)

    Kempfle, Judith S; Nguyen, Kim; Hamadani, Christine; Koen, Nicholas; Edge, Albert S; Kashemirov, Boris A; Jung, David H; McKenna, Charles E

    2018-04-18

    Hearing loss affects more than two-thirds of the elderly population, and more than 17% of all adults in the U.S. Sensorineural hearing loss related to noise exposure or aging is associated with loss of inner ear sensory hair cells (HCs), cochlear spiral ganglion neurons (SGNs), and ribbon synapses between HCs and SGNs, stimulating intense interest in therapies to regenerate synaptic function. 7,8-Dihydroxyflavone (DHF) is a selective and potent agonist of tropomyosin receptor kinase B (TrkB) and protects the neuron from apoptosis. Despite evidence that TrkB agonists can promote survival of SGNs, local delivery of drugs such as DHF to the inner ear remains a challenge. We previously demonstrated in an animal model that a fluorescently labeled bisphosphonate, 6-FAM-Zol, administered to the round window membrane penetrated the membrane and diffused throughout the cochlea. Given their affinity for bone mineral, including cochlear bone, bisphosphonates offer an intriguing modality for targeted delivery of neurotrophic agents to the SGNs to promote survival, neurite outgrowth, and, potentially, regeneration of synapses between HCs and SGNs. The design and synthesis of a bisphosphonate conjugate of DHF (Ris-DHF) is presented, with a preliminary evaluation of its neurotrophic activity. Ris-DHF increases neurite outgrowth in vitro, maintains this ability after binding to hydroxyapatite, and regenerates synapses in kainic acid-damaged cochlear organ of Corti explants dissected in vitro with attached SGNs. The results suggest that bisphosphonate-TrkB agonist conjugates have promise as a novel approach to targeted delivery of drugs to treat sensorineural hearing loss.

  10. Radiographic findings of bisphosphonate-related osteonecrosis of ...

    African Journals Online (AJOL)

    Objective: The aim of this study is to assess radiographic findings of bisphosphonate-related osteonecrosis of the jaws (BRONJ) and to evaluate the efficiency of cone-beam computed tomography (CBCT) and panoramic radiography (PR) by comparing with each other. Materials and Methods: The data of 46 patients treated ...

  11. Malignancy associated hypercalcaemia-responsiveness to IV bisphosphonates and prognosis in a palliative population.

    Science.gov (United States)

    Mallik, Shreyashee; Mallik, Girijasankar; Macabulos, Shireen Teves; Dorigo, Andrew

    2016-04-01

    Hypercalcaemia is a potentially fatal paraneoplastic complication of malignancy. It primarily manifests during the advanced phase of cancer, with the life expectancy of patients ranging from weeks to months. The mainstay of treatment is with bisphosphonates, but these are not frequently used in a palliative population due to potential conflict with goals of care. The goals of this study was to determine the reversibility of hypercalcaemia amongst patients whose underlying malignancy is not being treated and assess whether correction results in improvement in symptoms attributable to hypercalcaemia, while identifying risk factors that can predict responsiveness. We conducted a retrospective cohort study of 63 patients aged >18 years who were admitted to the St Joseph's Palliative Care Unit, Australia between 2007 and 2013, having evidence of malignancy-associated hypercalcaemia which was treated with bisphosphonates. We assessed the response to bisphosphonates based on improvement of symptoms attributable to hypercalcaemia, as well as a reduction in serum calcium. We used the Kaplan-Meier survival method and parametric survival analysis to estimate the effect of the independent variables on time till death. Thirty-six of sixty three patients achieved normocalcaemia following treatment with an intravenous bisphosphonate. Complete response was influenced by the number of instances of hypercalcaemia in the past and patient factors, such as age and albumin levels. We found that a reduction in calcium level was associated with a significantly prolonged survival, as well as symptomatic improvement, irrespective of whether normocalcaemia was achieved. Our study suggests that bisphosphonates can be recommended as a palliative measure for selected patients to improve symptoms and prolong survival.

  12. Low Bone Density and Bisphosphonate Use and the Risk of Kidney Stones.

    Science.gov (United States)

    Prochaska, Megan; Taylor, Eric; Vaidya, Anand; Curhan, Gary

    2017-08-07

    Previous studies have demonstrated lower bone density in patients with kidney stones, but no longitudinal studies have evaluated kidney stone risk in individuals with low bone density. Small studies with short follow-up reported reduced 24-hour urine calcium excretion with bisphosphonate use. We examined history of low bone density and bisphosphonate use and the risk of incident kidney stone as well as the association with 24-hour calcium excretion. We conducted a prospective analysis of 96,092 women in the Nurses' Health Study II. We used Cox proportional hazards models to adjust for age, body mass index, thiazide use, fluid intake, supplemental calcium use, and dietary factors. We also conducted a cross-sectional analysis of 2294 participants using multivariable linear regression to compare 24-hour urinary calcium excretion between participants with and without a history of low bone density, and among 458 participants with low bone density, with and without bisphosphonate use. We identified 2564 incident stones during 1,179,860 person-years of follow-up. The multivariable adjusted relative risk for an incident kidney stone for participants with history of low bone density compared with participants without was 1.39 (95% confidence interval [95% CI], 1.20 to 1.62). Among participants with low bone density, the multivariable adjusted relative risk for an incident kidney stone for bisphosphonate users was 0.68 (95% CI, 0.48 to 0.98). In the cross-sectional analysis of 24-hour urine calcium excretion, the multivariable adjusted mean difference in 24-hour calcium was 10 mg/d (95% CI, 1 to 19) higher for participants with history of low bone density. However, among participants with history of low bone density, there was no association between bisphosphonate use and 24-hour calcium with multivariable adjusted mean difference in 24-hour calcium of -2 mg/d (95% CI, -25 to 20). Low bone density is an independent risk factor for incident kidney stone and is associated with

  13. Risk of atrial fibrillation among bisphosphonate users: a multicenter, population-based, Italian study.

    Science.gov (United States)

    Herrera, L; Leal, I; Lapi, F; Schuemie, M; Arcoraci, V; Cipriani, F; Sessa, E; Vaccheri, A; Piccinni, C; Staniscia, T; Vestri, A; Di Bari, M; Corrao, G; Zambon, A; Gregori, D; Carle, F; Sturkenboom, M; Mazzaglia, G; Trifiro, G

    2015-05-01

    Bisphosphonate treatment is used to prevent bone fractures. A controversial association of bisphosphonate use and risk of atrial fibrillation has been reported. In our study, current alendronate users were associated with a higher risk of atrial fibrillation as compared with those who had stopped bisphosphonate (BP) therapy for more than 1 year. Bisphosphonates are widely used to prevent bone fractures. Controversial findings regarding the association between bisphosphonate use and the risk of atrial fibrillation (AF) have been reported. The aim of this study was to evaluate the risk of AF in association with BP exposure. We performed a nested case-control study using the databases of drug-dispensing and hospital discharge diagnoses from five Italian regions. The data cover a period ranging from July 1, 2003 to December 31, 2006. The study population comprised new users of bisphosphonates aged 55 years and older. Patients were followed from the first BP prescription until an occurrence of an AF diagnosis (index date, i.e., ID), cancer, death, or the end of the study period, whichever came first. For the risk estimation, any AF case was matched by age and sex to up to 10 controls from the same source population. A conditional logistic regression was performed to obtain the odds ratio with 95% confidence intervals (CI). The BP exposure was classified into current (reference point. A subgroup analysis by individual BP was then carried out. In comparison with distant past users of BP, current users of BP showed an almost twofold increased risk of AF: odds ratio (OR) = 1.78 and 95% CI = 1.46-2.16. Specifically, alendronate users were mostly associated with AF as compared with distant past use of BP (OR, 1.97; 95% CI, 1.59-2.43). In our nested case-control study, current users of BP are associated with a higher risk of atrial fibrillation as compared with those who had stopped BP treatment for more than 1 year.

  14. A case of early detection of bisphosphonate-related osteonecrosis of the jaw

    OpenAIRE

    Mori, Miyu; Koide, Tetsuro; Matsui, Yuriyo; Matsuda, Toru

    2015-01-01

    Osteonecrosis of the jaws is an adverse reaction associated with the use of bisphosphonates. Although the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is based on symptomatology, it is often detected late because the patients become symptomatic only after osteonecrosis is well established. We describe a case of early oral BRONJ detected by magnetic resonance imaging (MRI) accidentally. Head MRI revealed low signal of T1-weight images in left mandibula. Patient had been...

  15. High-Dose Hypofractionated Radiation Therapy for Noncompressive Vertebral Metastases in Combination With Zoledronate: A Phase 1 Study

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    Pichon, Baptiste [Department of Radiation Oncology, ICO Cancer Center, Saint-Herblain (France); Campion, Loïc [Department of Biostatistics, ICO Cancer Center, Saint-Herblain (France); Delpon, Grégory [Department of Medical Physics, ICO Cancer Center, Saint-Herblain (France); CRCNA, Inserm U892, CNRS UMR 6299, Nantes (France); Thillays, François [Department of Radiation Oncology, ICO Cancer Center, Saint-Herblain (France); Carrie, Christian [Department of Radiation Oncology, Léon Bérard Center, Lyon (France); Cellier, Patrice [Department of Radiation Oncology, ICO Cancer Center, Angers (France); Pommier, Pascal; Laude, Cécile [Department of Radiation Oncology, Léon Bérard Center, Lyon (France); Mervoyer, Augustin [Department of Radiation Oncology, ICO Cancer Center, Saint-Herblain (France); Hamidou, Hadji [Department of Radiation Oncology, ICO Cancer Center, Angers (France); Mahé, Marc-André [Department of Radiation Oncology, ICO Cancer Center, Saint-Herblain (France); Supiot, Stéphane, E-mail: stephane.supiot@ico.unicancer.fr [Department of Radiation Oncology, ICO Cancer Center, Saint-Herblain (France); CRCNA, Inserm U892, CNRS UMR 6299, Nantes (France)

    2016-11-15

    Introduction: Hypofractionated stereotactic radiation therapy (HSRT) for vertebral metastases gives good results in terms of local control but increases the risk of fracture in the treated volume. Preclinical and clinical studies have shown that zoledronate not only reduces the risk of fracture and stimulates osteoclastic remodeling but also increases the immune response and radiosensitivity. This study aimed to evaluate the tolerability and effectiveness of zoledronate in association with radiation therapy. Patients and Methods: We conducted a multicenter phase 1 study that combined HSRT (3 × 9 Gy) and zoledronate in patients with vertebral metastasis ( (NCT01219790)). The principal objective was the absence of spinal cord adverse reactions at 1 year. The secondary objectives were acute tolerability, the presentation of a bone event, local tumor control, pain control, progression-free survival, and overall survival. Results: Thirty patients (25 male, 5 female), median age 66 years, who were followed up for a median period of 19.2 months, received treatment for 49 vertebral metastases. A grade 3 acute mucosal adverse event occurred in 1 patient during the treatment and in 2 more at 1 month. No late neurologic adverse events were reported at 1 year. The mean pain scores diminished significantly at 1 month (1.35; P=.0125) and 3 months (0.77; P<.0001) compared with pain scores at study entry (2.49). Vertebral collapse in the irradiated zone occurred in 1 (2%) treated vertebra. Control of local disease was achieved in 94% of irradiated patients (3 local recurrences). Conclusion: The combination of zoledronate and HSRT in the treatment of vertebral metastasis is well tolerated and seems to reduce the rate of vertebral collapse, effectively relieve pain, and achieve good local tumor control with no late neurologic adverse effects.

  16. Gastrointestinal events and association with initiation of treatment for osteoporosis

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    Modi A

    2015-11-01

    Full Text Available Ankita Modi,1 Ethel S Siris,2 Jackson Tang,3 Shiva Sajjan,1 Shuvayu S Sen1 1Center for Observational and Real-World Evidence, Merck & Co., Inc, Kenilworth, NJ, 2Toni Stabile Osteoporosis Center, Columbia University Medical Center, NY Presbyterian Hospital, New York, NY, 3Asclepius Analytics Ltd, Brooklyn, NY, USA Background: Preexisting gastrointestinal (GI events may deter the use of pharmacologic treatment in patients diagnosed with osteoporosis (OP. The objective of this study was to examine the association between preexisting GI events and OP pharmacotherapy initiation among women diagnosed with OP. Methods: The study utilized claims data from a large US managed care database to identify women aged ≥55 years with a diagnosis code for OP (index date during 2002–2009. Patients with a claim for pharmacologic OP treatment in the 12-month pre-index period (baseline were excluded. OP treatment initiation in the post-index period was defined as a claim for bisphosphonates (alendronate, ibandronate, risedronate, zoledronic acid, calcitonin, raloxifene, or teriparatide. During the post-index period (up to 12 months, GI events were identified before treatment initiation. A time-dependent Cox regression model was used to investigate the likelihood of initiating any OP treatment. Among patients initiating OP treatment, a discrete choice model was utilized to assess the relationship between post-index GI events and likelihood of initiating with a bisphosphonate versus a non-bisphosphonate. Results: In total, 65,344 patients (mean age 66 years were included; 23.7% had a GI event post diagnosis and before treatment initiation. Post-index GI events were associated with a 75% lower likelihood of any treatment initiation (hazard ratio 0.25; 95% confidence interval 0.24–0.26. Among treated patients (n=23,311, those with post-index GI events were 39% less likely to receive a bisphosphonate versus a non-bisphosphonate (odds ratio 0.61; 95% confidence

  17. Bisphosphonate-Related Osteonecrosis of the Jaw: A Review of the Literature

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    Eder Alberto Sigua-Rodriguez

    2014-01-01

    Full Text Available Bisphosphonates (BPs are a class of drugs used to treat osteoporosis and malignant bone metastasis. BPs show high binding capacity to the bone matrix, especially in sites of active bone metabolism. The American Society for Bone and Mineral Research defines BRONJ as “an area of exposed bone in the maxillofacial region that has not healed within 8 weeks after identification by a healthcare provider in a patient who is receiving or has been exposed to a bisphosphonate and has not had radiation therapy to the craniofacial region.” Bisphosphonate-related osteonecrosis of the jaw (BRONJ can adversely affect quality of life, as it may produce significant morbidity. The American Association of Oral and Maxillofacial Surgeons (AAOMS considers as vitally important that information on BRONJ be disseminated to other dental and medical specialties. The purpose of this work is to offer a perspective on how dentists should manage patients on BPs, to show the benefits of accurately diagnosing BRONJ, and to present diagnostic aids and treatments strategies for the condition.

  18. Future of bisphosphonates and denosumab for men with advanced prostate cancer

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    Iranikhah, Maryam; Stricker, Steve; Freeman, Maisha Kelly

    2014-01-01

    Prostate cancer is the most common cancer occurring in American men of all races. It is also the second leading cause of cancer death among men in the USA. Bone metastasis is a frequent occurrence in men with advanced prostate cancer, with skeletal-related events being a common complication and having negative consequences, leading to severe pain, increased health care costs, increased risk of death, and decreased quality of life for patients. Bone loss can also result from antiandrogen therapy, which can further contribute to skeletal-related events. Treatment with antiresorptive agents bisphosphonates, and the newly approved denosumab, a receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitor, has been shown to reduce the risk of skeletal-related complications and prevent treatment-induced bone loss in patients with advanced prostate cancer. This review discusses the role of antiresorptive agents bisphosphonates and RANK-L inhibitor in the current treatment of advanced prostate cancer by examining the primary literature and also focuses on the likely role of the bisphosphonates in the treatment of advanced prostate cancer in the future

  19. Effect of Long-Term Use of Bisphosphonates on Forearm Bone: Atypical Ulna Fractures in Elderly Woman with Osteoporosis

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    Yusuf Erdem

    2016-01-01

    Full Text Available Osteoporosis is a common musculoskeletal disease of the elderly population characterized by decreased bone mineral density and subsequent fractures. Bisphosphonates are a widely accepted drug therapy which act through inhibition of bone resorption and prevent fractures. However, in long-term use, atypical bisphosphonate induced fractures may occur, particularly involving the lower weight bearing extremity. Atypical ulna fracture associated with long-term bisphosphonate use is rarely reported in current literature. We present a 62-year-old woman with atypical ulna due to long-term alendronate therapy without a history of trauma or fall. Clinicians should be aware of stress fracture in a patient who has complaints of upper extremity pain and history of long-term bisphosphonate therapy.

  20. Combining Vγ9Vδ2 T Cells with a Lipophilic Bisphosphonate Efficiently Kills Activated Hepatic Stellate Cells

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    Xiaoying Zhou

    2017-10-01

    Full Text Available Activated hepatic stellate cells (aHSCs are now established as a central driver of fibrosis in human liver injury. In the presence of chronic or repeated injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC can occur, so there is interest in down-regulating aHSCs activity in order to treat these diseases. Here, we report that Vγ9Vδ2 T cells are reduced in patients with liver cirrhosis, stimulating us to investigate possible interactions between Vγ9Vδ2 T cells and aHSCs. We find that Vγ9Vδ2 T cells kill aHSCs and killing is enhanced when aHSCs are pretreated with BPH-1236, a lipophilic analog of the bone resorption drug zoledronate. Cytotoxicity is mediated by direct cell-to-cell contact as shown by Transwell experiments and atomic force microscopy, with BPH-1236 increasing the adhesion between aHSCs and Vγ9Vδ2 T cells. Mechanistically, BPH-1236 functions by inhibiting farnesyl diphosphate synthase, leading to accumulation of the phosphoantigen isopentenyl diphosphate and recognition by Vγ9Vδ2 T cells. The cytolytic process is largely dependent on the perforin/granzyme B pathway. In a Rag2−/−γc−/− immune-deficient mouse model, we find that Vγ9Vδ2 T cells home-in to the liver, and when accompanied by BPH-1236, kill not only orthotopic aHSCs but also orthotopic HCC tumors. Collectively, our results provide the first proof-of-concept of a novel immunotherapeutic strategy for the treatment of fibrosis–cirrhosis–HCC diseases using adoptively transferred Vγ9Vδ2 T cells, combined with a lipophilic bisphosphonate.

  1. Adherence With Bisphosphonates and Long-Term Risk of Hip Fractures: A Nested Case-Control Study Using Real-World Data.

    Science.gov (United States)

    Shalev, Varda; Sharman Moser, Sarah; Goldshtein, Inbal; Yu, Jingbo; Weil, Clara; Ish-Shalom, Sophia; Rouach, Vanessa; Chodick, Gabriel

    2017-09-01

    Hip fracture is a major complication of osteoporosis. Bisphosphonate medication is the mainstay of treatment for osteoporosis. However, concerns have been raised regarding the effectiveness of bisphosphonates in reducing hip fracture risk after long-term use, particularly among patients with suboptimal adherence. To examine the association between adherence with bisphosphonate therapy and long-term risk of hip fracture. Included in the present nested case-control study were osteoporotic women (n = 14 357) who initiated bisphosphonate therapy in 2000-2010 and were retrospectively followed for incident hip fracture through November 2014. Within this cohort, each case of primary hip fractures was individually matched to 3 controls without a primary hip fracture. Proportion of follow-up days covered (PDC) with bisphosphonates was calculated from bisphosphonate purchases. Adherence was categorized into the following groups: purchase of 1 or 2 months' supply (reference group), at least 3 months' supply to PDC ≤20%, PDC >20% to ≤80%, PDC >80% to ≤100%. Included in the analysis were 426 case-control groups with a mean age (SD) of 73.7 years (7.9). Compared with the reference group, PDC of 80% to 100% with bisphosphonates was associated with a significant reduction in hip fracture risk for patients with 8 to 15 years of follow-up (OR = 0.39; 95% CI = 0.18-0.87). Among patients with a follow-up of up to 3 years, OR was 0.58 (95% CI = 0.31-1.06). Adherence with bisphosphonates among osteoporotic patients is associated with lower risk of hip fracture, with no indication of diminished effectiveness with long-term use.

  2. Influence of Bisphosphonate Treatment on Medullary Macrophages and Osteoclasts: An Experimental Study

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    Natalia Daniela Escudero

    2012-01-01

    Full Text Available Nitrogen-containing bisphosphonates are widely used for treating diverse bone pathologies. They are anticatabolic drugs that act on osteoclasts inhibiting bone resorption. It remains unknown whether the mechanism of action is by decreasing osteoclast number, impairing osteoclast function, or whether they continue to effectively inhibit bone resorption despite the increase in osteoclast number. There is increasing evidence that bisphosphonates also act on bone marrow cells like macrophages and monocytes. The present work sought to evaluate the dynamics of preosteoclast fusion and possible changes in medullary macrophage number in bisphosphonate-treated animals. Healthy female Wistar rats received olpadronate, alendronate, or vehicle during 5 weeks, and 5-bromo-2-deoxyuridine (BrdU on day 7, 28, or 34 of the experiment. Histomorphometric studies were performed to study femurs and evaluate: number of nuclei per osteoclast (N.Nu/Oc; number of BrdU-positive nuclei (N.Nu BrdU+/Oc; percentage of BrdU-positive nuclei per osteoclast (%Nu.BrdU+/Oc; medullary macrophage number (mac/mm2 and correlation between N.Nu/Oc and mac/mm2. Results showed bisphosphonate-treated animals exhibited increased N.Nu/Oc, caused by an increase in preosteoclast fusion rate and evidenced by higher N.Nu BrdU+/Oc, and significantly decreased mac/mm2. Considering the common origin of osteoclasts and macrophages, the increased demand for precursors of the osteoclast lineage may occur at the expense of macrophage lineage precursors.

  3. Bisphosphonate-associated atypical sub-trochanteric femur fractures: paired bone biopsy quantitative histomorphometry before and after teriparatide administration.

    Science.gov (United States)

    Miller, Paul D; McCarthy, Edward F

    2015-04-01

    Bisphosphonate-associated atypical sub-trochanteric femur fractures (ASFF) may be seen with long-term bisphosphonate use, though these fractures are also seen in patients never exposed to bisphosphonates. One theory for the mechanism of action whereby bisphosphonates may induce these ASFF is over-suppression of bone turnover. Bisphosphonates suppress bone turnover, but in bisphosphonate clinical trials, over-suppression defined whether by maintaining the biochemical markers of bone turnover below the defined reference range or by quantitative bone histomorphometry, has not been observed. We studied 15 clinic patients referred to The Colorado Center for Bone Research (CCBR) after they had a bisphosphonate-associated ASFF and performed quantitative bone histomorphometry both before and after 12 months of teriparatide (20µg SQ/day). All patients had been on long-term alendronate (mean = 7 years, range: 6-11 years) and had already had intramedullary rods placed when first seen (6 weeks to 7 months after rod placement). Alendronate had been discontinued in all patients at the time of their first clinic visit to CCBR. All of the fractures fulfilled The American Society for Bone and Mineral Research major radiological criteria for ASFF. Three key dynamic histomorphometric features show that 7 of the 15 patients had unmeasurable bone formation, mineralizing surface, and mineral apposition, while the other 8 patients had measurable dynamic parameters; although for all 15 patients, the mean values for all 3 dynamic parameters was far below the average for the published normal population. Administration of teriparatide was associated with an increase in all 3 dynamic histomorphometric parameters. Baseline bone turnover markers did not correlate with the baseline histomorphometry. While there is heterogeneity in the bone turnover in patients with bisphosphonate ASFF, there is a large portion in this uncontrolled series that had absent bone turnover at the standard biopsy site

  4. Bone Loss Prevention of Bisphosphonates in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

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    Yan Hu

    2017-01-01

    Full Text Available Objective. The purpose of this study was to evaluate the effect of bisphosphonates in improving bone mineral density (BMD and decreasing the occurrence rate of fractures and adverse events in patients with inflammatory bowel disease (IBD. Methods. Randomized controlled trials (RCTs which use bisphosphonates in IBD patients were identified in PubMed, MEDLINE database, EMBASE database, Web of Knowledge, and the Cochrane Databases between 1990 and June 2016. People received bisphosphonate or placebos with a follow-up of at least one year were also considered. STATA 12.0 software was used for the meta-analysis. Results. Eleven randomized clinical trials were included in the meta-analysis. The data indicated that the percentage change in the increased BMD in the bisphosphonates groups was superior to that of the control groups at the lumbar spine and total hip. At the femoral neck, there was no significant difference between the two groups. The incidence of new fractures during follow-up showed significant reduction. The adverse event analysis revealed no significant difference between the two groups. Conclusion. Our results demonstrate that bisphosphonates therapy has an effect on bone loss in patients with IBD but show no evident efficiency at increasing the incidence of adverse events.

  5. Bone mineral density changes of lumbar spine and femur in osteoporotic patient treated with bisphosphonates and beta-hydroxy-beta-methylbutyrate (HMB): Case report.

    Science.gov (United States)

    Tatara, Marcin R; Krupski, Witold; Majer-Dziedzic, Barbara

    2017-10-01

    Currently available approaches to osteoporosis treatment include application of antiresorptive and anabolic agents influencing bone tissue metabolism. The aim of the study was to present bone mineral density (BMD) changes of lumbar spine in osteoporotic patient treated with bisphosphonates such as ibandronic acid and pamidronic acid, and beta-hydroxy-beta-methylbutyrate (HMB). BMD and volumetric BMD (vBMD) of lumbar spine were measured during the 6 year observation period with the use of dual-energy X-ray absorptiometry (DEXA) and quantitative computed tomography (QCT). The described case report of osteoporotic patient with family history of severe osteoporosis has shown site-dependent response of bone tissue to antiosteoporotic treatment with bisphosphonates. Twenty-five-month treatment with ibandronic acid improved proximal femur BMD with relatively poor effects on lumbar spine BMD. Over 15-month therapy with pamidronic acid was effective to improve lumbar spine BMD, while in the proximal femur the treatment was not effective. A total of 61-week long oral administration with calcium salt of HMB improved vBMD of lumbar spine in the trabecular and cortical bone compartments when monitored by QCT. Positive effects of nearly 2.5 year HMB treatment on BMD of lumbar spine and femur in the patient were also confirmed using DEXA method. The results obtained indicate that HMB may be applied for the effective treatment of osteoporosis in humans. Further studies on wider human population are recommended to evaluate mechanisms influencing bone tissue metabolism by HMB.

  6. Disorder-derived, strong tunneling attenuation in bis-phosphonate monolayers

    Science.gov (United States)

    Pathak, Anshuma; Bora, Achyut; Liao, Kung-Ching; Schmolke, Hannah; Jung, Antje; Klages, Claus-Peter; Schwartz, Jeffrey; Tornow, Marc

    2016-03-01

    Monolayers of alkyl bisphosphonic acids (bisPAs) of various carbon chain lengths (C4, C8, C10, C12) were grown on aluminum oxide (AlO x ) surfaces from solution. The structural and electrical properties of these self-assembled monolayers (SAMs) were compared with those of alkyl monophosphonic acids (monoPAs). Through contact angle (CA) and Kelvin-probe (KP) measurements, ellipsometry, and infrared (IR) and x-ray photoelectron (XPS) spectroscopies, it was found that bisPAs form monolayers that are relatively disordered compared to their monoPA analogs. Current-voltage (J-V) measurements made with a hanging Hg drop top contact show tunneling to be the prevailing transport mechanism. However, while the monoPAs have an observed decay constant within the typical range for dense monolayers, β mono  =  0.85  ±  0.03 per carbon atom, a surprisingly high value, β bis  =  1.40  ±  0.05 per carbon atom, was measured for the bisPAs. We attribute this to a strong contribution of ‘through-space’ tunneling, which derives from conformational disorder in the monolayer due to strong interactions of the distal phosphonic acid groups; they likely form a hydrogen-bonding network that largely determines the molecular layer structure. Since bisPA SAMs attenuate tunnel currents more effectively than do the corresponding monoPA SAMs, they may find future application as gate dielectric modification in organic thin film devices.

  7. Efficacy and safety of bisphosphonates in management of low bone density in inflammatory bowel disease: A meta-analysis.

    Science.gov (United States)

    Yao, Liwei; Wang, Haiqing; Dong, Wenwei; Liu, Zhenxin; Mao, Haijiao

    2017-01-01

    This study aims to determine whether bisphosphonates are safe, as well as effective against bone mineral loss in inflammatory bowel disease (IBD). A computerized search of electronic databases from 1966 to 2016 was performed. Randomized controlled trials (RCTs) were included in this review to evaluate the role of bisphosphonates in the management of osteoporosis in IBD patients. A revised 7-point Jadad scale was used to evaluate the quality of each study. Overall, 13 RCTs and 923 patients met the inclusion criteria of this meta-analysis. The result showed that bisphosphonates decreased bone mass density (BMD) loss at the lumbar spine (P = 0.0002), reduced the risk of new fractures (P = 0.01), and retained the similar adverse events (P = 0.86). Bisphosphonates may provide protection and safety against bone mineral loss in IBD patients.

  8. Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

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    Xiang Zhou

    2014-07-01

    Full Text Available A set of bisphosphonate ethers has been prepared through sequential phosphonylation and alkylation of monophosphonate ethers. After formation of the corresponding phosphonic acid salts, these compounds were tested for their ability to inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS. Five of the new compounds show IC50 values of less than 1 μM against GGDPS with little to no activity against the related enzyme farnesyl diphosphate synthase (FDPS. The most active compound displayed an IC50 value of 82 nM when assayed with GGDPS, and no activity against FDPS even at a 10 μM concentration.

  9. Uptake of a fluorinated bisphosphonate by cultured bones

    International Nuclear Information System (INIS)

    Rowe, D.J.; Etre, L.A.

    1988-01-01

    The uptake of bisphosphonates into bone was studied using 19-day-old fetal rat bones cultured with a new fluorinated bisphosphonate, difluoromethylidene bisphosphonate (F2MBP). F2MBP uptake was assessed by determining the weight percent of fluoride using electron probe microanalysis. By 30 min the weight percent of fluoride was significantly greater in the F2MBP-treated bones than in controls and continually increased throughout the duration of the experiment to reach a fluoride concentration 6-fold greater than controls after 120 h of incubation. When the peripheral cortical bone was analyzed separately from the interior trabecular bone in the F2MBP-treated bones, the fluoride concentration in the periphery increased until 24 h and then remained somewhat constant, while the interior, which is more actively remodeling, showed a continual increase. The uptake of F2MBP during the 1 to 6 h time intervals demonstrated no differences between vital and devitalized bone and, thus, is not cell-mediated. Because analysis of free fluoride in F2MBP media incubated with bones showed that the concentration of fluoride was less than 1% of the total amount of fluoride, the fluoride detected by the probe was most likely that of the intact molecule and not free fluoride. The rapid uptake of the F2MBP molecule was supported by assessing the effects of short-term F2MBP treatment on subsequent bone resorption, as determined by the release of 45Ca from prelabeled bones. Bones treated with F2MBP for only 5 min exhibited reductions in the percentage of 45Ca released during the remainder of the 120 h incubation period similar to that when F2MBP was continuously in the medium

  10. Bisphosphonates and their clinical implications in endodontic therapy.

    Science.gov (United States)

    Moinzadeh, A-T; Shemesh, H; Neirynck, N A M; Aubert, C; Wesselink, P R

    2013-05-01

    This review gives an overview of the factors that may play a role in the development of osteonecrosis of the jaw in patients treated with bisphosphonates (BPs) and undergoing nonsurgical endodontic treatment as well as some recommendations for its prevention. BPs are a widely prescribed group of drugs for diverse bone diseases. The occasional but devastating adverse effect of these drugs has been described as bisphosphonate-related osteonecrosis of the jaw (BRONJ). As this condition is debilitating and difficult to treat, all efforts should be made to prevent its occurence in patients at risk. The main triggering event is considered to be dental extraction. Even though nonsurgical endodontic treatment appears to be a relatively safe procedure, care remains essential. After an overview of this class of drugs, the clinical presentation, epidemiology and pathogenesis of BRONJ, as well as the possible risk factors associated with its development after nonsurgical endodontic treatment will be described. Finally, several strategies will be proposed for the prevention of BRONJ during nonsurgical endodontic treatment. © 2012 International Endodontic Journal. Published by Blackwell Publishing Ltd.

  11. Interest of bone scintigraphy in the care of maxillary osteo-necroses induced by bis-phosphonates

    International Nuclear Information System (INIS)

    Agossa, Kevimy

    2012-01-01

    First cases of bis-phosphonates related osteonecrosis of jaws (BRONJ) have been described in 2003. Since then, this subject is one of the central concerns of several scientific communities, well beyond the oral sphere. The prevalence of BRONJ is evolving. Their etiology is not well established and the results of the treatments are inconstant. So many points that make the care to patients under bis-phosphonates really complex. Early diagnosis is essential in treatment outcome. So nuclear imaging including scintigraphy with technetium 99m seems to be helpful. It may allow detection before the onset of symptoms, facilitate localization of necrosis and it may be useful for the monitoring of such lesions after surgery. These are new applications for oncologist and dentist, in order to improve the management of patients treated by bis-phosphonates. (author) [fr

  12. Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

    International Nuclear Information System (INIS)

    Odri, Guillaume; Kim, Pui-Pui; Lamoureux, François; Charrier, Céline; Battaglia, Séverine; Amiaud, Jérôme; Heymann, Dominique; Gouin, François; Redini, Françoise

    2014-01-01

    Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 10 6 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs

  13. Bone Health in Patients with Breast Cancer: Recommendations from an Evidence-Based Canadian Guideline

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    Alexander H. G. Paterson

    2013-12-01

    Full Text Available Bone loss is common in patients with breast cancer. Bone modifying agents (BMAs, such as bisphosphonates and denosumab, have been shown to reverse or stabilize bone loss and may be useful in the primary and metastatic settings. The purpose of this review is to provide clear evidence-based strategies for the management of bone loss and its symptoms in breast cancer. A systematic review of clinical trials and meta-analyses published between 1996 and 2012 was conducted of MEDLINE and EMBASE. Reference lists were hand-searched for additional publications. Recommendations were developed based on the best available evidence. Zoledronate, pamidronate, clodronate, and denosumab are recommended for metastatic breast cancer patients; however, no one agent can be recommended over another. Zoledronate or any oral bisphosphonate and denosumab should be considered in primary breast cancer patients who are postmenopausal on aromatase inhibitor therapy and have a high risk of fracture and/or a low bone mineral density and in premenopausal primary breast cancer patients who become amenorrheic after therapy. No one agent can be recommended over another. BMAs are not currently recommended as adjuvant therapy in primary breast cancer for the purpose of improving survival, although a major Early Breast Cancer Cooperative Trialists’ Group meta-analysis is underway which may impact future practice. Adverse events can be managed with appropriate supportive care.

  14. Utilization of bone densitometry for prediction and administration of bisphosphonates to prevent osteoporosis in patients with prostate cancer without bone metastases receiving antiandrogen therapy

    International Nuclear Information System (INIS)

    Holt, Abby; Khan, Muhammad A; Gujja, Swetha; Govindarajan, Rangaswmy

    2014-01-01

    Prostate cancer subjects with prostate-specific antigen (PSA) relapse who are treated with androgen deprivation therapy (ADT) are recommended to have baseline and serial bone densitometry and receive bisphosphonates. The purpose of this community population study was to assess the utilization of bone densitometry and bisphosphonate therapy in men receiving ADT for non-metastatic prostate cancer. A cohort study of men aged 65 years or older with non-metastatic incident diagnoses of prostate cancer was obtained from the Surveillance Epidemiology End Results (SEER)-linked Medicare claims between 2004 and 2008. Claims were used to assess prescribed treatment of ADT, bone densitometry, and bisphosphonates. A total of 30,846 incident prostate cancer cases receiving ADT and aged 65 years or older had no bone metastases; 87.3% (n=26,935) on ADT did not receive either bone densitometry or bisphosphonate therapy. Three percent (n=931) of the cases on ADT received bisphosphonate therapy without ever receiving bone densitometry, 8.8% (n=2,702) of the cases on ADT received bone densitometry without receiving intravenous bisphosphonates, while nearly 1% (0.90%, n=278) of the cases on ADT received both bone densitometry and bisphosphonates. Analysis showed treatment differed by patient characteristics. Contrary to the recommendations, bone densitometry and bisphosphonate therapy are underutilized in men receiving ADT for non-metastatic prostate cancer

  15. Expression of Dlx-5 and Msx-1 in Craniofacial Skeletons and Ilia of Rats Treated With Zoledronate.

    Science.gov (United States)

    Xuan, Bin; Yang, Pan; Wu, Shichao; Li, Lin; Zhang, Jian; Zhang, Wenyi

    2017-05-01

    Because of the different embryologic origins of the craniofacial skeleton and ilium, differences in gene expression patterns have been observed between the jaw bones and ilium. Distal-less homeobox (Dlx) genes and Msh homeobox genes, particularly Dlx-5 and Msx-1, play major roles in cell differentiation and osteogenesis. The purpose of this study was to investigate the effects of zoledronate (ZOL) on the craniofacial skeleton and ilium by detecting changes in Dlx-5 and Msx-1 expression at both the protein and messenger RNA levels. A total of 24 female Sprague-Dawley rats were randomly divided into 2 groups: ZOL group (n = 12), in which the rats were injected intraperitoneally with zoledronic acid for 12 weeks, and control group (n = 12), in which the rats were injected with saline solution for 12 weeks. By use of immunohistochemistry, Western blotting, and real-time reverse transcription polymerase chain reaction, the expression levels of Dlx-5 and Msx-1 in the craniofacial skeleton (including the maxilla, mandible, and parietal bone) and ilium were examined. Dlx-5 expression in the maxilla and mandible was increased at the protein and messenger RNA levels in the ZOL group compared with the control group (P Msx-1 expression in the maxilla and mandible was decreased in the ZOL group (P Msx-1 expression in the ilium was decreased in the ZOL group (P Msx-1 expression in the parietal bone was observed between the 2 groups (P > .05). Site-specific differences in the effects of ZOL on the craniofacial skeleton and ilium could be explained by differently altered tendencies in Dlx-5 and Msx-1 expression. The jaw bones were more susceptible to the effects of ZOL than the parietal bone and ilium. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  16. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment.

    Science.gov (United States)

    Sato, Atsuko; Ouellet, Jean; Muneta, Takeshi; Glorieux, Francis H; Rauch, Frank

    2016-05-01

    Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Bifunctional Bisphosphonates for Delivering Biomolecules to Bone

    Science.gov (United States)

    2012-01-13

    formation could be analyzed after a few weeks. Scanning electron microscopy (SEM), FT-IR, X- ray Diffraction (XRD), and high-resolution X- ray computed...Bisphosphonates: Mode of action and pharmacology, Pediatrics 119 Suppl 2, S150-162. 36. Roelofs, A. J., Thompson, K., Gordon, S., and Rogers, M. J...E., Mahmood, A., Jones, A. G., Cantley, L. C., and Frangioni, J. V. (2001) In vivo near- infrared fluorescence imaging of osteoblastic activity

  18. Disorder-derived, strong tunneling attenuation in bis-phosphonate monolayers

    International Nuclear Information System (INIS)

    Pathak, Anshuma; Bora, Achyut; Tornow, Marc; Liao, Kung-Ching; Schwartz, Jeffrey; Schmolke, Hannah; Jung, Antje; Klages, Claus-Peter

    2016-01-01

    Monolayers of alkyl bisphosphonic acids (bisPAs) of various carbon chain lengths (C4, C8, C10, C12) were grown on aluminum oxide (AlO x ) surfaces from solution. The structural and electrical properties of these self-assembled monolayers (SAMs) were compared with those of alkyl monophosphonic acids (monoPAs). Through contact angle (CA) and Kelvin-probe (KP) measurements, ellipsometry, and infrared (IR) and x-ray photoelectron (XPS) spectroscopies, it was found that bisPAs form monolayers that are relatively disordered compared to their monoPA analogs. Current–voltage (J–V) measurements made with a hanging Hg drop top contact show tunneling to be the prevailing transport mechanism. However, while the monoPAs have an observed decay constant within the typical range for dense monolayers, β mono   =  0.85  ±  0.03 per carbon atom, a surprisingly high value, β bis   =  1.40  ±  0.05 per carbon atom, was measured for the bisPAs. We attribute this to a strong contribution of ‘through-space’ tunneling, which derives from conformational disorder in the monolayer due to strong interactions of the distal phosphonic acid groups; they likely form a hydrogen-bonding network that largely determines the molecular layer structure. Since bisPA SAMs attenuate tunnel currents more effectively than do the corresponding monoPA SAMs, they may find future application as gate dielectric modification in organic thin film devices. (paper)

  19. Radiographic and MR Imaging Findings of the Spine after Bisphosphonate Treatment, in a Child with Idiopathic Juvenile Osteoporosis

    Directory of Open Access Journals (Sweden)

    Olympia Papakonstantinou

    2015-01-01

    Full Text Available Bisphosphonates are employed with increasing frequency in various pediatric disorders, mainly associated with osteoporosis. After cessation of bisphosphonate treatment in children, skeletal radiologic changes have been documented including dense metaphyseal lines of the long bones and “bone in bone” appearance of the vertebrae. However, the evolution of these radiographic changes has not been fully explored. We describe the MR imaging appearance of the spine that, to our knowledge, has not been previously addressed in a child with idiopathic juvenile osteoporosis who had received bisphosphonates and emphasize the evolution of the radiographic findings of the spine and pelvis over a four-year period.

  20. Applying orthodontic tooth extrusion in a patient treated with bisphosphonate and irradiation: a case report.

    Science.gov (United States)

    Morita, Hiromitsu; Imai, Yuko; Yoneda, Masahiro; Hirofuji, Takao

    2017-01-01

    Bisphosphonates and irradiation are useful medical treatments, but can often cause oral complications such as medication-related oral necrosis of the jaw (MRONJ) and osteoradionecrosis (ORN) during oral surgery, including tooth extraction. Therefore, we should take all risks into consideration carefully before choosing dental treatment for patients with a medical history of such therapies. A 55-year-old woman who underwent cord blood transplantation to treat extranodal natural killer T (NK/T) cell lymphoma (nasal type IVB) had a medical history of bisphosphonate and irradiation treatments. We treated her residual tooth root by applying orthodontic extrusion to avoid extraction and successfully restored the tooth. Application of an orthodontic tooth extrusion technique for conservative treatment of a residual tooth is a useful means of avoiding MRONJ or ORN in patients who have a medical history of bisphosphonate and irradiation treatments. © 2016 Special Care Dentistry Association and Wiley Periodicals, Inc.

  1. Teriparatide versus low-dose bisphosphonates before and after surgery for adult spinal deformity in female Japanese patients with osteoporosis.

    Science.gov (United States)

    Seki, Shoji; Hirano, Norikazu; Kawaguchi, Yoshiharu; Nakano, Masato; Yasuda, Taketoshi; Suzuki, Kayo; Watanabe, Kenta; Makino, Hiroto; Kanamori, Masahiko; Kimura, Tomoatsu

    2017-08-01

    Complications of adult spinal deformity surgery are problematic in osteoporotic individuals. We compared outcomes between Japanese patients treated perioperatively with teriparatide vs. low-dose bisphosphonates. Fifty-eight osteoporotic adult Japanese female patients were enrolled and assigned to perioperative teriparatide (33 patients) and bisphosphonate (25 patients) groups in non-blinded fashion. Pre- and post-operative X-ray and computed tomography imaging were used to assess outcome, and rates were compared between the groups and according to age. Pain scores and Oswestry Disability Indices (ODI) were calculated before and 2 years after surgery. Adjacent vertebral fractures and implant failure, fusion failure, and poor pain and ODI outcomes were significantly more common in the bisphosphonates group than the teriparatide group. Perioperative administration of teriparatide is more effective than that of low-dose bisphosphonates in preventing complications and maintaining fusion rates in osteoporotic Japanese females with spinal deformities undergoing surgery.

  2. Fractures and mortality in relation to different osteoporosis treatments.

    Science.gov (United States)

    Yun, Huifeng; Delzell, Elizabeth; Saag, Kenneth G; Kilgore, Meredith L; Morrisey, Michael A; Muntner, Paul; Matthews, Robert; Guo, Lingli; Wright, Nicole; Smith, Wilson; Colón-Emeric, Cathleen; O'Connor, Christopher M; Lyles, Kenneth W; Curtis, Jeffrey R

    2015-01-01

    Few studies have assessed the effectiveness of different drugs for osteoporosis (OP). We aimed to determine if fracture and mortality rates vary among patients initiating different OP medications. We used the Medicare 5% sample to identify new users of intravenous (IV) zoledronic acid (n=1.674), oral bisphosphonates (n=32.626), IV ibandronate (n=492), calcitonin (n=2.606), raloxifene (n=1.950), or parathyroid hormone (n=549). We included beneficiaries who were ≥65 years of age, were continuously enrolled in fee-for-service Medicare and initiated therapy during 2007-2009. Outcomes were hip fracture, clinical vertebral fracture, and all-cause mortality, identified using inpatient and physician diagnosis codes for fracture, procedure codes for fracture repair, and vital status information. Cox regression models compared users of each medication to users of IV zoledronic acid, adjusting for multiple confounders. During follow-up (median, 0.8-1.5 years depending on the drug), 787 subjects had hip fractures, 986 had clinical vertebral fractures, and 2.999 died. Positive associations included IV ibandronate with hip fracture (adjusted hazard ratio (HR), 2.37; 95% confidence interval (CI) 1.25-4.51), calcitonin with vertebral fracture (HR=1.59, 95%CI 1.04-2.43), and calcitonin with mortality (HR=1.31; 95%CI 1.02-1.68). Adjusted HRs for other drug-outcome comparisons were not statistically significant. IV ibandronate and calcitonin were associated with higher rates of some types of fracture when compared to IV zolendronic acid. The relatively high mortality associated with use of calcitonin may reflect the poorer health of users of this agent.

  3. Nitrogen-containing bisphosphonate, YM529/ONO-5920 (a novel minodronic acid), inhibits RANKL expression in a cultured bone marrow stromal cell line ST2

    International Nuclear Information System (INIS)

    Nishida, Shozo; Tsubaki, Masanobu; Hoshino, Mayumi; Namimatsu, Ayumi; Uji, Hiromi; Yoshioka, Shohei; Tanimori, Yoshihiro; Yanae, Masashi; Iwaki, Masahiro; Irimajiri, Kiyohiro

    2005-01-01

    Increase in bone resorption by osteoclasts can cause metabolic bone diseases, such as osteoporosis. Recent attention has been paid to the receptor activator of the NF-κB ligand (RANKL), an accelerator of osteoclast differentiation. RANKL is expressed on the bone marrow-derived stromal cell membrane and induces the differentiation of osteoclasts by binding to RANK expressed on the osteoclast precursor cell membrane. Since the inhibition of RANKL expression can lead to the inhibition of osteoclastic bone resorption, the clinical application of RANKL inhibition could be expected to have a major effect on metabolic bone disease therapy. In this study, we investigated whether or not YM529/ONO-5920, a nitrogen-containing bisphosphonate (a novel minodronic acid), inhibits RANKL expression in a bone marrow-derived stromal cell line (ST2 cells). Reverse transcription-polymerase chain reaction revealed that the administration of YM529/ONO-5920 to ST2 cells inhibited RANKL mRNA expression and reduced RANKL proteins as assessed by Western blot analysis. The inhibition of RANKL mRNA expression was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination. Furthermore, YM529/ONO-5920 reduced phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and similarly, U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, inhibited RANKL expression. Pretreatment with GGPP reversed the YM529/ONO-5920-induced decrease in phosphorylation of ERK. Furthermore, YM529/ONO-5920 decreased TRAP-positive cells in co-culture of ST2 cells and an osteoclast cell line, C7 cells, and this decrease was inhibited by pretreatment with GGPP. This indicates that YM529/ONO-5920 inhibits GGPP biosynthesis in the mevalonate pathway and then signal transduction in the Ras-mitogen-activated protein kinase pathway, thereby inhibiting RANKL expression on ST2 cells. These results suggest a newly elucidated action of bisphosphonates in

  4. A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.

    Science.gov (United States)

    Clive, Amelia O; Hooper, Clare E; Edey, Anthony J; Morley, Anna J; Zahan-Evans, Natalie; Hall, David; Lyburn, Iain; White, Paul; Braybrooke, Jeremy P; Sequeiros, Iara; Lyen, Stephen M; Milton, Tim; Kahan, Brennan C; Maskell, Nick A

    2015-01-01

    Animal studies have shown Zoledronic Acid (ZA) may diminish pleural fluid accumulation and tumour bulk in malignant pleural disease (MPD). We performed a pilot study to evaluate its effects in humans. We undertook a single centre, double-blind, placebo-controlled trial in adults with MPD. Patients were randomised (1:1) to receive 2 doses of intravenous ZA or placebo, 3 weeks apart and were followed-up for 6 weeks. The co-primary outcomes were change in Visual Analogue Scale (VAS) score measured breathlessness during trial follow-up and change in the initial area under the curve (iAUC) on thoracic Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) from randomisation to week 5. Multiple secondary endpoints were also evaluated. Between January 2010 and May 2013, 30 patients were enrolled, 24 randomised and 4 withdrew after randomisation (1 withdrew consent; 3 had a clinical decline). At baseline, the ZA group were more breathless, had more advanced disease on radiology and worse quality of life than the placebo group. There was no significant difference between the groups with regards change in breathlessness (Adjusted mean difference (AMD) 4.16 (95%CI -4.7 to 13.0)) or change in DCE-MRI iAUC (AMD -15.4 (95%CI -58.1 to 27.3). Two of nine (22%) in the ZA arm had a >10% improvement by modified RECIST (vs 0/11 who received placebo). There was no significant difference in quality of life measured by the QLQ-C30 score (global QOL: AMD -4.1 (-13.0 to 4.9)), side effects or serious adverse event rates. This is the first human study to evaluate ZA in MPD. The study is limited by small numbers and imbalanced baseline characteristics. Although no convincing treatment effect was identified, potential benefits for specific subgroups of patients cannot be excluded. This study provides important information regarding the feasibility of future trials to evaluate the effects of ZA further. UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com.

  5. A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.

    Directory of Open Access Journals (Sweden)

    Amelia O Clive

    Full Text Available Animal studies have shown Zoledronic Acid (ZA may diminish pleural fluid accumulation and tumour bulk in malignant pleural disease (MPD. We performed a pilot study to evaluate its effects in humans.We undertook a single centre, double-blind, placebo-controlled trial in adults with MPD. Patients were randomised (1:1 to receive 2 doses of intravenous ZA or placebo, 3 weeks apart and were followed-up for 6 weeks. The co-primary outcomes were change in Visual Analogue Scale (VAS score measured breathlessness during trial follow-up and change in the initial area under the curve (iAUC on thoracic Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI from randomisation to week 5. Multiple secondary endpoints were also evaluated.Between January 2010 and May 2013, 30 patients were enrolled, 24 randomised and 4 withdrew after randomisation (1 withdrew consent; 3 had a clinical decline. At baseline, the ZA group were more breathless, had more advanced disease on radiology and worse quality of life than the placebo group. There was no significant difference between the groups with regards change in breathlessness (Adjusted mean difference (AMD 4.16 (95%CI -4.7 to 13.0 or change in DCE-MRI iAUC (AMD -15.4 (95%CI -58.1 to 27.3. Two of nine (22% in the ZA arm had a >10% improvement by modified RECIST (vs 0/11 who received placebo. There was no significant difference in quality of life measured by the QLQ-C30 score (global QOL: AMD -4.1 (-13.0 to 4.9, side effects or serious adverse event rates.This is the first human study to evaluate ZA in MPD. The study is limited by small numbers and imbalanced baseline characteristics. Although no convincing treatment effect was identified, potential benefits for specific subgroups of patients cannot be excluded. This study provides important information regarding the feasibility of future trials to evaluate the effects of ZA further.UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com.

  6. Differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates

    Directory of Open Access Journals (Sweden)

    Karthik Balachandran

    2014-01-01

    Full Text Available Context: Tumoral calcinosis is a disorder of phosphate metabolism characterized by ectopic calcification around major joints. Surgery is the current treatment of choice, but a suboptimal choice in recurrent and multicentric lesions. Aims: To evaluate the efficacy of bisphosphonates for the management of tumoral calcinosis on optimized medical treatment. Settings and Design: The study was done in the endocrine department of a tertiary care hospital in South India. We prospectively studied two patients with recurrent tumoral calcinosis who had failed therapy with phosphate lowering measures. Materials and Methods: After informed consent, we treated both patients with standard age adjusted doses of bisphosphonates for 18 months. The response was assessed by X ray and whole body 99mTc-methylene diphosphonate bone scan at the beginning of therapy and at the end of 1 year. We also estimated serum phosphate levels and urinary phosphate to document serial changes. Results: Two patients (aged 19 and 5 years with recurrent idiopathic hyperphosphatemic tumoral calcinosis, following surgery were studied. Both patients had failed therapy with conventional medical management − low phosphate diet and phosphate binders. They had restriction of joint mobility. Both were given standard doses of oral alendronate and parenteral pamidronate respectively for more than a year, along with phosphate lowering measures. At the end of 1 year, one of the patients had more than 95% and 90% reduction in the size of the lesions in right and left shoulder joints respectively with total improvement in range of motion. In contrast, the other patient (5-year-old had shown no improvement, despite continuing to maintain normophosphatemia following treatment. Conclusions: Bisphosphonate therapy in tumoral calcinosis is associated with lesion resolution and may be used as a viable alternative to surgery, especially in cases with multicentric recurrence or treatment failure to other

  7. Effect of Zoledronic Acid and Denosumab in Patients With Low Back Pain and Modic Change: A Proof-of-Principle Trial.

    Science.gov (United States)

    Cai, Guoqi; Laslett, Laura L; Aitken, Dawn; Halliday, Andrew; Pan, Feng; Otahal, Petr; Speden, Deborah; Winzenberg, Tania M; Jones, Graeme

    2018-05-01

    The aim of this study was to evaluate the effect of zoledronic acid (ZA) and denosumab on low back pain (LBP) and Modic change (MC) over 6 months. Adults aged ≥40 years with significant LBP for at least 6 months duration and MC (type 1, 2, or mixed) were randomized to receive ZA (5 mg/100 mL), denosumab (60 mg), or placebo. LBP was measured monthly by visual analogue scale (VAS) and the LBP Rating Scale (RS). MC was measured from MRIs of T 12 -S 1 vertebrae at screening and 6 months. A total of 103 participants with moderate/severe LBP (mean VAS = 57 mm; mean RS = 18) and median total MC area 538 mm 2 were enrolled. Compared to placebo, LBP reduced significantly at 6 months in the ZA group for RS (-3.3; 95% CI, -5.9 to -0.7) but not VAS (-8.2; 95% CI, -18.8 to +2.4) with similar findings for denosumab (RS, -3.0; 95% CI, -5.7 to -0.3; VAS, -10.7; 95% CI, -21.7 to +0.2). There was little change in areal MC size overall and no difference between groups with the exception of denosumab in those with type 1 Modic change (-22.1 mm 2 ; 95% CI, -41.5 to -2.7). In post hoc analyses, both medications significantly reduced VAS LBP in participants with milder disc degeneration and non-neuropathic pain, and denosumab reduced VAS LBP in those with type 1 MC over 6 months, compared to placebo. Adverse events were more frequent in the ZA group. These results suggests a potential therapeutic role for ZA and denosumab in MC-associated LBP. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research.

  8. Bisphosphonates in osteoporosis: Where do we stand in 2009? | de ...

    African Journals Online (AJOL)

    Gastrointestinal side-effects are common, but can often be avoided by taking medication in the prescribed fashion. The acute phase response to intravenous administration can be prevented by co-administration of oral paracetamol or ibuprofen. Bisphosphonates can cause bone pain. The Food and Drug Administration ...

  9. Cost-effectiveness of combined oral bisphosphonate therapy and falls prevention exercise for fracture prevention in the USA.

    Science.gov (United States)

    Mori, T; Crandall, C J; Ganz, D A

    2017-02-01

    We developed a Markov microsimulation model among hypothetical cohorts of community-dwelling US white women without prior major osteoporotic fractures over a lifetime horizon. At ages 75 and 80, adding 1 year of exercise to 5 years of oral bisphosphonate therapy is cost-effective at a conventionally accepted threshold compared with bisphosphonates alone. The purpose of this study was to examine the cost-effectiveness of the combined strategy of oral bisphosphonate therapy for 5 years and falls prevention exercise for 1 year compared with either strategy in isolation. We calculated incremental cost-effectiveness ratios [ICERs] (2014 US dollars per quality-adjusted life year [QALY]), using a Markov microsimulation model among hypothetical cohorts of community-dwelling US white women with different starting ages (65, 70, 75, and 80) without prior history of hip, vertebral, or wrist fractures over a lifetime horizon from the societal perspective. At ages 65, 70, 75, and 80, the combined strategy had ICERs of $202,020, $118,460, $46,870, and $17,640 per QALY, respectively, compared with oral bisphosphonate therapy alone. The combined strategy provided better health at lower cost than falls prevention exercise alone at ages 70, 75, and 80. In deterministic sensitivity analyses, results were particularly sensitive to the change in the opportunity cost of participants' time spent exercising. In probabilistic sensitivity analyses, the probabilities of the combined strategy being cost-effective compared with the next best alternative increased with age, ranging from 35 % at age 65 to 48 % at age 80 at a willingness-to-pay of $100,000 per QALY. Among community-dwelling US white women ages 75 and 80, adding 1 year of exercise to 5 years of oral bisphosphonate therapy is cost-effective at a willingness-to-pay of $100,000 per QALY, compared with oral bisphosphonate therapy only. This analysis will help clinicians and policymakers make better decisions about treatment

  10. Bisphosphonate associated osteonecrosis of the jaw.

    Science.gov (United States)

    Khan, Aliya A; Sándor, George K B; Dore, Edward; Morrison, Archibald D; Alsahli, Mazen; Amin, Faizan; Peters, Edmund; Hanley, David A; Chaudry, Sultan R; Lentle, Brian; Dempster, David W; Glorieux, Francis H; Neville, Alan J; Talwar, Reena M; Clokie, Cameron M; Mardini, Majd Al; Paul, Terri; Khosla, Sundeep; Josse, Robert G; Sutherland, Susan; Lam, David K; Carmichael, Robert P; Blanas, Nick; Kendler, David; Petak, Steven; Ste-Marie, Louis Georges; Brown, Jacques; Evans, A Wayne; Rios, Lorena; Compston, Juliet E

    2009-03-01

    In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BP) were published. These cases occurred in patients with cancer receiving high-dose intravenous BP; however, 5% of the cases were in patients with osteoporosis receiving low-dose bisphosphonate therapy. We present the results of a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BP associated ONJ. We conducted a comprehensive literature search for relevant studies on BP associated ONJ in oncology and osteoporosis patients published before February 2008.All selected relevant articles were sorted by area of focus. Data for each area were abstracted by 2 independent reviewers. The results showed that the diagnosis is made clinically. Prospective data evaluating the incidence and etiologic factors are very limited. In oncology patients receiving high-dose intravenous BP, ONJ appears to be dependent on the dose and duration of therapy, with an estimated incidence of 1%-12% at 36 months of exposure. In osteoporosis patients, it is rare, with an estimated incidence < 1 case per 100,000 person-years of exposure. The incidence of ONJ in the general population is not known. Currently, there is insufficient evidence to confirm a causal link between low-dose BP use in the osteoporosis patient population and ONJ. We concluded BP associated ONJ is associated with high-dose BP therapy primarily in the oncology patient population. Prevention and treatment strategies are currently based on expert opinion and focus on maintaining good oral hygiene and conservative surgical intervention.

  11. A review of minodronic acid hydrate for the treatment of osteoporosis

    Directory of Open Access Journals (Sweden)

    Tanishima S

    2013-02-01

    Full Text Available Shinji Tanishima, Yasuo MorioDepartment of Orthopedic Surgery, Misasa Onsen Hospital, Misasa, Tottori, JapanAbstract: Minodronic acid hydrate was the first bisphosphonate developed and approved for osteoporosis treatment in Japan. With regard to inhibition of bone resorption, minodronic acid hydrate is 1000 times more effective than etidronic acid and 10–100 times more effective than alendronic acid. Clinical trials conducted to date have focused on postmenopausal female patients suffering from primary osteoporosis. In these trials, 1 mg of oral minodronic acid hydrate was administrated once daily, and a significant increase was observed in lumbar-spine and hip-joint bone density 1–2 years after administration. All markers of bone metabolism urinary collagen type 1 cross-linked N-telopeptide, urinary free deoxypyridinoline, serum bone alkaline phosphatase, and serum osteocalcin were decreased. The incidence rate of new vertebral and nonvertebral fractures was also decreased. Therefore, effectiveness in fracture prevention was confirmed. A form of minodronic acid (50 mg requiring once-monthly administration has been developed and is currently being used clinically. A comparative study between this new formulation and once-daily minodronic acid (1 mg showed no significant differences between the two formulations in terms of improvement rates in lumbar-spine and hip-joint bone density, changes in bone metabolism markers, or incidence of side effects. This indicates the noninferiority of the monthly formulation. Side effects such as osteonecrosis of the jaw or atypical femoral fractures were not reported with other bisphosphonates, although it is believed that these side effects may emerge as future studies continue to be conducted. On the basis of studies conducted to date, minodronic acid hydrate is considered effective for improving bone density and preventing fractures. We anticipate further investigations in the future

  12. 5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial.

    Science.gov (United States)

    Wagner-Johnston, Nina D; Sloan, Jeff A; Liu, Heshan; Kearns, Ann E; Hines, Stephanie L; Puttabasavaiah, Suneetha; Dakhil, Shaker R; Lafky, Jacqueline M; Perez, Edith A; Loprinzi, Charles L

    2015-08-01

    Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms. © 2015 American Cancer Society.

  13. Time to onset of bisphosphonate-related osteonecrosis of the jaws

    DEFF Research Database (Denmark)

    Fung, Ppl; Bedogni, G; Bedogni, A

    2017-01-01

    OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to esti...

  14. Nanocomposite hydrogels stabilized by self-assembled multivalent bisphosphonate-magnesium nanoparticles mediate sustained release of magnesium ion and promote in-situ bone regeneration.

    Science.gov (United States)

    Zhang, Kunyu; Lin, Sien; Feng, Qian; Dong, Chaoqun; Yang, Yanhua; Li, Gang; Bian, Liming

    2017-12-01

    Hydrogels are appealing biomaterials for applications in regenerative medicine due to their tunable physical and bioactive properties. Meanwhile, therapeutic metal ions, such as magnesium ion (Mg 2+ ), not only regulate the cellular behaviors but also stimulate local bone formation and healing. However, the effective delivery and tailored release of Mg 2+ remains a challenge, with few reports on hydrogels being used for Mg 2+ delivery. Bisphosphonate exhibits a variety of specific bioactivities and excellent binding affinity to multivalent cations such as Mg 2+ . Herein, we describe a nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. These nanoparticles bearing acrylate groups on the surface not only function as effective multivalent crosslinkers to strengthen the hydrogel network structure, but also promote the mineralization of hydrogels and mediate sustained release of Mg 2+ . The released Mg 2+ ions facilitate stem cell adhesion and spreading on the hydrogel substrates in the absence of cell adhesion ligands, and promote osteogenesis of the seeded hMSCs in vitro. Furthermore, the acellular porous hydrogels alone can support in situ bone regeneration without using exogenous cells and inductive agents, thereby greatly simplifying the approaches of bone regeneration therapy. In this study, we developed a novel bioactive nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. Such hydrogels are stabilized by the multivalent crosslinking domains formed by the aggregation of Ac-BP-Mg NPs, and therefore show enhanced mechanical properties, improved capacity for mineralization, and controlled release kinetics of Mg 2+ . Moreover, the released Mg 2+ can enhance cell adhesion and spreading, and further promote the osteogenic differentiation of hMSCs. Owing to these unique properties, these acellular hydrogels alone can well facilitate the in vivo

  15. Cost-effectiveness of increasing bisphosphonates adherence for osteoporosis in community pharmacies

    NARCIS (Netherlands)

    Van Boven, J.F.M.; Oosterhof, P.; Hiddink, E.G.; Stuurman-Bieze, A.G.G.; Postma, M.J.; Vegter, S.

    2011-01-01

    OBJECTIVES: Increasing real-life adherence to bisphosphonates therapy is important to achieve the clinical benefits of reducing fractures reported in randomized clinical trials (RCTs). The aim of this pharmacoeconomic analysis was to determine the cost-effectiveness of a pharmaceutical care

  16. Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis.

    Science.gov (United States)

    Sagar, Devi Rani; Ashraf, Sadaf; Xu, Luting; Burston, James J; Menhinick, Matthew R; Poulter, Caroline L; Bennett, Andrew J; Walsh, David A; Chapman, Victoria

    2014-08-01

    Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. Our data suggest that early targeting of osteoclasts may reduce pain associated with OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  17. Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss: SMO-021

    Data.gov (United States)

    National Aeronautics and Space Administration — The original intent of this study was to test 10 long-duration crewmembers taking one of two bisphosphonate regimens: either 70 mg per week alendronate or a single...

  18. Gastrointestinal tolerability with ibandronate after previous weekly bisphosphonate treatment.

    Science.gov (United States)

    Derman, Richard; Kohles, Joseph D; Babbitt, Ann

    2009-01-01

    Data from two open-label trials (PRIOR and CURRENT) of women with postmenopausal osteoporosis or osteopenia were evaluated to assess whether monthly oral and quarterly intravenous (IV) ibandronate dosing improved self-reported gastrointestinal (GI) tolerability for patients who had previously experienced GI irritation with bisphosphonate (BP) use. In PRIOR, women who had discontinued daily or weekly BP treatment due to GI intolerance received monthly oral or quarterly IV ibandronate for 12 months. The CURRENT subanalysis included women receiving weekly BP treatment who switched to monthly oral ibandronate for six months. GI symptom severity and frequency were assessed using the Osteoporosis Patient Satisfaction Questionnaire. In PRIOR, mean GI tolerability scores increased significantly at month 1 from screening for both treatment groups (oral: 79.3 versus 54.1; IV: 84.4 versus 51.0; p 90% at Month 10). In the CURRENT subanalysis >60% of patients reported improvements in heartburn or acid reflux and >70% indicated improvement in other stomach upset at month 6. Postmenopausal women with GI irritability with daily or weekly BPs experienced improvement in symptoms with extended dosing monthly or quarterly ibandronate compared with baseline.

  19. Comparison of nonexposed and exposed bisphosphonate-induced osteonecrosis of the jaws

    DEFF Research Database (Denmark)

    Schiodt, Morten; Reibel, Jesper; Oturai, Peter

    2014-01-01

    Nonexposed osteonecrosis of the jaws (NE-ONJ) does not fit into the current definition of osteonecrosis, which requires exposed bone. A modification of the classification of bisphosphonate-induced osteonecrosis of the jaws (ONJ) is proposed. This study aimed to test proposed criteria for NE...

  20. Bisphosphonate ISS Flight Experiment

    Science.gov (United States)

    LeBlanc, Adrian; Matsumoto, Toshio; Jones, Jeffrey; Shapiro, Jay; Lang, Thomas; Shackleford, Linda; Smith, Scott M.; Evans, Harlan; Spector, Elizabeth; Ploutz-Snyder, Robert; hide

    2014-01-01

    The bisphosphonate study is a collaborative effort between the NASA and JAXA space agencies to investigate the potential for antiresorptive drugs to mitigate bone changes associated with long-duration spaceflight. Elevated bone resorption is a hallmark of human spaceflight and bed rest (common zero-G analog). We tested whether an antiresorptive drug in combination with in-flight exercise would ameliorate bone loss and hypercalcuria during longduration spaceflight. Measurements include DXA, QCT, pQCT, and urine and blood biomarkers. We have completed analysis of 7 crewmembers treated with alendronate during flight and the immediate postflight (R+week) data collection in 5 of 10 controls without treatment. Both groups used the advanced resistive exercise device (ARED) during their missions. We previously reported the pre/postflight results of crew taking alendronate during flight (Osteoporosis Int. 24:2105-2114, 2013). The purpose of this report is to present the 12-month follow-up data in the treated astronauts and to compare these results with preliminary data from untreated crewmembers exercising with ARED (ARED control) or without ARED (Pre-ARED control). Results: the table presents DXA and QCT BMD expressed as percentage change from preflight in the control astronauts (18 Pre-ARED and the current 5 ARED-1-year data not yet available) and the 7 treated subjects. As shown previously the combination of exercise plus antiresorptive is effective in preventing bone loss during flight. Bone measures for treated subjects, 1 year after return from space remain at or near baseline values. Except in one region, the treated group maintained or gained bone 1 year after flight. Biomarker data are not currently available for either control group and therefore not presented. However, data from other studies with or without ARED show elevated bone resorption and urinary Ca excretion while bisphosphonate treated subjects show decreases during flight. Comparing the two control

  1. Antioxidant effect of bisphosphonates and simvastatin on chondrocyte lipid peroxidation

    International Nuclear Information System (INIS)

    Dombrecht, E.J.; De Tollenaere, C.B.; Aerts, K.; Cos, P.; Schuerwegh, A.J.; Bridts, C.H.; Van Offel, J.F.; Ebo, D.G.; Stevens, W.J.; De Clerck, L.S.

    2006-01-01

    The objective of this study was to evaluate the effect of bisphosphonates (BPs) and simvastatin on chondrocyte lipid peroxidation. For this purpose, a flow cytometrical method using C11-BODIPY 581/591 was developed to detect hydroperoxide-induced lipid peroxidation in chondrocytes. Tertiary butylhydroperoxide (t-BHP) induced a time and concentration dependent increase in chondrocyte lipid peroxidation. Addition of a Fe 2+ /EDTA complex to t-BHP or hydrogen peroxide (H 2 O 2 ) clearly enhanced lipid peroxidation. The lipophilic simvastatin demonstrated a small inhibition in the chondrocyte lipid peroxidation. None of three tested BPs (clodronate, pamidronate, and risedronate) had an effect on chondrocyte lipid peroxidation induced by t-BHP. However, when Fe 2+ /EDTA complex was added to t-BHP or H 2 O 2 , BPs inhibited the lipid peroxidation process varying from 25% to 58%. This study demonstrates that BPs have antioxidant properties as iron chelators, thereby inhibiting the chondrocyte lipid peroxidation. These findings add evidence to the therapeutic potential of bisphosphonates and statins in rheumatoid arthritis

  2. Bisphosphonate-related osteonecrosis of the jaw in a multiple myeloma patient: A case report with characteristic radiographic features

    International Nuclear Information System (INIS)

    Lee, Byung Do; Kwon, Kyung Hwan; Park, Moo Rim

    2015-01-01

    A 59-year-old male who had suffered from multiple myeloma for nine years and had been administered bisphosphonates for seven years visited a dental hospital for pain relief due to extensive caries in his left maxillary molars. The molars were extracted, leaving an exposed wound for three months. The radiograph showed sequestra formation and irregular bone destruction in the left maxilla. Sudden pain and gingival swelling in the right mandibular molar area occurred six months later. The interseptum of the right lower second molar was observed to be necrotic during surgery. These findings coincided with the features of bisphosphonate-related osteonecrosis of the jaw (BRONJ). In this case, the long intravenous administration of bisphosphonates and tooth extraction were likely the etiologic factors of BRONJ in a patient with multiple myeloma; moreover, the bilateral occurrence of BRONJ is a characteristic feature

  3. Bisphosphonate-related osteonecrosis of the jaw in a multiple myeloma patient: A case report with characteristic radiographic features.

    Science.gov (United States)

    Lee, Byung-Do; Park, Moo-Rim; Kwon, Kyung-Hwan

    2015-09-01

    A 59-year-old male who had suffered from multiple myeloma for nine years and had been administered bisphosphonates for seven years visited a dental hospital for pain relief due to extensive caries in his left maxillary molars. The molars were extracted, leaving an exposed wound for three months. The radiograph showed sequestra formation and irregular bone destruction in the left maxilla. Sudden pain and gingival swelling in the right mandibular molar area occurred six months later. The interseptum of the right lower second molar was observed to be necrotic during surgery. These findings coincided with the features of bisphosphonate-related osteonecrosis of the jaw (BRONJ). In this case, the long intravenous administration of bisphosphonates and tooth extraction were likely the etiologic factors of BRONJ in a patient with multiple myeloma; moreover, the bilateral occurrence of BRONJ is a characteristic feature.

  4. Bisphosphonate-related osteonecrosis of the jaw in a multiple myeloma patient: A case report with characteristic radiographic features

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Byung Do; Kwon, Kyung Hwan [College of Dentistry, Wonkwang University, Iksan (Korea, Republic of); Park, Moo Rim [Dept. of Internal Medicine, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)

    2015-09-15

    A 59-year-old male who had suffered from multiple myeloma for nine years and had been administered bisphosphonates for seven years visited a dental hospital for pain relief due to extensive caries in his left maxillary molars. The molars were extracted, leaving an exposed wound for three months. The radiograph showed sequestra formation and irregular bone destruction in the left maxilla. Sudden pain and gingival swelling in the right mandibular molar area occurred six months later. The interseptum of the right lower second molar was observed to be necrotic during surgery. These findings coincided with the features of bisphosphonate-related osteonecrosis of the jaw (BRONJ). In this case, the long intravenous administration of bisphosphonates and tooth extraction were likely the etiologic factors of BRONJ in a patient with multiple myeloma; moreover, the bilateral occurrence of BRONJ is a characteristic feature.

  5. Gorham-Stout syndrome of the pelvic girdle treated by radiation therapy. A case report

    International Nuclear Information System (INIS)

    Heyd, Reinhard; Tselis, Nikolaos; Zamboglou, Nikolaos; Rabeneck, Daniela; Universitaetsklinikum Frankfurt, Frankfurt am Main; Doernenburg, Oliver

    2011-01-01

    The Gorham-Stout syndrome (GSS) is a rare, benign idiopathic and progressive disorder causing massive osteolysis due to a vascular hyperproliferation replacing the bony structure. Clinical experience concerning the efficacy of radiation therapy (RT) is limited to about 50 of an overall 200 cases reported worldwide. Case Report: A 24-year-old bedridden woman had histologically proven GSS with destruction of the anterior pelvic girdle and received RT for a total dose of 45.0 Gy applied in 5 weekly fractions of 1.8 Gy. In addition, the patient received intravenously 4 mg zoledronic acid once a month. One year after the combined treatment, complete pain relief occurred, and the patient was able to walk without the use of appliances. Imaging studies revealed no progression of the osteolysis but only minimal signs of remineralization. Conclusion: Combined treatment with RT and bisphosphonate administration can prevent the progression of osteolysis in GSS. Total doses of 40-45 Gy are recommended. (orig.)

  6. Gorham-Stout syndrome of the pelvic girdle treated by radiation therapy. A case report

    Energy Technology Data Exchange (ETDEWEB)

    Heyd, Reinhard; Tselis, Nikolaos; Zamboglou, Nikolaos [Klinikum Offenbach, Offenbach am Main (Germany). Strahlenklinik; Rabeneck, Daniela [Klinikum Offenbach, Offenbach am Main (Germany). Strahlenklinik; Universitaetsklinikum Frankfurt, Frankfurt am Main (Germany). Klinik fuer Strahlentherapie und Onkologie; Doernenburg, Oliver [Klinikum Offenbach, Offenbach am Main (Germany). Inst. fuer Diagnostische und Interventionelle Radiologie

    2011-02-15

    The Gorham-Stout syndrome (GSS) is a rare, benign idiopathic and progressive disorder causing massive osteolysis due to a vascular hyperproliferation replacing the bony structure. Clinical experience concerning the efficacy of radiation therapy (RT) is limited to about 50 of an overall 200 cases reported worldwide. Case Report: A 24-year-old bedridden woman had histologically proven GSS with destruction of the anterior pelvic girdle and received RT for a total dose of 45.0 Gy applied in 5 weekly fractions of 1.8 Gy. In addition, the patient received intravenously 4 mg zoledronic acid once a month. One year after the combined treatment, complete pain relief occurred, and the patient was able to walk without the use of appliances. Imaging studies revealed no progression of the osteolysis but only minimal signs of remineralization. Conclusion: Combined treatment with RT and bisphosphonate administration can prevent the progression of osteolysis in GSS. Total doses of 40-45 Gy are recommended. (orig.)

  7. Kinetic release studies of nitrogen-containing bisphosphonate fromgum acacia crosslinked hydrogels

    CSIR Research Space (South Africa)

    Aderibigbe, BA

    2014-11-01

    Full Text Available on the release mechanism of nitrogen-containing bisphosphonate (BP) wasstudied at pH 1.2 and 7.4. The hydrogels exhibited high swelling ratios at pH 7.4 and low swelling ratiosat pH 1.2. The release study was performed using UV–Visible spectroscopy via complex...

  8. Design and methods for a Scandinavian pharmacovigilance study of osteonecrosis of the jaw and serious infections among cancer patients treated with antiresorptive agents for the prevention of skeletal-related events

    Directory of Open Access Journals (Sweden)

    Acquavella J

    2016-07-01

    . Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Follow-up will extend from the first administration of antiresorptive treatment to the earliest of death, loss-to-follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naïve patients, zoledronic acid-naïve patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly established national ONJ databases and adjudicated by the committee that functioned during the XGEVA® clinical trials program. Conclusion: This study will provide a real world counterpart to the clinical trial-estimated risks for ONJ and serious infections for cancer patients initiating denosumab or zoledronic acid. The establishment of ONJ databases in the three Scandinavian countries will have potential benefits outside this study for the elucidation of ONJ risk factors and the evaluation of ONJ treatment strategies. Keywords: cohort study, osteonecrosis of the jaw, pharmacovigilance, postmarketing drug surveillance, denosumab, zoledronic acid

  9. Risk factors of osteonecrosis of the jaw after tooth extraction in osteoporotic patients on oral bisphosphonates

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Ho Gui; Hwang, Jae Joon; Lee, Jeong Hee; Kim, Young Hyun; Na, Ji Yeon; Han, Sang Sun [Dept. of Oral and Maxillofacial Radiology, Yonsei University, College of Dentistry, Seoul (Korea, Republic of)

    2017-03-15

    The aim of this study was to investigate the incidence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) after tooth extraction in patients with osteoporosis on oral bisphosphonates in Korea and to evaluate local factors affecting the development of BRONJ. The clinical records of 320 patients who underwent dental extraction while receiving oral bisphosphonates were reviewed. All patients had a healing period of more than 6 months following the extractions. Each patient's clinical record was used to assess the incidence of BRONJ; if BRONJ occurred, a further radiographic investigation was carried out to obtain a more definitive diagnosis. Various local factors including age, gender, extraction site, drug type, duration of administration, and C-terminal telopeptide (CTx) level were retrieved from the patients' clinical records for evaluating their effect on the incidence of BRONJ. Among the 320 osteoporotic patients who underwent tooth extraction, 11 developed BRONJ, reflecting an incidence rate of 3.44%. Out of the local factors that may affect the incidence of BRONJ, gender, drug type, and CTx level showed no statistically significant effects, while statistically significant associations were found for age, extraction site, and duration of administration. The incidence of BRONJ increased with age, was greater in the mandible than the maxilla, and was associated with a duration of administration of more than 3 years. Tooth extraction in patients on oral bisphosphonates requires careful consideration of their age, the extraction site, and the duration of administration, and close postoperative follow-up should be carried out to facilitate effective early management.

  10. Is Administration of Trastuzumab an Independent Risk Factor for Developing Osteonecrosis of the Jaw Among Metastatic Breast Cancer Patients Under Zoledronic Acid Treatment?

    Science.gov (United States)

    Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

    2015-01-01

    Abstract One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect. Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients’ ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits. Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13–82) and the mean number of ZA infusions was 38 (range: 15–56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively). The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab. PMID:25950681

  11. Bisphosphonate-modified gold nanoparticles: a useful vehicle to study the treatment of osteonecrosis of the femoral head

    Energy Technology Data Exchange (ETDEWEB)

    Fanord, Fedena; Fairbairn, Korie; Bhethanabotla, Venkat; Gupta, Vinay K [Department of Chemical and Biomedical Engineering, University of South Florida, 4202 E. Fowler Avenue, ENB 118, Tampa, FL 33620 (United States); Kim, Harry [Shriners Hospitals for Children, 12502 USF Pine Drive, Tampa, FL 33612 (United States); Garces, Amanda, E-mail: vkgupta@usf.edu [Lisa Muma Weitz Microscopy and Cell Imaging, Department of Pathology and Cell Biology, University of South Florida, 12901 Bruce B Downs Boulevard, Tampa, FL 33612 (United States)

    2011-01-21

    Legg-Calve-Perthes disease (LCPD) is a juvenile form of osteonecrosis of the femoral head that presents in children aged 2-14 years. To date, there is no effective medical therapy for treating LCPD largely due to an inability to modulate the repair process, including the predominance of bone resorption. This investigation aims to evaluate the feasibility of using gold nanoparticles (GNPs) that are surface modified with a bisphosphonate compound for the treatment of osteonecrosis at the cellular level. Studies have found osteoclast-mediated resorption to be a process that contributes significantly to the pathogenesis of femoral head deformities arising from Perthes disease. Our in vitro model was designed to elucidate the effect of alendronate-(a bisphosphonate) modified GNPs, on osteoclastogenesis and osteoclast function. RAW 264.7 macrophage cells were cultured with recombinant mouse receptor activator of NF-{kappa}B ligand (RANKL), which stimulates osteoclastogenesis, and were then treated with alendronate-modified GNPs for 24, 48, and 72 h. Cell proliferation, osteoclast function, and osteoclast morphology were evaluated by trypan blue dye exclusion assay, tartrate-resistant acid phosphatase (TRAP) staining, and transmission electron microscopy (TEM) imaging. Comparative studies were performed with GNPs that were only stabilized with citrate ions and with alendronate alone. Neither osteoclastogenesis nor osteoclast function were adversely affected by the presence of the citrate-GNP. Alendronate-modified GNPs had an enhanced effect on inducing osteoclast apoptosis and impairing osteoclast function when compared to unbound alendronate populations.

  12. Bisphosphonate-modified gold nanoparticles: a useful vehicle to study the treatment of osteonecrosis of the femoral head

    International Nuclear Information System (INIS)

    Fanord, Fedena; Fairbairn, Korie; Bhethanabotla, Venkat; Gupta, Vinay K; Kim, Harry; Garces, Amanda

    2011-01-01

    Legg-Calve-Perthes disease (LCPD) is a juvenile form of osteonecrosis of the femoral head that presents in children aged 2-14 years. To date, there is no effective medical therapy for treating LCPD largely due to an inability to modulate the repair process, including the predominance of bone resorption. This investigation aims to evaluate the feasibility of using gold nanoparticles (GNPs) that are surface modified with a bisphosphonate compound for the treatment of osteonecrosis at the cellular level. Studies have found osteoclast-mediated resorption to be a process that contributes significantly to the pathogenesis of femoral head deformities arising from Perthes disease. Our in vitro model was designed to elucidate the effect of alendronate-(a bisphosphonate) modified GNPs, on osteoclastogenesis and osteoclast function. RAW 264.7 macrophage cells were cultured with recombinant mouse receptor activator of NF-κB ligand (RANKL), which stimulates osteoclastogenesis, and were then treated with alendronate-modified GNPs for 24, 48, and 72 h. Cell proliferation, osteoclast function, and osteoclast morphology were evaluated by trypan blue dye exclusion assay, tartrate-resistant acid phosphatase (TRAP) staining, and transmission electron microscopy (TEM) imaging. Comparative studies were performed with GNPs that were only stabilized with citrate ions and with alendronate alone. Neither osteoclastogenesis nor osteoclast function were adversely affected by the presence of the citrate-GNP. Alendronate-modified GNPs had an enhanced effect on inducing osteoclast apoptosis and impairing osteoclast function when compared to unbound alendronate populations.

  13. Implant failure caused by non-union of bisphosphonate-associated subtrochanteric femur fracture.

    LENUS (Irish Health Repository)

    O'Neill, Barry James

    2014-04-03

    Bisphosphonate use has been identified as a contributory factor in atypical subtrochanteric fracture of the femur. These fractures are commonly treated with an intramedullary device. We present a case of implant failure of an intrameduallary device caused by non-union of an atypical subtrochanteric fracture.

  14. Prostate-specific antigen kinetics and outcomes in patients with bone metastases from castration-resistant prostate cancer treated with or without zoledronic acid.

    Science.gov (United States)

    Saad, Fred; Segal, Scott; Eastham, James

    2014-01-01

    Zoledronic acid (ZOL) is a standard therapy for the prevention of skeletal-related events (SREs) in patients with castration-resistant prostate cancer (CRPC). Although prostate-specific antigen (PSA) is an established marker for monitoring prostate cancer patients, correlations between PSA and disease outcomes during ZOL therapy are unclear. To evaluate the relationships among PSA kinetics, bone-directed therapy with ZOL, and clinical outcomes in men with bone metastases from CRPC using a ZOL phase 3 trial database. Exploratory analyses from a phase 3 trial in men with bone metastases from CRPC (n=643) randomized to ZOL or placebo every 3 wk. PSA levels during the first 3 mo of the study were evaluated in linear and logarithmic (log) models stratified using prognostic factors established in a ZOL phase 3 trial and a CRPC nomogram. Relative risks of SREs, bone disease progression (BDP), and death were calculated per 1 log (nanograms per milliliter) PSA increase. Baseline PSA models used the study median (PSA: 77.3 ng/ml) as the high/low cut-off point. A total of 202 placebo- and 434 ZOL-treated patients were assessable. In both groups, PSA increases correlated with significantly increased risks of death, BDP, and first SRE. In the placebo and ZOL groups, associated increases in risk per 1 log (nanograms per milliliter) PSA increase were 29% (p<0.0001) and 10% (p<0.0074), respectively, for BDP, and 24% (p=0.0010) and 13% (p=0.0079), respectively, for first SRE. Limitations include the retrospective nature of these analyses and the potential confounding effects of concurrent antineoplastic therapies. PSA is an important prognostic tool for survival in patients with bone metastases from CRPC, and these analyses show that PSA is also prognostic for BDP and SREs regardless of bone-targeted therapy. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  15. Bisphosphonate-adsorbed ceramic nanoparticles increase bone formation in an injectable carrier for bone tissue engineering

    Directory of Open Access Journals (Sweden)

    Tegan L Cheng

    2015-10-01

    Full Text Available Sucrose acetate isobutyrate (SAIB is a sugar-based carrier. We have previously applied SAIB as a minimally invasive system for the co-delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2 and found synergy when co-delivering zoledronic acid (ZA and hydroxyapatite (HA nanoparticles. Alternative bioceramics were investigated in a murine SAIB/rhBMP-2 injection model. Neither beta-tricalcium phosphate (TCP nor Bioglass (BG 45S5 had a significant effect on bone volume (BV alone or in combination with the ZA. 14C-labelled ZA binding assays showed particle size and ceramic composition affected binding with nano-HA > micro-HA > TCP > BG. Micro-HA and nano-HA increased BV in a rat model of rhBMP-2/SAIB injection (+278% and +337%, and BV was further increased with ZA–adsorbed micro-HA and nano-HA (+530% and +889%. These data support the use of ZA–adsorbed nanoparticle-sized HA as an optimal additive for the SAIB/rhBMP-2 injectable system for bone tissue engineering.

  16. Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties

    DEFF Research Database (Denmark)

    Ding, Ming

    2004-01-01

    and trabecular architecture independently. Conventional histomorphometry and microdamage data were obtained from the second and third lumbar vertebrae of the same dogs [Bone 28 (2001) 524]. Bisphosphonate treatment resulted in an increased apparent Young's modulus, decreased bone turnover, increased calcified...... matrix density, and increased microdamage. We could not detect any change in the effective Young's modulus of the calcified matrix in the bisphosphonate treated groups. The observed increase in apparent Young's modulus was due to increased bone mass and altered trabecular architecture rather than changes...... in the calcified matrix modulus. We hypothesize that the expected increase in the Young's modulus of the calcified matrix due to the increased calcified matrix density was counteracted by the accumulation of microdamage. Udgivelsesdato: 2004 May...

  17. Comparison of serum Dkk1 (Dickkopf-1) and bone mineral density in patients on bisphosphonate treatment vs no treatment.

    LENUS (Irish Health Repository)

    Memon, Adeel R

    2013-05-17

    Complex pathways affect bone metabolism at the cellular level, and a balance between osteoblast and osteoclast activity is critical to bone remodeling. One of the major pathways affecting bone metabolism is Wnt\\/β-catenin signaling, and its disturbances lead to a wide range of bone abnormalities. An important antagonist of this pathway is Dickkopf-1 (Dkk1). Higher Dkk1 levels have been associated with increased bone loss due to inhibition of Wnt pathway. Currently, bisphosphonates are the most commonly used agents to treat primary osteoporotic patients. This study demonstrates the effect of bisphosphonates on Dkk1 levels and its correlation with bone mineral density (BMD). Eighty patients with low BMD were recruited and divided into 2 groups of 40 each (bisphosphonate treatment group and control group). The mean Dkk1 level in the treatment group was significantly reduced to 2358.18 vs 3749.80 pg\\/mL in the control group (p<0.001). Pearson correlation coefficient showed negative correlation between Dkk1 and BMD at lumbar spine (r=-0.55) and femoral neck in the control group; however, no such correlation was found in the treatment group (r=-0.05). Hence, bisphosphonate therapy leads to reduction in Dkk1 levels, but it does not correlate with BMD in such patients.

  18. Treatment of Atypical Ulnar Fractures Associated with Long-Term Bisphosphonate Therapy for Osteoporosis: Autogenous Bone Graft with Internal Fixation

    Directory of Open Access Journals (Sweden)

    Yohei Shimada

    2017-01-01

    Full Text Available Long-term bisphosphonate use has been suggested to result in decreased bone remodelling and an increased risk of atypical fractures. Fractures of this nature commonly occur in the femur, and relatively few reports exist to show that they occur in other bones. Among eight previous reports of atypical ulnar fractures associated with bisphosphonate use, one report described nonunion in a patient who was treated with cast immobilization and another described ulna nonunion in one of three patients, all of whom were treated surgically with a locking plate. The remaining two surgical patients achieved bone union uneventfully following resection of the osteosclerotic lesion and iliac bone grafting before rigid fixation. We hypothesized that the discontinuation of bisphosphonate therapy, the use of teriparatide treatment, and low-intensity pulsed ultrasound (LIPUS might have been associated with fracture healing.

  19. Efficacy of Bisphosphonates for the Treatment of Osteoporosis in Patients with Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    İlke Coşkun Benlidayı

    2015-08-01

    Full Text Available Objective: The aim of this study was to evaluate the effectiveness of bisphosphonates in osteoporotic patients with multiple sclerosis. Materials and Methods: Patients with multiple sclerosis, who were started on treatment with a diagnosis of osteoporosis, at the Department of Physical Medicine and Rehabilitation, Faculty of Medicine Çukurova University, between January 2011 and January 2014, were included in this study. Patients were allocated into control (calcium-vitamin D alone and active treatment (calcium-vitamin D and bisphosphonate groups according to their medications. Response to the 12-month treatment in terms of bone mineral density (BMD values and biological marker levels were evaluated, both within and between groups. Results: The study group consisted of 29 patients (14 controls and 15 active treatment. Evaluation performed within each group revealed no significant difference between baseline and post-treatment values of BMD and biological markers in controls. However, regarding the active treatment group, a significant increase in L1-L4 T-score and 25(OHD was detected. When delta values were taken into account, comparison between groups revealed no significant difference in terms of BMD and biological marker levels. Conclusion: The effect of calcium-vitamin D alone on BMD and biologic markers was similar to that of calcium-vitamin D and bisphosphonate combination, in multiple sclerosis patients with osteoporosis. However, prospective, randomized, controlled studies are required on this issue. (Turkish Journal of Osteoporosis 2015;21: 53-7

  20. Inherited multicentric osteolysis: case report of three siblings treated with bisphosphonate

    Directory of Open Access Journals (Sweden)

    Whitewood Colin

    2010-04-01

    Full Text Available Abstract Inherited Multicentric Osteolysis (IMO is an uncommon familial condition of idiopathic pathophysiology causing bone osteolysis and dysplasia. These patients present with common rheumatologic complaints of pain, dysfunction and disability, and are often initially misdiagnosed as a chronic rheumatic disease of childhood such as juvenile idiopathic arthritis. We report a case of three siblings diagnosed with IMO. Diagnosis was made during childhood, with each sibling having different manifestations and course of disease. One had a previous history of bilateral hip dysplasia. Two had osteolysis of the foot, distal tibia and femur (lower limb bones, whilst one had osteolysis of the rib and unusual clavicular fractures. Unusually, all siblings appear to experience decreased pain sensation compared to norms. All siblings were treated with bisphosphonates and experienced a rapid improvement in pain symptoms, decreased analgesic requirements. Two had bone mineral density testing performed and both had increases post-bisphosphonate. In all three, there was subjective evidence of stabilisation of bone disease. Testing for matrix metalloproteinase-2 (MMP2 gene was negative.

  1. Clinical Aspects, Imaging Features, and Considerations on Bisphosphonate-Related Osteonecrosis Risk in a Pediatric Patient with Osteogenesis Imperfecta

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    Fábio Wildson Gurgel Costa

    2014-01-01

    Full Text Available Osteogenesis imperfecta (OI is a rare hereditary condition caused by changes in collagen metabolism. It is classified into four types according to clinical, genetic, and radiological criteria. Clinically, bone fragility, short stature, blue sclerae, and locomotion difficulties may be observed in this disease. OI is often associated to severe dental problems, such as dentinogenesis imperfecta (DI and malocclusions. Radiographically, affected teeth may have crowns with bulbous appearance, accentuated constriction in the cementoenamel junction, narrowed roots, large root canals due to defective dentin formation, and taurodontism (enlarged pulp chambers. There is no definitive cure, but bisphosphonate therapy is reported to improve bone quality; however, there is a potential risk of bisphosphonate-related osteonecrosis of the jaw. In this study we report a case of OI in a male pediatric patient with no family history of OI who was receiving ongoing treatment with intravenous perfusion of bisphosphonate and who required dental surgery. In addition, we discussed the clinical and imaging findings and briefly reviewed the literature.

  2. Management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures.

    Science.gov (United States)

    Saleh, Anas; Hegde, Vishal V; Potty, Anish G; Schneider, Robert; Cornell, Charles N; Lane, Joseph M

    2012-07-01

    Long-term bisphosphonate use has often been associated with atypical femoral fractures. These fractures evolve from incomplete femoral fractures. A previous study demonstrated that the presence of a radiolucent line in an incomplete fracture can indicate a high risk of progression to complete fracture. The aim of this study is to present a management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures. Specific study questions include the following: (1) Is there a difference in the prognosis of these fractures based on the presence or absence of a radiolucent fracture line? (2) Can treatment with teriparatide assist in clinical/radiographic healing of these incomplete fractures? (3) Is there a characteristic biochemical profile in these patients? We retrospectively examined all femur radiographs ordered by the metabolic bone disease service at our hospital between July 1, 2006 and July 1, 2011 and identified 10 patients with a total of 14 incomplete fractures. Nine patients received bisphosphonates for a mean duration of 10 ± 5 years (range, 4-17). The mean follow-up since the time of diagnosis was 20 ± 11 months (range, 6-36 months). Five fractures did not have a radiolucent fracture line and were treated conservatively with partial weight-bearing restrictions and pharmacologic therapy. All five of these fractures healed with conservative management. Nine fractures had a radiolucent fracture line, and only two of these were treated successfully with conservative management including teriparatide. Six of the eight patients with a radiolucent line elected for surgical prophylaxis after 3 months of conservative management, whereas one patient underwent surgical prophylaxis without a trial of conservative management. Regarding the biochemical profiles, bone turnover markers for our patient cohort were in the lower quartile. Fractures without a radiolucent line appear to respond to conservative management and not

  3. Beneficial Effects of Concentrated Growth Factors and Resveratrol on Human Osteoblasts In Vitro Treated with Bisphosphonates

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    Elisa Borsani

    2018-01-01

    Full Text Available Bisphosphonates are primary pharmacological agents against osteoclast-mediated bone loss and widely used in the clinical practice for prevention and treatment of a variety of skeletal conditions, such as low bone density and osteogenesis imperfecta, and pathologies, such as osteoporosis, malignancies metastatic to bone, Paget disease of bone, multiple myeloma, and hypercalcemia of malignancy. However, long-term bisphosphonate treatment is associated with pathologic conditions including osteonecrosis of the jaw, named BRONJ, which impaired bone regeneration process. Clinical management of BRONJ is controversy and one recent approach is the use of platelet concentrates, such as Concentrated Growth Factors, alone or together with biomaterials or antioxidants molecules, such as resveratrol. The aim of the present study was to investigate the in vitro effects of Concentrated Growth Factors and/or resveratrol on the proliferation and differentiation of human osteoblasts, treated or not with bisphosphonates. Human osteoblasts were stimulated for 3 days in complete medium and for 21 days in mineralization medium. At the end of the experimental period, the in vitro effect on osteoblast proliferation and differentiation was evaluated using different techniques such as MTT, ELISA for the quantification/detection of osteoprotegerin and bone morphogenetic protein-2, immunohistochemistry for sirtuin 1 and collagen type I, and the Alizarin Red S staining for the rate of mineralization. Results obtained showed that Concentrated Growth Factors and/or resveratrol significantly increased osteoblast proliferation and differentiation and that the cotreatment with Concentrated Growth Factors and resveratrol had a protective role on osteoblasts treated with bisphosphonates. In conclusion, these data suggest that this approach could be promised in the clinical management of BRONJ.

  4. Persistence with weekly and monthly bisphosphonates among postmenopausal women: analysis of a US pharmacy claims administrative database

    Directory of Open Access Journals (Sweden)

    Fan T

    2013-11-01

    Full Text Available Tao Fan, Qiaoyi Zhang, Shuvayu S Sen Global Health Outcomes, Merck, Whitehouse Station, NJ, USA Background: Bisphosphonates are available in daily, weekly, and monthly dosing formulations to treat postmenopausal osteoporosis. Some researchers suggested that adherence to monthly bisphosphonate might be different from that with weekly or daily bisphosphonate because of different dosing regimens. However, the actual persistency rates in regular practice settings are unknown. Objectives: To compare persistence rates with alendronate 70 mg once weekly (AOW, risedronate 35 mg once weekly (ROW, and ibandronate 150 mg once monthly (IOM in a US pharmacy claims database. Methods: In this retrospective cohort study, pharmacy claims data of patients with new bisphosphonate prescriptions were extracted for women aged ≥ 50 years who had an AOW, ROW, or IOM prescription (index prescription between December 30, 2004 and May 31, 2005 (the index period and did not have the index Rx during the previous 12 months. Patients’ records were reviewed for at least 5 months from their index date to November 2, 2005 (the follow-up period. Patients were considered persistent if they neither discontinued (failed to refill the index Rx within a 45-day period following the last supply day of the previous dispensing nor switched (changed to another bisphosphonate during the follow-up period. Medication-possession ratio was defined as days with index prescription supplies/total days of follow-up. Results: Among 44,635 patients, 25,207 (56.5% received prescriptions of AOW, 18,689 (41.9% ROW, and 739 (1.7% IOM as the index prescription. In all, 35.1% of AOW patients, 32.5% of ROW patients, and 30.4% of IOM patients (P < 0.0001 AOW vs ROW or IOM had persisted with their initial therapy, whereas 64.0% of AOW, 66.4% of ROW, and 68.2% of IOM patients discontinued (P < 0.0001 during follow-up. The medication-possession ratio (days with index prescription supplies/total days of

  5. Do bisphosphonates inhibit direct fracture healing?: A laboratory investigation using an animal model.

    Science.gov (United States)

    Savaridas, T; Wallace, R J; Salter, D M; Simpson, A H R W

    2013-09-01

    Fracture repair occurs by two broad mechanisms: direct healing, and indirect healing with callus formation. The effects of bisphosphonates on fracture repair have been assessed only in models of indirect fracture healing. A rodent model of rigid compression plate fixation of a standardised tibial osteotomy was used. Ten skeletally mature Sprague-Dawley rats received daily subcutaneous injections of 1 µg/kg ibandronate (IBAN) and ten control rats received saline (control). Three weeks later a tibial osteotomy was rigidly fixed with compression plating. Six weeks later the animals were killed. Fracture repair was assessed with mechanical testing, radiographs and histology. The mean stress at failure in a four-point bending test was significantly lower in the IBAN group compared with controls (8.69 Nmm(-2) (sd 7.63) vs 24.65 Nmm(-2) (sd 6.15); p = 0.017). On contact radiographs of the extricated tibiae the mean bone density assessment at the osteotomy site was lower in the IBAN group than in controls (3.7 mmAl (sd 0.75) vs 4.6 mmAl (sd 0.57); p = 0.01). In addition, histological analysis revealed progression to fracture union in the controls but impaired fracture healing in the IBAN group, with predominantly cartilage-like and undifferentiated mesenchymal tissue (p = 0.007). Bisphosphonate treatment in a therapeutic dose, as used for risk reduction in fragility fractures, had an inhibitory effect on direct fracture healing. We propose that bisphosphonate therapy not be commenced until after the fracture has united if the fracture has been rigidly fixed and is undergoing direct osteonal healing.

  6. Structure of human farnesyl pyrophosphate synthase in complex with an aminopyridine bisphosphonate and two molecules of inorganic phosphate

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jaeok [McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 (Canada); Lin, Yih-Shyan [McGill University, 801 Rue Sherbrooke Ouest, Montreal, QC H3A 0B8 (Canada); Tsantrizos, Youla S. [McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 (Canada); McGill University, 801 Rue Sherbrooke Ouest, Montreal, QC H3A 0B8 (Canada); McGill University, 3649 Promenade Sir William Osler, Montreal, QC H3G 0B1 (Canada); Berghuis, Albert M., E-mail: albert.berghuis@mcgill.ca [McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 (Canada); McGill University, 3649 Promenade Sir William Osler, Montreal, QC H3G 0B1 (Canada); McGill University, 3775 Rue University, Montreal, QC H3A 2B4 (Canada)

    2014-02-19

    A co-crystal structure of human farnesyl pyrophosphate synthase in complex with an aminopyridine bisphosphonate, YS0470, and two molecules of inorganic phosphate has been determined. The identity of the phosphate ligands was confirmed by anomalous diffraction data. Human farnesyl pyrophosphate synthase (hFPPS) produces farnesyl pyrophos@@phate, an isoprenoid essential for a variety of cellular processes. The enzyme has been well established as the molecular target of the nitrogen-containing bisphosphonates (N-BPs), which are best known for their antiresorptive effects in bone but are also known for their anticancer properties. Crystal structures of hFPPS in ternary complexes with a novel bisphosphonate, YS0470, and the secondary ligands inorganic phosphate (P{sub i}), inorganic pyrophosphate (PP{sub i}) and isopentenyl pyrophosphate (IPP) have recently been reported. Only the co-binding of the bisphosphonate with either PP{sub i} or IPP resulted in the full closure of the C-@@terminal tail of the enzyme, a conformational change that is required for catalysis and that is also responsible for the potent in vivo efficacy of N-BPs. In the present communication, a co-crystal structure of hFPPS in complex with YS0470 and two molecules of P{sub i} is reported. The unusually close proximity between these ligands, which was confirmed by anomalous diffraction data, suggests that they interact with one another, with their anionic charges neutralized in their bound state. The structure also showed the tail of the enzyme to be fully disordered, indicating that simultaneous binding of two P{sub i} molecules with a bisphosphonate cannot induce the tail-closing conformational change in hFPPS. Examination of homologous FPPSs suggested that this ligand-dependent tail closure is only conserved in the mammalian proteins. The prevalence of P{sub i}-bound hFPPS structures in the PDB raises a question regarding the in vivo relevance of P{sub i} binding to the function of the enzyme.

  7. Opsismodysplasia: Phosphate wasting osteodystrophy responds to bisphosphonate therapy

    Directory of Open Access Journals (Sweden)

    Ansab eKhwaja

    2015-06-01

    Full Text Available We present two siblings affected with opsismodysplasia, a rare skeletal dysplasia caused by mutations in the INPPL1 gene. The skeletal findings include short stature with postnatal onset micromelia, marked platyspondyly, squared metacarpals, delayed skeletal ossification, metaphyseal cupping and postnatal micromelia. Respiratory compromise, delayed ambulation, and progressive lower extremity deformities are described. The severity of findings is variable. Renal phosphate wasting is associated with severe bone demineralization and a more severe phenotype. This report represents the first described cases of opsismodysplasia treated with intravenous bisphosphonate (pamidronate. Surgical management for lower extremity deformities associated with OPS is also reviewed.

  8. A large case-control study reveals a positive association between bisphosphonate use and delayed dental healing and osteonecrosis of the jaw.

    Science.gov (United States)

    Borromeo, Gelsomina L; Brand, Caroline; Clement, John G; McCullough, Michael; Crighton, Lisa; Hepworth, Graham; Wark, John D

    2014-06-01

    This study sought to investigate, using a case-control study design, the association between bisphosphonate therapy and delayed dental healing and osteonecrosis of the jaw. Identification of potential cases of delayed dental healing was by consecutive screening of Specialist Oral and Maxillofacial and Special Needs Dentist clinic records for patients aged older than 50 years, during a 6-month window, in Victoria, Australia. Cases were confirmed by a case adjudication panel blinded to bisphosphonate status. Cases associated with malignancy or local radiotherapy were excluded. Controls were matched for age, sex, and source of dental referral (1:4, n = 160 controls). Variables of interest were dental precipitants, dental clinic type, smoking history, and medical comorbidities. A total of 4212 of 22,358 patients met inclusion criteria, of which 69 were potential cases with 40 (0.95%) confirmed cases. The odds ratio (OR) for developing delayed dental healing when taking an oral bisphosphonate was 13.1 (95% confidence interval [CI] 4.4 to 39.3; p associated with intravenous bisphosphonate use. There was some evidence of an interaction with age, sex, and clinic type. When adjusted for smoking, the estimated odds ratio was 11.6 (95% CI 1.9 to 69.4; p = 0.01). There was an association between having another illness and delayed dental healing (OR = 2.3; 95% CI 1.0 to 5.2). A dental precipitant was present in 39 of 40 (97.5%) delayed dental healing cases. An important association between bisphosphonate use and delayed dental healing in the setting of benign bone disease, predominately in individuals with a dental precipitant, has been demonstrated. © 2014 American Society for Bone and Mineral Research.

  9. Treatment of bisphosphonate related osteonecrosis following root canal therapy at the 1-year follow-up: report of two cases

    Directory of Open Access Journals (Sweden)

    Kaptan F

    2013-12-01

    Full Text Available Figen Kaptan,1 Meric Karapinar Kazandag,1 Ufuk Iseri21Yeditepe University, Faculty of Dentistry, Department of Endodontics, 2Department of Prosthodontics, Istanbul, TurkeyAbstract: The objective of this report was to use topical gaseous ozone as an adjunct to conventional treatment methods and to describe the multidisciplinary management of bisphosphonate associated bone necrosis, which developed following endodontic treatment. No complaints were noted by the patients at their 1-year follow-up and the treatment showed favorable prognosis.Keywords: bisphosphonate, osteonecrosis, BRONJ, endodontics, oxygen, ozone

  10. Interaction between Bisphosphonates and Mineral Water: Study of Oral Risedronate Absorption in Rats.

    Science.gov (United States)

    Itoh, Akihisa; Akagi, Yuuki; Shimomura, Hitoshi; Aoyama, Takao

    2016-01-01

    Bisphosphonates are antiosteoporotic agents prescribed for patients with osteoporosis. Drug package inserts for bisphosphonate supplements indicate that their bioavailability is reduced by high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards for these cations in water used for taking risedronate have not been defined. Here, we examined the effect of calcium and magnesium in mineral waters on the bioavailability of the third-generation bisphosphonate, risedronate, following oral administration in rats. As risedronate is unchanged and eliminated renally, risedronate absorption was estimated from the amount excreted in the urine. Risedronate was dissolved in mineral water samples and administered orally at 0.35 mg/kg. Urine samples were collected for 24 h after dosing. Risedronate was extracted from urine using ion-pair solid-phase cartridges and quantified by HPLC with UV detection (262 nm). Cumulative recovery of risedronate was calculated from the amount excreted in the urine. The 24-h recovery of risedronate from evian® (0.32±0.02% [mean±standard deviation (S.D.)], n=4) and Contrex(®) (0.22±0.05%) mineral waters was significantly lower than that from tap water (0.47±0.04%, pAbsorption of risedronate in calcium chloride and magnesium chloride aqueous solutions of the same hardness (822 mg/L) was 54% (0.27±0.04%) and 12% (0.51±0.08%) lower, respectively, compared with ultrapure water; suggesting that absorption of risedronate declines as the calcium concentration of mineral waters increases. Consumption of mineral waters containing high levels of calcium (80 mg/L or above), such as evian® and Contrex(®), is therefore not recommended when taking risedronate.

  11. Atypical form of active melorheostosis and its treatment with bisphosphonate

    Energy Technology Data Exchange (ETDEWEB)

    Donath, Judit; Poor, Gyula; Kiss, Csaba [National Institute of Rheumatology and Physiotherapy, 1027 Budapest (Hungary); Fornet, Bela [Semmelweis University Department of Radiology, Budapest (Hungary); Genant, Harry [University of California Department of Radiology, San Francisco, California (United States)

    2002-12-01

    We present the case of a 38-year-old man in whom extensive bilateral melorheostosis was associated with elevated serum alkaline phosphatase, swelling of the right foot and progressive deformity of the left hand, left leg and right foot. Radiography, computed tomography and bone scintigraphy were performed. Following treatment with bisphosphonate (30 mg/day of pamidronate for 6 days) infusion, the pain and swelling of his right foot showed improvement and his elevated serum alkaline phosphatase decreased. (orig.)

  12. Early inhibitory effects of zoledronic acid in tooth extraction sockets in dogs are negated by recombinant human bone morphogenetic protein.

    Science.gov (United States)

    Gerard, David A; Carlson, Eric R; Gotcher, Jack E; Pickett, David O

    2014-01-01

    This study was conducted with 2 purposes. The first was to determine the effect of a single dose of zoledronic acid (ZA) on the healing of a tooth extraction socket in dogs. The second was to determine if placement of recombinant human bone morphogenetic protein-2 (rhBMP-2)/absorbable collagen sponge (ACS) - INFUSE, (Medtronic, Memphis, TN) into these extraction sockets would inhibit the inhibition on bone healing and remodeling by ZA. Nine adult female beagle dogs (2 to 3 yr old) were placed into 3 groups of 3 dogs each. Group I received 15 mL of sterile saline intravenously; group II received 2.5 mg of ZA intravenously; and group III received 5 mg of ZA intravenously. Forty-five days after treatment, all dogs underwent extraction of noncontiguous right and left mandibular first molars and second premolars. In group I, the right mandibular extraction sockets had nothing placed in them, whereas the left mandibular sockets had only ACS placed in them. In groups II and III, the right mandibular sockets had rhBMP-2/ACS placed in them, whereas the left mandibular sockets had only ACS placed. All extraction sockets were surgically closed. Tetracycline was given intravenously 5 and 12 days later, and all animals were euthanized 15 days after tooth extraction. The extraction sockets and rib and femur samples were harvested immediately after euthanasia, processed, and studied microscopically. A single dose of ZA significantly inhibited healing and bone remodeling in the area of the tooth extractions. The combination of rhBMP-2/ACS appeared to over-ride some of the bone remodeling inhibition of the ZA and increased bone fill in the extraction sites, and remodeling activity in the area was noted. The effects of rhBMP-2/ACS were confined to the area of the extraction sockets because bone activity at distant sites was not influenced. A single dose of ZA administered intravenously inhibits early healing of tooth extraction sockets and bone remodeling in this animal model. The

  13. Oral bisphosphonate use and total knee/hip implant survival

    DEFF Research Database (Denmark)

    Prieto-Alhambra, Daniel; Lalmohamed, Arief; Abrahamsen, Bo

    2014-01-01

    of disease-modifying antirheumatic drugs as well as patients with rheumatoid arthritis, Paget's disease, or hip fracture. Participants were classified as bisphosphonate users if they had been receiving treatment for ≥6 months. A time-varying exposure was used to avoid immortal time bias. Up to 6...... was conducted within the Danish nationwide registries (5.5 million residents). Using procedure codes of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, we identified patients age ≥40 years undergoing total joint replacement in 1998-2007. We excluded users...

  14. Structural and thermodynamic basis of the inhibition of Leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates

    Energy Technology Data Exchange (ETDEWEB)

    Aripirala, Srinivas [Johns Hopkins University, 725 North Wolfe Street WBSB 605, Baltimore, MD 21210 (United States); Gonzalez-Pacanowska, Dolores [López-Neyra Institute of Parasitology and Biomedicine, 18001 Granada (Spain); Oldfield, Eric [University of Illinois at Urbana-Champaign, Urbana, IL 61801 (United States); Kaiser, Marcel [University of Basel, Petersplatz 1, CH-4003 Basel (Switzerland); Amzel, L. Mario, E-mail: mamzel@jhmi.edu [Johns Hopkins University School of Medicine, 725 N. Wolfe Street WBSB 604, Baltimore, MD 21205 (United States); Gabelli, Sandra B., E-mail: mamzel@jhmi.edu [Johns Hopkins University School of Medicine, 725 N. Wolfe Street WBSB 604, Baltimore, MD 21205 (United States); Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Johns Hopkins University, 725 North Wolfe Street WBSB 605, Baltimore, MD 21210 (United States)

    2014-03-01

    Structural insights into L. major farnesyl diphosphate synthase, a key enzyme in the mevalonate pathway, are described. Farnesyl diphosphate synthase (FPPS) is an essential enzyme involved in the biosynthesis of sterols (cholesterol in humans and ergosterol in yeasts, fungi and trypanosomatid parasites) as well as in protein prenylation. It is inhibited by bisphosphonates, a class of drugs used in humans to treat diverse bone-related diseases. The development of bisphosphonates as antiparasitic compounds targeting ergosterol biosynthesis has become an important route for therapeutic intervention. Here, the X-ray crystallographic structures of complexes of FPPS from Leishmania major (the causative agent of cutaneous leishmaniasis) with three bisphosphonates determined at resolutions of 1.8, 1.9 and 2.3 Å are reported. Two of the inhibitors, 1-(2-hydroxy-2,2-diphosphonoethyl)-3-phenylpyridinium (300B) and 3-butyl-1-(2,2-diphosphonoethyl)pyridinium (476A), co-crystallize with the homoallylic substrate isopentenyl diphosphate (IPP) and three Ca{sup 2+} ions. A third inhibitor, 3-fluoro-1-(2-hydroxy-2,2-diphosphonoethyl)pyridinium (46I), was found to bind two Mg{sup 2+} ions but not IPP. Calorimetric studies showed that binding of the inhibitors is entropically driven. Comparison of the structures of L. major FPPS (LmFPPS) and human FPPS provides new information for the design of bisphosphonates that will be more specific for inhibition of LmFPPS. The asymmetric structure of the LmFPPS–46I homodimer indicates that binding of the allylic substrate to both monomers of the dimer results in an asymmetric dimer with one open and one closed homoallylic site. It is proposed that IPP first binds to the open site, which then closes, opening the site on the other monomer, which closes after binding the second IPP, leading to the symmetric fully occupied FPPS dimer observed in other structures.

  15. What Animal Models Have Taught Us About the Safety and Efficacy of Bisphosphonates in Chronic Kidney Disease.

    Science.gov (United States)

    Allen, Matthew R; Aref, Mohammad W

    2017-06-01

    Bisphosphonates (BPs) have long been the gold-standard anti-remodeling treatment for numerous metabolic bone diseases. Since these drugs are excreted unmetabolized through the kidney, they are not recommended for individuals with compromised kidney function due to concerns of kidney and bone toxicity. The goal of this paper is to summarize the preclinical BP work in models of kidney disease with particular focus on the bone, kidney, and vasculature. Summative data exists showing positive effects on bone and vascular calcifications with minimal evidence for bone or kidney toxicity in animal models. Preclinical data suggest it may be worthwhile to take a step back and reconsider the use of bisphosphonates to lessen skeletal/vascular complications associated with compromised kidney function.

  16. Aspects of osseous, peritoneal and renal handling of bisphosphonate during peritoneal dialysis: a methodological study

    DEFF Research Database (Denmark)

    Joffe, P; Henriksen, Jens Henrik Sahl

    1996-01-01

    to continuous ambulatory peritoneal dialysis (CAPD). The aims were: to assess the kinetics of 99m-technetium MBP (99mTc-MBP) in CAPD, and to evaluate the correctness of the assumption that the peritoneal and renal clearances of 99mTc-MBP equal the total plasma clearance of 51-chromium ethylenediamine tetra......-acetic acid (51Cr-EDTA). Eight patients on CAPD were studied cross-sectionally. The mean plasma clearances of 99mTc-MBP and 51Cr-EDTA in the steady state (4h) were 38.2 and 12.2 ml min-1 (p peritoneal clearances (0-4 h) were 5.2 and 7.2 ml min-1 (p ....5 and 2.8 ml min-1 (not significant), respectively. The bone bisphosphonate clearance (BBC) at steady state was 26.0 ml min-1, a value which was significantly higher than that at infinity (16.5 ml min-1, p peritoneal and renal clearances of 99m...

  17. Subtrochanteric Fracture In A Chinese Woman With Paget’s Disease Of Bone And On Long Term Bisphosphonate Therapy: Could It Be An Insufficiency Fracture?

    Directory of Open Access Journals (Sweden)

    CK Lee

    2011-03-01

    Full Text Available Paget’s disease is common in Western countries but is very rare in Chinese populations. Although bisphosphonate has been widely used to treat symptomatic Paget’s disease, prolonged use may be associated with insufficiency fracture. We highlight this rare case of Paget’s disease in a Chinese lady who presented with an insufficiency fracture following long-term use of bisphosphonate.

  18. Bis-phosphonate sequestering agents. Synthesis and preliminary evaluation for in vitro and in vivo uranium(VI) chelation

    Energy Technology Data Exchange (ETDEWEB)

    Sawicki, M.; Lecercle, D.; Taran, F. [CEA Saclay, IBiTecS, Serv Chim Bioorgan et Marquage, F-91191 Gif Sur Yvette (France); Grillon, G.; Le Gall, B.; Serandour, A.L.; Poncy, J.L. [CEA, DSV, DRR, Lab Radiotoxicol, F-91680 Bruyeres Le Chatel (France); Bailly, T.; Burgada, R.; Lecouvey, M.; Challeix, V. [CNRS, Lab Chim Struct Biomol, UMR 7033, F-93017 Bobigny (France); Leydier, A.; Pellet-Rostaing, S. [Univ Lyon 1, ICBMS, UMR 5246, Lab Catalyse et Synth Organ, F-69622 Villeurbanne (France); Ansoborlo, E. [CEA, DEN, DRCP, CETAMA, VRH Marcoule, F-30207 Bagnols Sur Ceze (France)

    2008-07-01

    A library of bis-phosphonate-based ligands was prepared using solution-phase parallel synthesis and tested for its uranium-binding properties. With the help of a screening method, based on a chromo-phoric complex displacement procedure, 23 dipodal and tripodal chelates bearing bis-phosphonate chelating functions were found to display very high affinity for the uranyl ion and were selected for evaluation of their in vivo uranyl-removal efficacy. Among them, 11 ligands induced a huge modification of the uranyl biodistribution by deviating the metal from kidney and bones to liver. Among the other ligands, the most potent was the dipodal bis-phosphonate 3C which reduced the retention of uranyl and increased its excretion by around 10% of the injected metal. (authors)

  19. Bisphosphonates for treatment of Complex Regional Pain Syndrome type 1: A systematic literature review and meta-analysis of randomized controlled trials versus placebo.

    Science.gov (United States)

    Chevreau, Maxime; Romand, Xavier; Gaudin, Philippe; Juvin, Robert; Baillet, Athan

    2017-07-01

    Complex Regional Pain Syndrome Type 1 is a severely disabling pain syndrome with no definite established treatment. We have performed a systematic literature review and meta-analysis of all randomized controlled trials to assess the benefit of bisphosphonates on pain and function in patients with Complex Regional Pain Syndrome Type 1. A systematic literature search was performed in the Medline, Embase and Cochrane databases. Two authors selected independently blinded randomized trials comparing bisphosphonates to placebo on short-term (J30 to J40) and medium term pain (M2-M3), safety and function in patients with CRPS 1. The methodological quality of the studies was analyzed. Data were aggregated using the method of the inverse of the variance. 258 articles were identified. Four trials of moderate to good quality comprising 181 patients (90 in the bisphosphonate group and 91 in the placebo group) were included in this meta-analysis. Short-term pain Visual Analog Scale was significantly lower in the bisphosphonate group versus the placebo group (SMD=-2.6, 95%CI [-1.8, -3.4], Ppain (SMD=-2.5, 95%CI [-1.4, -3.6], Ppain in patients with Complex Regional Pain Syndrome type 1. Other studies are needed to determine their effectiveness. Copyright © 2017. Published by Elsevier SAS.

  20. Atypical femoral fractures related to bisphosphonate therapy

    Directory of Open Access Journals (Sweden)

    Tarun Pankaj Jain

    2012-01-01

    Full Text Available Bisphosphonates (BP are a commonly prescribed class of drugs for the prevention of osteoporosis-related fractures. Paradoxically, however, they have recently been linked to atypical fractures in the shaft of the femur. Since many physicians including radiologists, are not aware of this entity, the incidence is likely underreported. These fractures usually occur in the sub-trochanteric region of the femur in the setting of low-energy trauma. It starts as a fracture line involving the lateral cortex and then progresses medially to give rise to a complete fracture. The fracture line is usually transverse, and there is a medial spike associated with a complete fracture. These fractures can be bilateral. Awareness of these atypical fractures and their radiological appearance should enable their early and accurate detection and thus lead to specific treatment.

  1. Bisphosphonate Treatment in Osteoporosis: Optimal Duration of Therapy and the Incorporation of a Drug Holiday.

    Science.gov (United States)

    Villa, Jordan C; Gianakos, Arianna; Lane, Joseph M

    2016-02-01

    Bisphosphonates are the most widely used treatment for osteoporosis. They accumulate in the bone for years, and therefore, their inhibitory effects on osteoclasts may persist after drug discontinuation. The ideal duration of therapy remains controversial. The purpose of this study is to review the literature to determine the (1) indications for drug holiday, (2) the duration of drug holiday, (3) the evaluation during drug holiday, and (4) the proper treatment and maintenance after drug holiday. A review of two electronic databases (PubMed/MEDLINE and EMBASE) was conducted using the term "(Drug holiday)," in January 29, 2015. Inclusion criteria were as follows: (1) clinical trials and case control, (2) human studies, (3) published in a peer-review journal, and (4) written in English. Exclusion criteria were as follows: (1) case reports, (2) case series, and (3) in vitro studies. The literature supports a therapeutic pause after 3-5 years of bisphosphonate treatment in patients with minor bone deficiencies and no recent fragility fracture (low risk) and in patients with moderate bone deficiencies and/or recent fragility fracture (moderate risk). In these patients, a bone health reevaluation is recommended every 1-3 years. Patients with high fracture risk should be maintained on bisphosphonate therapy without drug holiday. The duration and length of drug holiday should be individualized for each patient. Evaluation should be based on serial bone mass measurements, bone turnover rates, and fracture history evaluation. If after drug therapy, assessments show an increased risk of fracture, the patient may benefit from initiating another treatment. Raloxifene, teriparatide, or denosumab are available options.

  2. Histology of peri-implant bone in a failed implant retrieved from an area of osteonecrosis of the jaw in a patient suffering from multiple myeloma and treated with intravenous bisphosphonates

    Directory of Open Access Journals (Sweden)

    Marco Degidi

    2012-03-01

    Full Text Available Background: Osteonecrosis of the jaw (ONJ has been reported in the past few years in patients undergoing treatment with bisphosphonates (BP. Few published histological studies of ONJ can be found in the literature and no study has been reported on the peri-implant bone around a dental implant retrieved from an area of ONJ. The aim of the present case was to report the histology of the peri-implant bone around an implant retrieved from an area of ONJ. Materials and methods: Multiple myeloma was diagnosed to a 72-year-old male. The patient underwent treatment with intravenous pamidronate for 2 years and with intravenous zoledronate for additional 3 years. Five years after the diagnosis, 7 immediately loaded dental implants were inserted in the mandible. A preoperative panoramic radiography did show no pre-existing bone lesions. No healing of the post-extraction sockets of the right third molar and of the left second molar was observed. Three years after the implant insertion a breakdown of the oral mucosa covering the implants was observed. The most distal implant was retrieved with a trephine bur, due to mobility. Discussion: The histological findings showed some areas with osseointegration in patients undergoing BP treatment for malignant disease. Conclusion: There is certainly a temporal association between BP use and development of ONJ, but a correlation does not necessarily mean causation. Moreover, generalisations about this complex relationship cannot be made on the basis of a single case report. In patients undergoing intravenous treatment, clinicians must be aware of the increased risk of implant failure and, probably, implant insertion should be avoided at all, until more conclusive data are available.

  3. Atypical metatarsal fracture in a patient on long term bisphosphonate therapy

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    Pavan Pradhan

    2012-01-01

    Full Text Available A 24 years old female of cushing disease had undergone adrenelectomy. She was put on alendronate and steroid. After six and a half years she developed pathological fracture subtrochanteric femur. The patient was treated with proximal femoral nailing and the fracture united. 2 years later she developed pain right foot. She was diagnosed as transverse fracture of fifth metatarsal. We report this rare case of atypical metatarsal fracture in a patient on long term bisphosphonate therapy.

  4. 3-Keto-1,5-bisphosphonates Alleviate Serum-Oxidative Stress in the High-fat Diet Induced Obesity in Rats.

    Science.gov (United States)

    Lahbib, Karima; Aouani, Iyadh; Cavalier, Jean-François; Touil, Soufiane

    2015-09-01

    Obesity has become a leading global health problem owing to its strong association with a high incidence of oxidative stress. Many epidemiologic studies showed that an antioxidant supplementation decreases the state of oxidative stress. In the present work, a HFD-induced rat obesity and oxidative stress were used to investigate the link between fat deposition and serum-oxidative stress markers. We also studied the effect of a chronic administration of 3-keto-1,5-bisphosphonates 1 (a & b) (40 μg/kg/8 weeks/i.p.). Exposure of rats to HFD during 16 weeks induced fat deposition, weight gain and metabolic disruption characterized by an increase in cholesterol, triglyceride and glycemia levels, and a decrease in ionizable calcium and free iron concentrations. HFD also induced serum-oxidative stress status vocalized by an increase in ROS (H2 O2 ), MDA and PC levels, with a decrease in antioxidant enzyme activity (CAT, GPx, SOD). Importantly, 3-keto-1,5-bisphosphonates corrected all the deleterious effects of HFD treatment in vivo, but it failed to inhibit lipases in vitro and in vivo. These studies suggest that 3-keto-1,5-bisphosphonates 1 could be considered as safe antioxidant agents that should also find other potential biological applications. © 2014 John Wiley & Sons A/S.

  5. The Electroporation as a Tool for Studying the Role of Plasma Membrane in the Mechanism of Cytotoxicity of Bisphosphonates and Menadione.

    Science.gov (United States)

    Šilkūnas, Mantas; Saulė, Rita; Batiuškaitė, Danutė; Saulis, Gintautas

    2016-10-01

    In this study, the role of the cell plasma membrane as a barrier in the mechanism of the cytotoxicity of nitrogen-containing bisphosphonates and menadione was studied, and the possibility of increasing the efficiency of bisphosphonates and menadione (vitamin K 3 ) as chemotherapeutic agents by permeabilizing the cell plasma membrane has been investigated in vitro. The plasma membrane barrier was reduced by electropermeabilization with the pulse of strong electric field. Two membrane-impermeant bisphosphonates with different hydrophilicities were chosen as study objects: ibandronate and pamidronate. For the comparison, an amphiphilic vitamin K 3 , which is able to cross the cell membrane, was studied as well. The impact of nitrogen-containing bisphosphonates and vitamin K 3 on MH-22A cells viability was evaluated for the case of long (9 days) and short (20 min) exposure. When cells were cultured in the medium with vitamin K 3 for 9-10 days, it exhibited toxicity of 50 % over the control at 6.2 µM for mouse hepatoma MH-22A cells. Ibandronate and pamidronate were capable of reducing drastically the cell viability only in the case of long 9-days incubation and at high concentrations (~20 µM for pamidronate and over 100 µM for ibandronate). Single, square-wave electric pulse with the duration of 100 µs and the field strength of 2 kV/cm was used to electroporate mouse hepatoma MH-22A cells in vitro. The results obtained here showed that the combination of the exposure of cells to membrane-impermeable bisphosphonates pamidronate and ibandronate with electropermeabilization of the cell plasma membrane did not increase their cytotoxicity. In the case of membrane-permeable vitamin K 3 , cell electropermeabilization did increase vitamin K 3 killing efficiency. However, this increase was not substantial, within the range of 20-30 % depending on the duration of the exposure. Electropermeabilization improved cytotoxic effect of vitamin K 3 but not of pamidronate

  6. Nano-technology based carriers for nitrogen-containing bisphosphonates delivery as sensitisers of γδ T cells for anticancer immunotherapy.

    Science.gov (United States)

    Hodgins, Naomi O; Wang, Julie Tzu-Wen; Al-Jamal, Khuloud T

    2017-05-15

    Nitrogen containing bisphosphonates (N-BPs) including zoledronate (ZOL) and alendronate (ALD) inhibit farnesyl diphosphate synthase, and have been shown to have a cytotoxic affect against cancer cells as a monotherapy and to also sensitise tumour cells to destruction by γδ T cells. γδ T cells are a subset of human T lymphocytes and have a diverse range of roles in the immune system including the recognition and destruction of cancer cells. This property of γδ T cells can be harnessed for use in cancer immunotherapy through in vivo expansion or the adoptive transfer of ex vivo activated γδ T cells. The use of N-BPs with γδ T cells has been shown to have a synergistic effect in in vitro, animal and clinical studies. N-BPs have limited in vivo activity due to rapid clearance from the circulation. By encapsulating N-BPs in liposomes (L) it is possible to increase the levels of N-BPs at non-osseous tumour sites. L-ZOL and L-ALD have been shown to have different toxicological profiles than free ZOL or ALD. Both L-ALD and L-ZOL led to increased spleen weight, leucocytosis, neutrophilia and lymphocytopenia in mice after intravenous injection. L-ALD was shown to be better tolerated than L-ZOL in murine studies. Biodistribution studies have been performed in order to better understand the interaction of N-BPs and γδ T cells in vivo. Additionally, in vivo therapy studies have shown that mice treated with both L-ALD and γδ T cells had a significant reduction in tumour growth compared to mice treated with L-ALD or γδ T cells alone. The use of ligand-targeted liposomes may further increase the efficacy of this combinatory immunotherapy. Liposomes targeting the αvβ6 integrin receptor using the peptide A20FMDV2 had a greater ability than untargeted liposomes in sensitising cancer cells to destruction by γδ T cells in αvβ6 positive cancer cell lines. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features.

    Science.gov (United States)

    Wehrhan, Falk; Hyckel, Peter; Ries, Jutta; Stockmann, Phillip; Nkenke, Emeka; Schlegel, Karl A; Neukam, Friedrich W; Amann, Kerstin

    2010-10-13

    Bone-destructive disease treatments include bisphosphonates and antibodies against the osteoclast differentiator, RANKL (aRANKL); however, osteonecrosis of the jaw (ONJ) is a frequent side-effect. Current models fail to explain the restriction of bisphosphonate (BP)-related and denosumab (anti-RANKL antibody)-related ONJ to jaws. Msx-1 is exclusively expressed in craniofacial structures and pivotal to cranial neural crest (CNC)-derived periodontal tissue remodeling. We hypothesised that Msx-1 expression might be impaired in bisphosphonate-related ONJ. The study aim was to elucidate Msx-1 and RANKL-associated signal transduction (BMP-2/4, RANKL) in ONJ-altered and healthy periodontal tissue. Twenty ONJ and twenty non-BP exposed periodontal samples were processed for RT-PCR and immunohistochemistry. An automated staining-based alkaline phosphatase-anti-alkaline phosphatase method was used to measure the stained cells:total cell-number ratio (labelling index, Bonferroni adjustment). Real-time RT-PCR was performed on ONJ-affected and healthy jaw periodontal samples (n = 20 each) to quantitatively compare Msx-1, BMP-2, RANKL, and GAPDH mRNA levels. Semi-quantitative assessment of the ratio of stained cells showed decreased Msx-1 and RANKL and increased BMP-2/4 (all p Msx-1 (p Msx-1 suppression in ONJ-adjacent periodontal tissue suggested a bisphosphonate-related impairment in cellular differentiation that occurred exclusively jaw remodelling. Further research on developmental biology-related unique features of jaw bone structures will help to elucidate pathologies restricted to maxillofacial tissue.

  8. Osteonecrosis de los maxilares asociada al empleo de bifosfonatos Bisphosphonate-associated osteonecrosis of the jaw

    Directory of Open Access Journals (Sweden)

    J.L. del Castillo Pardo de Vera

    2007-10-01

    Full Text Available Los bifosfonatos constituyen un grupo de fármacos inhibidores de la resorción ósea, utilizados en el tratamiento de numerosas patologías como la osteoporosis, la enfermedad de Paget, el mieloma múltiple, la hipercalcemia maligna y las metástasis óseas asociadas al cáncer de mama o de próstata. El principal efecto farmacológico de los bifosfonatos es la inhibición de la resorción ósea, mediante una disminución de la actividad de los osteoclastos, sin intervenir en la formación y mineralización del hueso. Son fármacos utilizados a nivel mundial con unos claros beneficios contrastados clínicamente. Numerosas publicaciones durante los últimos tres años, y debido a su utilización masiva, consideran que la osteonecrosis de los maxilares está asociada al tratamiento con bifosfonatos. Es importante que los pacientes sean informados del riesgo de presentarse esta complicación, para tener la oportunidad de someterse a procedimientos dentales previos al inicio del tratamiento. Las medidas preventivas deben realizarse antes, durante y después del tratamiento con bifosfonatos. El tratamiento quirúrgico debe reservarse para aquellos pacientes que presenten síntomas. Son necesarias nuevas investigaciones que clarifiquen esta complicación.Bisphosphonates constitute a group of inhibitors of bone resorption that are used for treating many disor-ders such as osteoporosis, Paget´s disease, multiple myeloma, malignant hypercalcemia and bone metas-tases associated with breast and prostate cancer. The main pharmacological effect of bisphosphonates is the inhibition of bone resorption, mediated by a decreased function of osteoclasts without interfering in bone formation and mineralization. These drugs are used worldwide, with clear and clinically proven benefits. Several publications within the last three years consider osteonecrosis of the jaw to be associated with bisphosphonate therapy as a result of their extensive use. It is important

  9. New Dimensional Staging of Bisphosphonate-Related Osteonecrosis of the Jaw Allowing a Guided Surgical Treatment Protocol: Long-Term Follow-Up of 266 Lesions in Neoplastic and Osteoporotic Patients from the University of Bari

    Directory of Open Access Journals (Sweden)

    Simonetta Franco

    2014-01-01

    Full Text Available Bisphosphonate-related osteonecrosis of the jaw (BRONJ is the most serious side effect in patients receiving bisphosphonates (BPs for neoplastic disease and osteoporosis. The aim of this study is to propose a new dimensional stage classification, guiding the surgical treatment of BRONJ patients, and to evaluate the success rate of this new management. From 2004 to 2013, 203 neoplastic and osteoporotic patients with 266 BRONJ lesions were referred to the Odontostomatology Unit of the University of Bari. All patients underwent surgery after suspension of BPs therapy and antibiotic treatment. The surgical procedure was complemented by piezosurgery and followed by the application of hyaluronate and amino acids. The new dimensional staging suggests the choice of the surgical approach, and allows the prediction of postoperative complications and soft and hard tissues healing time, guiding the surgical treatment protocol. This protocol could be a successful management strategy for BRONJ, considering the low recurrences rate and the good stabilisation of the surgical sites observed after a long-term follow-up.

  10. Updated recommendations for managing the care of patients receiving oral bisphosphonate therapy: an advisory statement from the American Dental Association Council on Scientific Affairs.

    Science.gov (United States)

    Edwards, Beatrice J; Hellstein, John W; Jacobsen, Peter L; Kaltman, Steven; Mariotti, Angelo; Migliorati, Cesar A

    2008-12-01

    and Overview. In 2005, the American Dental Association (ADA) Council on Scientific Affairs convened an expert panel to develop clinical recommendations for dentists treating patients who are receiving oral bisphosphonate therapy. The Journal of the American Dental Association published the resulting report in 2006. This 2008 advisory statement is the first of projected periodic updates of the 2006 clinical recommendations. This 2008 advisory statement concludes, on the basis of a review of the current literature, that for patients receiving bisphosphonate therapy, the risk of developing bisphosphonate-associated osteonecrosis (BON) of the jaw apparently remains low. It also newly concludes that current screening and diagnostic tests are unreliable for predicting a patient's risk of developing the condition. This statement updates the 2006 recommendations regarding general dentistry, management of periodontal diseases, implant placement and maintenance, oral and maxillofacial surgery, endodontics, restorative dentistry and prosthodontics, and orthodontics.

  11. Bisphosphonate-associated osteonecrosis of jaw reoccurrence after methotrexate therapy: a case report.

    Science.gov (United States)

    Alsalleeh, Fahd; Keippel, Jeffery; Adams, Lyde; Bavitz, Bruce

    2014-09-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-known complication caused by amino-bisphosphonate therapy. We document one case of BRONJ associated with oral administration of methotrexate, a known immunosuppressive drug used to treat rheumatoid arthritis. A 66-year-old woman was referred for evaluation and endodontic surgery of recently re-treated tooth 13. Tooth 14 was extracted 3 months prior, and the extraction site had not completely healed. Her medical history revealed rheumatoid arthritis and osteoporosis. She had been taking Fosamax (alendronate) 70 mg daily. Because of adequate root canal therapy of tooth 13, endodontic surgery was performed. Five months after apicoectomy, her symptoms had not changed. Tooth 13 was extracted, and the socket healed without complications. The socket of extracted tooth 14 was also healing. At the 3-month recall visit, bone exposure and purulent discharge at the site of extracted tooth 14 were noted. The patient had recently received methotrexate. The methotrexate was discontinued, and she was given course of amoxicillin. At the 18-month follow-up, the healing progressed, and the wound was closed. A medication that suppresses the immune system such as methotrexate may complicate the management of BRONJ. Once a diagnosis of BRONJ is made, a closely monitored conservative approach is recommended. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  12. Osteonecrose maxilar em pacientes portadores de doenças neoplásicas sob uso de bisfosfonatos Jaw osteonecrosis in patients with neoplastic diseases taking bisphosphonates

    Directory of Open Access Journals (Sweden)

    Paulo S. S. Santos

    2008-12-01

    Full Text Available A osteonecrose induzida por bisfosfonatos é uma complicação que pode ocorrer em pacientes acometidos por doença osteolítica tais como mieloma múltiplo, portadores de metástases tumorais em tecido ósseo, osteoporose e que fizeram uso de droga do grupo dos bisfosfonatos. A despeito dos benefícios do uso destes fármacos, a osteonecrose maxilar é uma importante complicação. Seu mecanismo de ação reduz a reabsorção óssea, o estímulo à atividade osteoblástica, a inibição do recrutamento e promoção da apoptose de osteoclastos. Até o presente momento, não há na literatura um protocolo de tratamento para a osteonecrose por bisfosfonatos. No presente trabalho, os autores fazem uma revisão da literatura e descrevem dois casos clínicos em pacientes do sexo feminino, com diferentes doenças, mieloma múltiplo e metástases ósseas por carcinoma de mama, acometidas por osteonecrose em mandíbula induzida por bisfosfonatos.The use of bisphosphonates among patients affected by osteolytic diseases, such as multiple myeloma, metastatic bone lesions and osteoporosis has been associated with the risk of osteonecrosis of the jaws. Bisphosphonates are found in areas of the bone that are undergoing inflammation or resorption. They are phagocytosed and internalized by osteoclasts. Once in the bone, these bisphosphonates cause apoptosis or cell death of the osteoclasts and as a result they may inhibit osteoclast-mediated bone resorption. Bisphosphonates seem to affect osteoclasts when it comes to both numbers and function. Although bisphosphonates are potent and valuable inhibitors of osteoclastic bone lesions, several unanswered questions exist regarding the risk of developing osteonecrosis and the management of this complication. This study reports two clinical cases of osteonecrosis of the jaws associated with the use of bisphosphonates. According to the findings, the two patients (women with different neoplasms: multiple myeloma and

  13. Bisphosphonate-associated osteonecrosis of the jaws

    Directory of Open Access Journals (Sweden)

    Pankaj Agarwal

    2012-01-01

    Full Text Available Bisphosphonates constitute a group of drugs capable of modulating bone turnover and reduce its remodeling when an excessive resorption occurs. This is why they are indicated in a large group of bone diseases like postmenopausal osteoporosis or osteolysis associated with breast cancer or multiple myeloma. Over the last few years and due to their extensive use, many cases of complications associated with their use have been published. Among the most important possible adverse effects are the oral ones, with the appearance of ulcerations and, especially, osteonecrosis of the jaws associated with this therapy. In this paper, we have analyzed the general characteristics of these drugs and their mechanisms of action as well as the described adverse effects, especially oral and maxillofacial, have been made special reference, regarding the prevention of osteonecrosis of the jaws, heightened by cases described in the medical and odontological literature. The preventive protocol backs up the fundamental role of the odontologist in the effective prevention of this process before, during and after the treatment.

  14. Effect of Bisphosphonates on the Levels of Rankl and Opg in Gingival Crevicular Fluid of Patients With Periodontal Disease and Post-menopausal Osteoporosis.

    Science.gov (United States)

    Verde, María E; Bermejo, Daniela; Gruppi, Adriana; Grenón, Miriam

    2015-12-01

    The Receptor activator of nuclear factor-kappa B ligand (RANKL)/RANK/Osteoprotegerine (OPG) system has been proposed as essential for osteoclast biology and identified as key part in regulating the physiology and pathology of the skeletal system. The study of the RANKL/RANK/OPG system has increased the understanding of the mechanisms involved in the bone remodeling process, especially in postmenopausal osteoporosis and periodontal disease. Bisphosphonates have become the mainstay of the treatment and prevention of post-menopausal osteoporosis. They inhibit the formation and dissolution of calcium phosphate crystals in bone and also osteoclasts, thus reducing bone turnover.Current investigations relate osteoporosis with the appearance and progression of periodontal disease. Although the etiology of both is different, the bone loss present in both shares several characteristics. Thus, therapy used for osteoporosis can be considered of value in the treatment of periodontal disease. The aim of this study was to evaluate the levels of RANKL, OPG and their relationship in gingival crevicular fluid (GCF) in patients with periodontal disease and postmenopausal osteoporosis/ osteopenia in relation to consumption of bisphosphonates. We studied 66 periodontal active sites obtained from 17 post- menopausal women patients aged between 45-70 years old with osteoporosis/osteopenia and periodontal disease. GCF samples were collected using sterile filter paper strips. To determine the concentration of RANKL and OPG, a commercial ELISA assay was used. The values of RANKL, OPG and their ratio (RANKL/ OPG) were compared with Mann-Whitney U Test. The values of RANKL, OPG and their ratio obtained in patients with osteoporosis/osteopenia and periodontal disease with or without bisphosphonates treatment showed no differences. Bisphosphonates do not alter the concentration of RANKL and OPG and their ratio in the GCF of patients with osteoporosis/ osteopenia and periodontal disease

  15. Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

    Science.gov (United States)

    Curtis, Ryan C; Custis, James T; Ehrhart, Nicole P; Ehrhart, E J; Condon, Keith W; Gookin, Sara E; Donahue, Seth W

    2016-01-01

    Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

  16. Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

    Directory of Open Access Journals (Sweden)

    Ryan C Curtis

    Full Text Available Clinical studies using definitive-intent stereotactic radiation therapy (SRT for the local treatment of canine osteosarcoma (OSA have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy. Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA and parathyroid hormone (PTH are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total. Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis 8 weeks after radiation in the combined (ZA/PTH treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

  17. The effect of bisphosphonates on bone mineral density in patients with ankylosing spondylitis in daily clinical practice

    NARCIS (Netherlands)

    Arends, S.; Veneberg, J.G.; Wink, F.R.; Bos, R.; Brouwer, E.; Van Der Veer, E.; Bootsma, H.; Van Roon, E.N.; Maas, F.; Spoorenberg, A.

    2016-01-01

    Background: Ankylosing spondylitis (AS) is not only characterized by excessive bone formation, but also by excessive bone loss which may lead to low bone mineral density (BMD). So far, little is known about the effect of treatment with bisphosphonates on BMD in patients with AS. Objectives: To

  18. Implications of bisphosphonate calcium ion depletion interfering with desmosome epithelial seal in osseointegrated implants and pressure ulcers.

    Science.gov (United States)

    Touyz, Louis Z G; Afrashtehfar, Kelvin I

    2017-09-01

    Osteoporosis (OP) is a global bone disease prevalent in aging in humans, especially in older women. Bisphosphonates (BPs) are commonly used as therapy for OP as it influences hard and soft tissues calcium metabolism. Mucosal and dermal ulceration with exposure of underlying bone arises from incomplete epithelial recovery due to reduced desmosome formation deriving from lack of available calcium. Pathological situations such as bisphosphonate-related osteonecrosis of the jaw have been described. This hypothesis states other situations which demand intact functional desmosomes such as healing skin over chronic pressure points leading to pressure ulcers (as well-known as bedsores, pressure sores, pressure injuries, decubitus ulcers), and hemidesmosomes such as epithelial seals in contact with titanium surfaces will have a higher prevalence of breakdown among patients being treated with BPs. This may be proven through the diminished modulation of calcium ions due to BPs, and its effect on the formation of intercellular gap junctions. Copyright © 2017. Published by Elsevier Ltd.

  19. Synthesis and applications of gem-bis-phosphonates, powerful complexing agents of metals

    International Nuclear Information System (INIS)

    Lecercle, D.

    2007-12-01

    This thesis was devoted to the development of new ways to prepare gem-bis-phosphonates compounds (BPs), and was carried out under the Program of Nuclear and Environmental Toxicology (ToxNuc-E). Two applications of these compounds have been investigated, the preparation of potent ligands of the uranyl ion for a target of decorporation, and the preparation of new anticancer compounds. The first of these applications was the consequence of work done in the laboratory, that have shown the strong uranium-binding properties of bis-phosphonic ligands. The in vivo tests performed on these compounds have shown the tendency of these ligands to cause liver accumulation of uranium, we wanted to address this problem by modifying the method of anchoring of the bis-phosphonates functions. To this end we have developed a new way to access to these compounds using a metal-carbenoid mediated poly-ols and poly-amines insertion, the metal-carbenoid species bearing the bis-phosphonate function. Regarding the preparation of BPs as anticancer agents, we have developed a new synthetic pathway using a phosphine catalyzed α-P addition of phosphorated pro-nucleophiles to alkynyl-phosphonates as a key step. This enabled us to prepare thirty compound whose activity was evaluated on two cell lines (A431 and HuH7). Five of these compounds possess an activity equivalent to that of the compound described as the most active, the Zoledronate. (author)

  20. Effective combination treatment of GD2-expressing neuroblastoma and Ewing's sarcoma using anti-GD2 ch14.18/CHO antibody with Vγ9Vδ2+ γδT cells.

    Science.gov (United States)

    Fisher, Jonathan P H; Flutter, Barry; Wesemann, Florian; Frosch, Jennifer; Rossig, Claudia; Gustafsson, Kenth; Anderson, John

    Gamma delta T lymphocytes (γδT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood γδT, which express the Vγ9Vδ2 T cell receptor (TCR) (Vδ2 T cells). Vγ9Vδ2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity FcγR CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluated in vitro cytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. Vδ2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred Vδ2+ T cells, expanded in vitro with zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or γδT cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible.

  1. Dgroup: DG00781 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00781 Chemical ... DGroup Clodronic acid ... D03545 ... Clodronic acid (USAN/INN) D03544 ... Clodron...ate disodium (USAN); Sodium clodronate hydrate (JAN) D07720 ... Clodronic acid disodium salt Other ... DG01600 ... Bisphosphonate ATC code: M05BA02 Bisphosphonates ...

  2. Bisphosphonate-Related Osteonecrosis of the Jaw Bone: Radiological Pattern and the Potential Role of CBCT in Early Diagnosis

    Directory of Open Access Journals (Sweden)

    James Olutayo

    2010-04-01

    Full Text Available Objectives: To systematize the clinico-radiological symptoms and course of bisphosphonate-related osteonecrosis of jaw bone and to evaluate the diagnostic potential of various radiological techniques to detect mild osteonecrosis in each stage of the disease.Material and Methods: The sample consisted of 22 patients previously diagnosed with extraoral malignant disease. Diagnosis was based on a clinical examination in conjunction to digital panoramic radiography and cone beam computed tomography (CBCT. Two dentomaxillofacial radiologists reviewed all images.Results: Twenty patients showed mandibular involvement clinically, while two others had a maxillary involvement. Four stages of the disease were proposed based on the clinico-radiological findings. Subclinical cortical and lamina dura thickening was detected with only three-dimensional CBCT and periapical images, while ulceration and cortical bone thickening was detected only by three-dimensional CBCT. Mixed sclerotic, lytic bone destruction involving alveolar and basal bone with or without encroachment on the mandibular canal, pathological mandibular fractures were detected by two-dimensional panoramic and three-dimensional CBCT images. Other findings are non healing extraction sockets, periapical radiolucencies, osteolysis, sequestra, oroantral fistula, and periosteal new bone formation.Conclusions: The present study showed that bisphosphonate-related osteonecrosis of jaw bone occurs in four distinct clinico-radiological stages. For mild cases, panoramic image diagnosis was much less obvious, whereas cone beam computed tomography was able to fully characterise the bony lesions and describe their extent and involvement of neighbouring structures in all cases. Thus cone beam computed tomography might better contribute to the prevention of bisphosphonate-related osteonecrosis of jaw bone as well to the disease management.

  3. Acyclic nucleoside bisphosphonates: Synthesis and properties of chiral 2-amino-4,6-bis[(phosphonomethoxy)alkoxy]pyrimidines

    Czech Academy of Sciences Publication Activity Database

    Doláková, Petra; Dračínský, Martin; Masojídková, Milena; Šolínová, Veronika; Kašička, Václav; Holý, Antonín

    2009-01-01

    Roč. 44, č. 6 (2009), s. 2408-2424 ISSN 0223-5234 R&D Projects: GA MŠk 1M0508 Grant - others:NIH(US) 1UC1AIO62540-01 Institutional research plan: CEZ:AV0Z40550506 Keywords : acyclic nucleoside phosphonates * pyrimidine * bisphosphonates Subject RIV: CC - Organic Chemistry Impact factor: 3.269, year: 2009

  4. Osteogenesis imperfecta type V: Genetic and clinical findings in eleven Chinese patients.

    Science.gov (United States)

    Liu, Yi; Wang, Jiawei; Ma, Doudou; Lv, Fang; Xu, Xiaojie; Xia, Weibo; Jiang, Yan; Wang, Ou; Xing, Xiaoping; Zhou, Peiran; Wang, Jianyi; Yu, Wei; Li, Mei

    2016-11-01

    Osteogenesis imperfecta (OI) type V is a rare inherited disease characterized by multiple fractures, intraosseous membrane calcification, and hypercallus formation. We investigate the causative gene, phenotype and also observe the effects of zoledronic acid in Chinese OI type V patients. The clinical phenotype and causative gene mutation was investigated in eleven patients with type V OI. Patients were given a dose of zoledronic acid 5mg intravenously. Fracture incidence and Z-score of bone mineral density (BMD) were evaluated. Serum levels of biomarkers such as cross linked C-telopeptide of type I collagen (β-CTX) and safety parameters were assessed. The c.-14C>T mutation in the 5' untranslated region of IFITM5 was detected in all patients. The phenotype was largely variable, and no significant correlation of genotype and phenotype was found. After one dose of zoledronic acid infusion, fracture incidence significantly dropped from 2fractures/year before treatment to 0fracture/year after treatment (P=0.01). Z score of lumbar spine BMD elevated from -2.6 to -1.3 (P<0.001). Serum β-CTX level decreased by 50% (P<0.05). No serious adverse event was found. No obvious correlation was found between the genotype and phenotype. Zoledronic acid had significantly skeletal protective effects in OI of type V. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features

    Directory of Open Access Journals (Sweden)

    Schlegel Karl A

    2010-10-01

    Full Text Available Abstract Background Bone-destructive disease treatments include bisphosphonates and antibodies against the osteoclast differentiator, RANKL (aRANKL; however, osteonecrosis of the jaw (ONJ is a frequent side-effect. Current models fail to explain the restriction of bisphosphonate (BP-related and denosumab (anti-RANKL antibody-related ONJ to jaws. Msx-1 is exclusively expressed in craniofacial structures and pivotal to cranial neural crest (CNC-derived periodontal tissue remodeling. We hypothesised that Msx-1 expression might be impaired in bisphosphonate-related ONJ. The study aim was to elucidate Msx-1 and RANKL-associated signal transduction (BMP-2/4, RANKL in ONJ-altered and healthy periodontal tissue. Methods Twenty ONJ and twenty non-BP exposed periodontal samples were processed for RT-PCR and immunohistochemistry. An automated staining-based alkaline phosphatase-anti-alkaline phosphatase method was used to measure the stained cells:total cell-number ratio (labelling index, Bonferroni adjustment. Real-time RT-PCR was performed on ONJ-affected and healthy jaw periodontal samples (n = 20 each to quantitatively compare Msx-1, BMP-2, RANKL, and GAPDH mRNA levels. Results Semi-quantitative assessment of the ratio of stained cells showed decreased Msx-1 and RANKL and increased BMP-2/4 (all p Conclusions These results explain the sclerotic and osteopetrotic changes of periodontal tissue following BP application and substantiate clinical findings of BP-related impaired remodeling specific to periodontal tissue. RANKL suppression substantiated the clinical finding of impaired bone remodelling in BP- and aRANKL-induced ONJ-affected bone structures. Msx-1 suppression in ONJ-adjacent periodontal tissue suggested a bisphosphonate-related impairment in cellular differentiation that occurred exclusively jaw remodelling. Further research on developmental biology-related unique features of jaw bone structures will help to elucidate pathologies restricted to

  6. The inhibition of subchondral bone lesions significantly reversed the weight-bearing deficit and the overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn in the monosodium iodoacetate induced model of osteoarthritis pain.

    Directory of Open Access Journals (Sweden)

    Degang Yu

    Full Text Available Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA. Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain.Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA into the rat knee joint. Zoledronic acid (ZOL, a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP in the dorsal root ganglion (DRG, and spinal glial activation status using glial fibrillary acidic protein (GFAP and ionized calcium binding adaptor molecule-1 (Iba-1 immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling.MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected.The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.

  7. Bisphosphonate-Induced Osteonecrosis of the Maxilla Resembling a Persistent Endodontic Lesion.

    Science.gov (United States)

    Mosaferi, Hossein; Fazlyab, Mahta; Sharifi, Sanaz; Rahimian, Sepideh

    2016-01-01

    A 52-year-old Caucasian woman suffering from pain in the anterior maxillary region, presented to the clinic. Examination revealed a draining sinus tract in the buccal vestibule of the maxilla in the left anterior segment and expansion in the middle of palate. On conventional radiographic examination the lesion was initially assumed to be a periapical problem related to the incisors but subsequently it was diagnosed to be a bisphosphonate osteonecrosis. Acquiring a comprehensive medical history from the patients, conducting the clinical vitality tests and most importantly being familiar with the non-odontogenic lesions that can be side effects of specific medications are important requirements for reaching a correct diagnosis.

  8. Advantages and Disadvantages of Bone Protective Agents in Metastatic Prostate Cancer: Lessons Learned

    Directory of Open Access Journals (Sweden)

    Christian Thomas

    2016-08-01

    Full Text Available Nine out of ten metastatic prostate cancer (PCa patients will develop osseous metastases. Of these, every second will suffer from skeletal-related events (SRE. SRE are associated with an increased risk for death, which is markedly increased in the presence of pathological fracture. Moreover, health insurance costs nearly double in the presence of SRE. Zoledronic acid and denosumab are both approved drugs for the prevention or delay of SRE in castration-resistant prostate cancer (CRPC patients with osseous metastases. However, long-term treatment with one of these two drugs is associated with the development of medication-related osteonecrosis of the jaw (MRONJ. Routine inspections of the oral cavity before and during treatment are mandatory in these patients. Regarding imaging techniques, bone scintigraphy seems to be a promising tool to detect early stage MRONJ. Zoledronic acid does not reduce the incidence of SRE in hormone-sensitive PCa. First data shows 3-monthly application of zoledronic acid to be equi-effective to monthly application.

  9. Poor medication adherence to bisphosphonates and high self-perception of aging in elderly female patients with osteoporosis.

    Science.gov (United States)

    Wu, X; Wei, D; Sun, B; Wu, X N

    2016-10-01

    Non-adherence to bisphosphonates exposes the elderly female osteoporosis patients to an increased risk of fracture. This was one of the first studies to explore the relationship between medication adherence and self-perception of aging. Feelings of lacking control and expectations for negative events, beliefs of illness's chronic duration nature, and its linkage with aging were associated with of poor medication adherence. To examine the relationship between medication adherence to bisphosphonates and self-perception of aging in elderly female patients with osteoporosis. This was a cross-sectional survey. A convenience sample of 245 elderly female patients with osteoporosis prescribed regular oral bisphosphonate therapy was recruited from three tertiary hospitals in China. Sociodemographic and osteoporosis-related data, Morisky Medication Adherence Scale-8 (MMAS-8) and Aging Perceptions Questionnaire (APQ) data were collected. Mean adherence score measured by MMAS-8 was 4.46(SD = 1.91; range, 0.25-7.00). Percentages of good and poor adherence were 28.6 and 71.4 %, which showed a poor medication adherence. Six domains of APQ statistically significantly associated with medication adherence. Interestingly, with control of age, educational status, marital status, and symptoms accompanying osteoporosis as covariates in the multivariate linear regression model, the effects of three domains disappeared. Significantly, worse adherence was observed in those patients who had higher feelings of lack of control, more expectations for negative events, more beliefs of osteoporosis's chronic duration nature and its linkage with aging. We conclude that feelings of lacking control, expectations for negative events, beliefs of illness's chronic duration nature, and its linkage with aging were associated with poor medication adherence in elderly female patients with osteoporosis. Concerns about self-perception of aging need to be addressed in order to improve medication adherence.

  10. Predictors of Adherence to Oral Bisphosphonate Therapy: A Register-based National Open Cohort Study

    DEFF Research Database (Denmark)

    Hansen, Carrinna; Pedersen, B D; Konradsen, Hanne

    Abstract: Aim: To assess adherence to oral bisphosphonates and determine what predicts early cessation of treatment as opposed to low refill compliance. We hypothesized that patients who stopped treatment very early would differ in demographics and comorbidity from other patients with poor...... with increasing age and in patients taking proton pump inhibitors. These findings suggest that other factors — such as patient understanding, education level and socioeconomics may be more important determinants of adherence to osteoporosis treatment....

  11. Comparison of orally administered bisphosphonate drugs in reducing the risk of hip fracture in older adults: a population-based cohort study.

    Science.gov (United States)

    Cadarette, Suzanne M; Lévesque, Linda; Mamdani, Muhammad; Perreault, Sylvie; Juurlink, David N; Paterson, J Michael; Carney, Greg; Gunraj, Nadia; Hawker, Gillian A; Tadrous, Mina; Wong, Lindsay; Dormuth, Colin R

    2013-09-01

    Orally administered bisphosphonate drugs (i.e., alendronate, etidronate, risedronate) can reduce the risk of vertebral fracture. However, only alendronate and risedronate have proven efficacy in reducing the risk of hip fracture. We sought to examine the comparative effectiveness of orally administered bisphosphonate drugs in reducing hip fractures among older adults. We identified new users of orally administered bisphosphonate drugs in British Columbia and Ontario between 2001 and 2008. We used province- and sex-specific propensity score-matching strategies to maximize comparability between exposure groups. We used Cox proportional hazards models to compare time-to-hip fracture within 1 year of treatment between exposures by sex in each province. Our secondary analyses considered hip fracture rates within 2 and 3 years' follow-up. We used alendronate as the reference for all comparisons and pooled provincial estimates using random effects variance-weighted meta-analysis. We identified 321 755 patients who were eligible for inclusion in the study. We found little difference in fracture rates between men (pooled hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74-1.14) or women (pooled HR 1.15, 95% CI 0.73-1.56) taking risedronate and those taking alendronate. We similarly identified little difference in fracture rates between women taking etidronate and those taking alendronate (pooled HR 1.00, 95% CI 0.82-1.18). However, we identified lower rates of hip fracture among men taking etidronate relative to alendronate (pooled HR 0.77, 95% CI 0.60-0.94). Results extended to 2 and 3 years' follow-up were similar. However, with 3 years' follow-up, rates of hip fracture were lower among women in British Columbia who had taken alendronate. We identified little overall difference between alendronate and risedronate in reducing the risk of hip fracture in men or women. Our finding that etidronate is associated with lower fracture risk among men is likely due to

  12. Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate-Danish National Register Based Cohort Study

    DEFF Research Database (Denmark)

    Pazianas, M; Abrahamsen, B; Eiken, Pia Agnete

    2012-01-01

    whether alendronate acts as chemopreventive. INTRODUCTION: When bisphosphonates are given by mouth, around 99% remains non-absorbed in the intestine. Based on their biochemical actions, we predicted that oral bisphosphonates might prevent colon cancers. METHODS: This is a Danish national register...... incidence and post-diagnosis survival in patients taking oral alendronate for osteoporosis. RESULTS: Cox proportional hazards analysis of death due to colon cancer showed lower risk in alendronate users, crude hazard ratio (HR) 0.69 (95% CI 0.59-0.81) with an adjusted HR of 0.62 (95% CI 0......In this Danish national register-based cohort study, we examined the effects of alendronate on the development of colon cancers and survival. The incidence of colon cancer and mortality rate, once colon cancer had been diagnosed, were lower in patients treated with alendronate, posing the question...

  13. Use of bisphosphonate might be important to improve bone mineral density in patients with rheumatoid arthritis even under tight control: the TOMORROW study.

    Science.gov (United States)

    Tada, Masahiro; Inui, Kentaro; Sugioka, Yuko; Mamoto, Kenji; Okano, Tadashi; Anno, Shohei; Koike, Tatsuya

    2017-06-01

    Although patients with rheumatoid arthritis (RA) are prone to osteoporosis, tight control of disease activity might have a positive effect on bone metabolism. We aimed to determine whether bisphosphonate use is still important to improve bone mineral density (BMD) in RA patients whose disease activity was tightly controlled and the dose of glucocorticoid was reduced. This study was a sub-analysis of the 10-year prospective cohort TOtal Management Of Risk factors in Rheumatoid arthritis patients to lOWer morbidity and mortality: the TOMORROW which started from 2010. We compared BMD between 192 patients with RA and age- and sex-matched volunteers between 2010 and 2013 using dual-energy X-ray absorptiometry (DXA) in whole body mode. We then determined ratios of changes in BMD (%ΔBMD) to assess factors influencing increases in BMD among the patients using multivariate logistic regression analysis. The BMD was significantly lower in the patients than in the controls at all sites surveyed during 2010 and 2013. The %ΔBMD of the total spine was significantly higher among the patients treated with, than without bisphosphonate (6.2 vs. 1.8%, P = 0.0001). Multivariate logistic regression analysis revealed that use of bisphosphonate was a significant factor contributing to BMD increase (odds ratio 2.13; 95% confidence interval, 1.03-4.38, P = 0.041). Meanwhile, use of biologic agents, reducing glucocorticoid dose, and control of disease activity were not significant factors for gain of BMD. The BMD was lower among patients with RA than non-RA controls. Use of bisphosphonate significantly increased the BMD of the spine in patients over a period of 3 years and was important for maintaining the BMD among patients with RA under the control of inflammation and disease activity.

  14. Labelling of m-trimethyl silylphenyl-ethylidene-1, i-bisphosphonate with /sup 99m/Tc and its evaluation as an imaging agent

    International Nuclear Information System (INIS)

    Sajid, K.M.; Mahmood, R.

    2012-01-01

    Technetium-99m labeled phosphates and phosphonates have since long been in use for bone imaging to diagnose bone infection, bone metastasis and bone fracture. /sup 131/ I -labeled bisphosphonates have also been prepared for targeted radiotherapy of bone metastasis. Although animal experiments show good accumulation of bisphosphonates in bone. The agent has never been tried in humans because of high gamma and beta energy. The agent must first be tested in humans using a relatively safe radioisotope. Technitium-99m (/sup 99m/Tc) a radioisotope with relatively low gamma energy 99m and short half-life can serve as a good label. Whether /sup 99m/Tc-labeled bisphosphonates can be used as good imaging agents is another aspect that needs further investigation. A study was therefore, conducted to label m-trimethyl silylphenyl)-ethylidene-1, 1-bisphosphonate with /sup 99m/Tc and standardize the labeling procedure. The labeling procedure - involved reduction of technetium (TcO/sub 4/) with stannous chloride followed by chelation of technetium with bisphosphonates. Radiochemical purity was checked by paper chromatography. Pyrogenicity was checked by administration of the labeled compound into rabbits. The stability of the compound was determined by noting the radiochemical binding at several intervals of half an hour after preparation. Biodistribution of the agent was studied by injecting the labeled compound into rabbits. The results showed that the compound could be labeled with /sup 99m/Tc without any difficulty. The ease of binding was excellent. There was more than 95% binding of technetium with the compound and the labelled compound was reasonably stable for 5 hours after labeling. The rectal temperature remained stable during this period, which showed that the animal accepted the compound and there were no pyrogenic reactions. Biodistribution studies on rabbit showed that accumulation of agent was poor in bones and the labeled compound remains in blood even after 4

  15. N-(2-PIRYDYLAMINO METHYLENEBISPHOSPHONIC ACID AS A SOLE SOURCE OF A FUNGI FUSARIUM STRAINS GROWING

    Directory of Open Access Journals (Sweden)

    Teresa Krzyśko-Łupicka

    2016-09-01

    The results of growth kinetics of the studied Fusarium fungi in the presence of N-(2-pirydyloamino methyle-nobisphosphonic acid, were expressed by dry weight [g·dm-3]. Only Fusarium oxysporum XVI has been capa-ble to grow in acidic medium (pH 4.0 using N-(2-pirydylamino methylene-bisphosphonic acid as an alterna-tive source of phosphorus. In these conditions the N-(2-pirydylamino methylenebisphosphonic acid degrada-tion was carried out to utilize phosphorus compounds as a source of nutrient components for this strain. The presence of N-(2-pirydylamino methylenebisphosphonic acid receded a growth rate of mycelium but did not have an effect on spores of tested fungi.

  16. Dgroup: DG00785 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00785 Chemical ... DGroup Ibandronic acid ... D08056 ... Ibandronic acid (INN) D04486 ... Ibandron...ate sodium (USAN); Ibandronate sodium hydrate (JAN) ... Other ... DG01600 ... Bisphosphonate ATC code: M05BA06 Bisphosphonates FDPS [HSA:2224] [KO:K00787] ...

  17. Dgroup: DG00782 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00782 Chemical ... DGroup Pamidronic acid ... D07281 ... Pamidronic acid (INN) D00941 ... Pamidron...ate disodium (USAN); Pamidronate disodium hydrate (JAN) ... Other ... DG01600 ... Bisphosphonate ATC code: M05BA03 Bisphosphonates FDPS [HSA:2224] [KO:K00787] ...

  18. Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults.

    Science.gov (United States)

    Hinson, Andrew M; Wilkerson, Bekka M; Rothman-Fitts, Ivy; Riggs, Ann T; Stack, Brendan C; Bodenner, Donald L

    2015-10-01

    To measure the effect of proton pump inhibitors (PPIs), with and without concurrent bisphosphonates, on parathyroid hormone (PTH), vitamin D, and calcium. Retrospective chart review of individuals 60 years and older. Subjects with reduced renal function (creatinine >1.3 mg/dL) and low vitamin D (hyperparathyroidism regardless of concurrent oral BP administration. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

  19. Effect of 3-keto-1,5-bisphosphonates on obese-liver's rats.

    Science.gov (United States)

    Lahbib, Karima; Touil, Soufiane

    2016-10-01

    Obesity is associated with an oxidative stress status, which is defined by an excess of reactive oxygen species (ROS) vs. the antioxidant defense system. We report in this present work, the link between fat deposition and oxidative stress markers using a High Fat Diet-(HFD) induced rat obesity and liver-oxidative stress. We further determined the impact of chronic administration of 3-keto-1, 5-BPs 1 (a & b) (40μg/kg/8 weeks/i.p.) on liver's level. In fact, exposure of rats to HFD during 16 weeks induced body and liver weight gain and metabolic disruption with an increase on liver Alanine amino transférase (ALAT) and Aspartate aminotransférase (ASAT) concentration. HFD increased liver calcium level as well as free iron, whereas, it provoked a decrease on liver lipase activity. HFD also induced liver-oxidative stress status vocalized by an increase in reactive oxygen species (ROS) as superoxide radical (O 2 ), hydroxyl radical (OH) and Hydrogen peroxide (H 2 O 2 ). Consequently, different deleterious damages as an increase on Malon Dialdehyde MDA, Carbonyl protein PC levels with a decrease in non-protein sulfhydryls NPSH concentrations, have been detected. Interestingly, our results demonstrate a decrease in antioxidant enzymes activities such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx) and peroxidases (POD). Importantly, 3-keto-1,5-bisphosphonates treatment corrected the majority of the deleterious effects caused by HFD, but it failed to correct some liver's disruptions as mineral profile, oxidative damages (PC and NPSH levels) as well as SOD and lipase activities. Our investigation point that 3-keto-1,5-bisphosphonates could be considered as safe antioxidant agents on the hepatic level that should also find other potential biological applications. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. Dgroup: DG00783 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00783 Chemical ... DGroup Alendronic acid ... D07119 ... Alendronic acid (INN) D00939 ... Alendron...ate sodium (USAN); Alendronate sodium hydrate (JP17) ... Other ... DG01600 ... Bisphosphonate ATC code: M05BA04 Bisphosphonates FDPS [HSA:2224] [KO:K00787] ...

  1. Osteonecrosis de los maxilares asociada al uso de bifosfonatos: revisión de ocho casos Bisphosphonate-related jaw osteonecrosis: Review of eight cases

    Directory of Open Access Journals (Sweden)

    J. Joshi Otero

    2011-03-01

    Full Text Available Introducción: A finales de 2003 se comienzan a publicar en forma creciente los primeros casos de exposición ósea en los maxilares con evolución tórpida, asociados al uso de bifosfonatos por vía intravenosa. Estos fármacos son usados en pacientes con osteoporosis, mieloma múltiple, hipercalcemia maligna y cáncer de pulmón, mama y próstata, principalmente por su capacidad de inhibir la resorción ósea. Material y método: Estudio prospectivo de los pacientes en el Hospital Virgen Macarena que presentaban lesiones maxilares asociadas al uso de bifosfonatos desde el año 2006 hasta la actualidad. Las variables que valoramos en el paciente son: sexo, edad, tratamiento con bifosfonatos, inicio de la osteonecrosis, relación con tratamientos dentales, tratamiento realizado y evolución. Resultados: Se estudiaron 8 pacientes con osteonecrosis maxilar secundaria a tratamiento con bifosfonatos intravenosos u orales por su patología previa oncológica u osteoporótica que fueron tratados según su estadio clínico-radiológico con antibioterapia, legrado y/o exéresis del secuestro según el caso. Presentamos los resultados con un seguimiento mínimo de 15 meses. Conclusiones: El aumento en la incidencia de la osteomielitis maxilar en los pacientes asociados al uso de bifosfonatos y la dificultad para su tratamiento hacen necesario establecer pautas terapéuticas estandarizadas. En nuestra experiencia, el tratamiento conservador basado en la antibioterapia además del legrado de la zona bajo anestesia local permite el control y la curación del proceso en algunos de los pacientes con OMRB grado II.Background: In late 2003, an increasing number of case reports began to appear on bone exposure of the jaw with a torpid evolution in association with intravenous bisphosphonate use. Bisphosphonates are used to inhibit bone resorption in patients with osteoporosis, multiple myeloma, hypercalcemia of malignancy, lung cancer, breast cancer and prostate

  2. International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates

    DEFF Research Database (Denmark)

    Diez-Perez, Adolfo; Naylor, K E; Abrahamsen, B

    2017-01-01

    Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug....

  3. Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study.

    Science.gov (United States)

    De Colli, Marianna; Tortorella, Paolo; Agamennone, Mariangela; Campestre, Cristina; Loiodice, Fulvio; Cataldi, Amelia; Zara, Susi

    2018-07-01

    Periodontitis is an inflammatory disease caused by anaerobic bacteria, including Porphyromonas gingivalis. Lipopolysaccharide (LPS)‑stimulated persistent inflammation is responsible for an increase in matrix metalloproteinase (MMP) expression, resulting in periodontal tissue destruction. The aim of the present study was to investigate synthesized bisphosphonic MMP inhibitors, in an in vitro model consisting of human gingival fibroblasts exposed to LPS, and to compare the biological responses to those induced by zoledronate (ZA), a commercial bisphosphonate. MTT and lactate dehydrogenase (LDH) assays were used to measure cell viability and cytotoxicity, respectively. ELISA was performed to evaluate prostaglandin E2 (PGE2), interleukin (IL)6 and collagen secretion, while western blotting was used to analyze MMP expression. No effect on viability and low cytotoxicity were observed following treatment with bisphosphonate compounds. In the present study, treatment with compound 1 did not increase the release of PGE2 and IL6. Increased levels of collagen I secretion were reported when compound 3 and ZA were administered. An increase of MMP8 was observed following ZA treatment, while a decrease of MMP9 and MMP14 following treatment with compounds 1, 2 and ZA were reported. The performance of compound 1 was optimal in terms of cell viability. Compound 1 also did not induce inflammation, and had the ability to counteract LPS‑induced increases in MMP expression. These data suggested that compound 1 was the most suitable treatment to progress to an in vivo animal study, with the aim to confirm its use for the treatment of periodontitis.

  4. Dgroup: DG00786 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00786 Chemical ... DGroup Risedronic acid ... D08484 ... Risedronic acid (INN) D00942 ... Risedron...ate sodium (USP) ... D03234 ... Sodium risedronate hydrate (JP17) ... Other ... DG01600 ... Bisphosphonate ATC code: M05BA07 Bisphosphonates FDPS [HSA:2224] [KO:K00787] ...

  5. Additive effects of nutritional supplementation, together with bisphosphonates, on bone mineral density after hip fracture: a 12-month randomized controlled study

    Directory of Open Access Journals (Sweden)

    Flodin L

    2014-07-01

    Full Text Available Lena Flodin,1,2 Maria Sääf,3 Tommy Cederholm,4 Amer N Al-Ani,2,5 Paul W Ackermann,5,6 Eva Samnegård,7 Nils Dalen,7 Margareta Hedström2,51Department of Geriatric Medicine, Karolinska University Hospital Stockholm, Sweden; 2Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden; 3Department of Endocrinology, Metabolism, and Diabetes, Karolinska University Hospital, Stockholm, Sweden; 4Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden; 5Department of Orthopedics, Karolinska University Hospital, Stockholm, Sweden; 6Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 7Department of Clinical Science, Division of Orthopedics, Karolinska Institutet, Danderyd Hospital, Stockholm, SwedenBackground: After a hip fracture, a catabolic state develops, with increased bone loss during the first year. The aim of this study was to evaluate the effects of postoperative treatment with calcium, vitamin D, and bisphosphonates (alone or together with nutritional supplementation on total hip and total body bone mineral density (BMD.Methods: Seventy-nine patients (56 women, with a mean age of 79 years (range, 61–96 years and with a recent hip fracture, who were ambulatory before fracture and without severe cognitive impairment, were included. Patients were randomized to treatment with bisphosphonates (risedronate 35 mg weekly for 12 months (B; n=28, treatment with bisphosphonates along with nutritional supplementation (40 g protein, 600 kcal daily for the first 6 months (BN; n=26, or to controls (C; n=25. All participants received calcium (1,000 mg and vitamin D3 (800 IU daily. Total hip and total body BMD were assessed with dual-energy X-ray absorptiometry at baseline, 6, and 12 months. Marker of bone resorption C-terminal telopeptide of collagen I and 25-hydroxy vitamin D were analyzed in serum

  6. Bisphosphonate-coated BSA nanoparticles lack bone targeting after systemic administration.

    Science.gov (United States)

    Wang, Guilin; Kucharski, Cezary; Lin, Xiaoyue; Uludağ, Hasan

    2010-09-01

    A polymeric conjugate of polyethyleneimine-graft-poly(ethylene glycol) and 2-(3-mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (PEI-PEG-thiolBP) was prepared and used for surface coating of bovine serum albumin (BSA) nanoparticles (NPs) designed for bone-specific delivery of bone morphogenetic protein-2 (BMP-2). The NP coating was achieved with a dialysis and an evaporation method, and the obtained NPs were characterized by particle size, zeta-potential, morphology, and cytotoxicity in vitro. The particle size and surface charge of the NPs could be effectively tuned by the PEG and thiolBP substitution ratios of the conjugate, the coating method, and the polymer concentration used for coating. The PEG modification on PEI reduced the toxicity of PEI and the coated NPs, based on in vitro assessment with human C2C12 cells and rat bone marrow stromal cells. On the basis of an alkaline phosphatase (ALP) induction assay, the NP-encapsulated BMP-2 displayed full retention of its bioactivity, except for BMP-2 in PEI-coated NPs. By encapsulating (125)I-labeled BMP-2, the polymer-coated NPs were assessed for hydroxyapatite (HA) affinity; all NP-encapsulated BMP-2 showed significant affinity to HA as compared with free BMP-2 in vitro, and the PEI-PEG-thiolBP coated NPs improved the in vivo retention of BMP-2 compared with uncoated NPs. However, the biodistribution of NPs after intravenous injection in a rat model indicated no beneficial effects of thiolBP-coated NPs for bone targeting. Our results suggested that the BP-conjugated NPs are useful for localized delivery of BMP-2 in bone repair and regeneration, but they are not effective for bone targeting after intravenous administration.

  7. Increased fracture rate in women with breast cancer: a review of the hidden risk

    Directory of Open Access Journals (Sweden)

    Body Jean-Jacques

    2011-08-01

    Full Text Available Abstract Background Women with breast cancer, particularly individuals diagnosed at a relatively early age, have an increased incidence of fractures. Fractures can have serious clinical consequences including the need for major surgery, increased morbidity and mortality, increased cost of disease management, and reduced quality of life for patients. The primary cause of the increased fracture risk appears to be an accelerated decrease in bone mineral density (BMD resulting from the loss of estrogenic signaling that occurs with most treatments for breast cancer, including aromatase inhibitors. However, factors other than BMD levels alone may influence treatment decisions to reduce fracture risk in this setting. Our purpose is to review current evidence for BMD loss and fracture risk during treatment for breast cancer and discuss pharmacologic means to reduce this risk. Results Fracture risk during treatment for breast cancer may be influenced by the rate of BMD loss and the consequent rapid alterations in bone microarchitecture, in addition to the established fracture risk factors in postmenopausal osteoporosis. The rapid decrease in BMD during adjuvant chemoendocrine therapy for breast cancer may necessitate more aggressive pharmacotherapy than is indicated for healthy postmenopausal women who develop osteoporosis. Over the last few years, clinical trials have established the effectiveness of bisphosphonates and other antiresorptive agents to preserve BMD during adjuvant therapy for early breast cancer. In addition, some bisphosphonates (eg, zoledronic acid may also delay disease recurrence in women with hormone-responsive tumors, thereby providing an adjuvant benefit in addition to preserving BMD and potentially preventing fractures. Conclusions It is likely that a combined fracture risk assessment (eg, as in the WHO FRAX algorithm will more accurately identify both women with postmenopausal osteoporosis and women with breast cancer who require

  8. Utilizing time-lapse micro-CT-correlated bisphosphonate binding kinetics and soft tissue-derived input functions to differentiate site-specific changes in bone metabolism in vivo.

    Science.gov (United States)

    Tower, R J; Campbell, G M; Müller, M; Glüer, C C; Tiwari, S

    2015-05-01

    The turnover of bone is a tightly regulated process between bone formation and resorption to ensure skeletal homeostasis. This process differs between bone types, with trabecular bone often associated with higher turnover than cortical bone. Analyses of bone by micro-computed tomography (micro-CT) reveal changes in structure and mineral content, but are limited in the study of metabolic activity at a single time point, while analyses of serum markers can reveal changes in bone metabolism, but cannot delineate the origin of any aberrant findings. To obtain a site-specific assessment of bone metabolic status, bisphosphonate binding kinetics were utilized. Using a fluorescently-labeled bisphosphonate, we show that early binding kinetics monitored in vivo using fluorescent molecular tomography (FMT) can monitor changes in bone metabolism in response to bone loss, stimulated by ovariectomy (OVX), or bone gain, resulting from treatment with the anabolic bone agent parathyroid hormone (PTH), and is capable of distinguishing different, metabolically distinct skeletal sites. Using time-lapse micro-CT, longitudinal bone turnover was quantified. The spine showed a significantly greater percent resorbing volume and surface in response to OVX, while mice treated with PTH showed significantly greater resorbing volume per bone surface in the spine and significantly greater forming surfaces in the knee. Correlation studies between binding kinetics and micro-CT suggest that forming surfaces, as assessed by time-lapse micro-CT, are preferentially reflected in the rate constant values while forming and resorbing bone volumes primarily affect plateau values. Additionally, we developed a blood pool correction method which now allows for quantitative multi-compartment analyses to be conducted using FMT. These results further expand our understanding of bisphosphonate binding and the use of bisphosphonate binding kinetics as a tool to monitor site-specific changes in bone metabolism in

  9. Treatment of bisphosphonate related osteonecrosis following root canal therapy at the 1-year follow-up: report of two cases.

    Science.gov (United States)

    Kaptan, Figen; Kazandag, Meric Karapinar; Iseri, Ufuk

    2013-01-01

    The objective of this report was to use topical gaseous ozone as an adjunct to conventional treatment methods and to describe the multidisciplinary management of bisphosphonate associated bone necrosis, which developed following endodontic treatment. No complaints were noted by the patients at their 1-year follow-up and the treatment showed favorable prognosis.

  10. Aspects of osseous, peritoneal and renal handling of bisphosphonate during peritoneal dialysis: a methodological study

    DEFF Research Database (Denmark)

    Joffe, P; Henriksen, Jens Henrik

    1996-01-01

    .5 and 2.8 ml min-1 (not significant), respectively. The bone bisphosphonate clearance (BBC) at steady state was 26.0 ml min-1, a value which was significantly higher than that at infinity (16.5 ml min-1, p ... by their different molecular weight. The differences in the BBCs at infinity and at steady state are most probably due to late recirculation of MBP from the bone compartment. Hence, the BBC technique can be applied in the CAPD setting....

  11. EFFICACY AND SAFETY OF ALENDRONIC ACID IN PATIENTS WITH JUVENILE RHEUMATOID ARTHRITIS AND OSTEOPOROSIS

    Directory of Open Access Journals (Sweden)

    A.O. Lisitsin

    2010-01-01

    Full Text Available Search for and practical application of new medications to treat of osteoporosis is one of the critical issues in pediatric rheumatology. The article reviews the efficacy and safety of alendronic acid in 64 subjects with juvenile rheumatoid arthritis and systemic osteoporosis. It is demonstrated that alendronate-based therapy in weekly 1 mg/kg doses over 12 months facilitated reliably increased bonedensity, decreased intensity of pain syndrome, and lowered C-terminal telopeptide serum concentration, which indicates improved bone metabolism processes.Key words: juvenile rheumatoid arthritis, osteoporosis, children, treatment, bisphosphonates, alendronic acid. (Pediatric Pharmacology. – 2010; 7(1:48-54

  12. Bilateral atypical insufficiency fractures of the proximal tibia and a unilateral distal femoral fracture associated with long-term intravenous bisphosphonate therapy: a case report

    Directory of Open Access Journals (Sweden)

    Imbuldeniya Arjuna

    2012-02-01

    Full Text Available Abstract Introduction Atypical insufficiency fractures of the femur in patients on long-term bisphosphonate therapy have been well described in recent literature. The majority of cases are associated with minimal or no trauma and occur in the subtrochanteric or diaphyseal region. Case presentation We describe the case of a 76-year-old British Caucasian woman who presented initially to an emergency department and then to her primary care physician with a long-standing history of bilateral knee pain after minor trauma. Plain radiographs showed subtle linear areas of sclerosis bilaterally in her proximal tibiae. Magnetic resonance imaging confirmed the presence of insufficiency fractures in these areas along with her left distal femur. There are very few reports of atypical insufficiency fractures involving the tibia in patients on long-term bisphosphonate therapy and this appears to be the only documented bilateral case involving the metaphyseal regions of the proximal tibia and distal femur. Conclusion In addition to existing literature describing atypical fractures in the proximal femur and femoral shaft, there is a need for increased awareness that these fractures can also occur in other weight-bearing areas of the skeleton. All clinicians involved in the care of patients taking long-term bisphosphonates need to be aware of the growing association between new onset lower limb pain and atypical insufficiency fractures.

  13. The effect of radiotherapy, and radiotherapy combined with bisphosphonates or RANK ligand inhibitors on bone quality in bone metastases. A systematic review

    NARCIS (Netherlands)

    Groenen, K.H.J.; Pouw, M.H.; Hannink, G.; Hosman, A.J.; van der Linden, Y.M.; Verdonschot, Nicolaas Jacobus Joseph; Tanck, E.

    2016-01-01

    Purpose The role of radiotherapy in stabilizing metastatic bones is unclear. This systematic review assessed the effects of (1) radiotherapy, (2) radiotherapy combined with bisphosphonates, and (3) radiotherapy combined with RANK ligand (RANKL) inhibitors on bone quality and bone strength in bone

  14. Synthesis of phosphonic acid derivatized bipyridine ligands and their ruthenium complexes.

    Science.gov (United States)

    Norris, Michael R; Concepcion, Javier J; Glasson, Christopher R K; Fang, Zhen; Lapides, Alexander M; Ashford, Dennis L; Templeton, Joseph L; Meyer, Thomas J

    2013-11-04

    Water-stable, surface-bound chromophores, catalysts, and assemblies are an essential element in dye-sensitized photoelectrosynthesis cells for the generation of solar fuels by water splitting and CO2 reduction to CO, other oxygenates, or hydrocarbons. Phosphonic acid derivatives provide a basis for stable chemical binding on metal oxide surfaces. We report here the efficient synthesis of 4,4'-bis(diethylphosphonomethyl)-2,2'-bipyridine and 4,4'-bis(diethylphosphonate)-2,2'-bipyridine, as well as the mono-, bis-, and tris-substituted ruthenium complexes, [Ru(bpy)2(Pbpy)](2+), [Ru(bpy)(Pbpy)2](2+), [Ru(Pbpy)3](2+), [Ru(bpy)2(CPbpy)](2+), [Ru(bpy)(CPbpy)2](2+), and [Ru(CPbpy)3](2+) [bpy = 2,2'-bipyridine; Pbpy = 4,4'-bis(phosphonic acid)-2,2'-bipyridine; CPbpy = 4,4'-bis(methylphosphonic acid)-2,2'-bipyridine].

  15. Osteomalacia: the missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws?

    Science.gov (United States)

    Bedogni, Alberto; Saia, Giorgia; Bettini, Giordana; Tronchet, Anita; Totola, Andrea; Bedogni, Giorgio; Tregnago, Paolo; Valenti, Maria Teresa; Bertoldo, Francesco; Ferronato, Giuseppe; Nocini, Pier Francesco; Blandamura, Stella; Dalle Carbonare, Luca

    2012-01-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ. This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%. In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair. Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration.

  16. Inhibitory actions by ibandronate sodium, a nitrogen-containing bisphosphonate, on calcium-activated potassium channels in Madin–Darby canine kidney cells

    Directory of Open Access Journals (Sweden)

    Sheng-Nan Wu

    2015-01-01

    Full Text Available The nitrogen-containing bisphosphonates used for management of the patients with osteoporosis were reported to influence the function of renal tubular cells. However, how nitrogen-containing bisphosphates exert any effects on ion currents remains controversial. The effects of ibandronate (Iban, a nitrogen-containing bisphosphonate, on ionic channels, including two types of Ca2+-activated K+ (KCa channels, namely, large-conductance KCa (BKCa and intermediate-conductance KCa (IKCa channels, were investigated in Madin–Darby canine kidney (MDCK cells. In whole-cell current recordings, Iban suppressed the amplitude of voltage-gated K+ current elicited by long ramp pulse. Addition of Iban caused a reduction of BKCa channels accompanied by a right shift in the activation curve of BKCa channels, despite no change in single-channel conductance. Ca2+ sensitivity of these channels was modified in the presence of this compound; however, the magnitude of Iban-mediated decrease in BKCa-channel activity under membrane stretch with different negative pressure remained unchanged. Iban suppressed the probability of BKCa-channel openings linked primarily to a shortening in the slow component of mean open time in these channels. The dissociation constant needed for Iban-mediated suppression of mean open time in MDCK cells was 12.2 μM. Additionally, cell exposure to Iban suppressed the activity of IKCa channels, and DC-EBIO or 9-phenanthrol effectively reversed its suppression. Under current-clamp configuration, Iban depolarized the cells and DC-EBIO or PF573228 reversed its depolarizing effect. Taken together, the inhibitory action of Iban on KCa-channel activity may contribute to the underlying mechanism of pharmacological or toxicological actions of Iban and its structurally similar bisphosphonates on renal tubular cells occurring in vivo.

  17. Toward a noncytotoxic glioblastoma therapy: blocking MCP-1 with the MTZ Regimen

    Directory of Open Access Journals (Sweden)

    Salacz ME

    2016-04-01

    Full Text Available Michael E Salacz,1,2 Richard E Kast,3 Najmaldin Saki,4 Ansgar Brüning,5 Georg Karpel-Massler,6 Marc-Eric Halatsch6 1Department of Internal Medicine, 2Department of Neurosurgery, University of Kansas, Kansas City, KS, USA; 3IIAIGC Study Center, Burlington, VT, USA; 4Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 5Molecular Biology Laboratory, University Hospital Munich, Munich, Germany; 6Department of Neurosurgery, University of Ulm, Ulm, Germany Abstract: To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant monocyte lineage cells (MLCs (monocyte, macrophage, microglia, dendritic cells that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%–30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic – minocycline, an antihypertensive drug – telmisartan, and a bisphosphonatezoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocycline, telmisartan, and zoledronic acid – the MTZ Regimen – have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low

  18. Is Bisphosphonate-Related Osteonecrosis of the Jaw an Infection? A Histological and Microbiological Ten-Year Summary

    Directory of Open Access Journals (Sweden)

    A. M. Hinson

    2014-01-01

    Full Text Available The role of infection in the etiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ is poorly understood. Large-scale epidemiological descriptions of the histology and microbiology of BRONJ are not found in the literature. Herein, we present a systematic review of BRONJ histology and microbiology (including demographics, immunocompromised associations, clinical signs and symptoms, disease severity, antibiotic and surgical treatments, and recovery status validating that infection should still be considered a prime component in the multifactorial disease.

  19. EFFECTIVENESS OF NITROGEN-CONTAINING BISPHOSPHONATES IN THE REGULATION OF MINERAL METABOLISM DISTURBANCES ASSOCIATED WITH ALIMENTARY OSTEOPOROSIS IN RATS

    OpenAIRE

    Komisarenko S. V.; Volochnyuk D. M.; Shymanskyy I. O.; Ivonin S. P.; Veliky M. M.1

    2015-01-01

    The aim of the study was to investigate the effectiveness of nitrogen-containing bisphosphonates synthesized as promising substances for correction of mineral metabolism in osteoporosis. The study was carried out on a model of alimentary osteoporosis that was characterized by hypocalcaemia, hypophosphatemia, decreased 25-Hydroxyvitamin D3 content in blood serum and severe bone tissue demineralization (reduced ash content and mineral components). It was found that synthesized novel nitrogen bi...

  20. New 1-hydroxy-1,1-bisphosphonates derived from 1H-pyrazolo[3,4-b]pyridine: synthesis and characterization

    Energy Technology Data Exchange (ETDEWEB)

    Teixeira, Fatima C.; Lucas, Carla; Curto, M. Joao M., E-mail: fatima.teixeira@lneg.pt [Laboratorio Nacional de Energia e Geologia, Lisboa (Portugal); Neves, M. [Instituto Superior Tecnico, Instituto Tecnologico e Nuclear (IST/ITN), Campus Tecnologico e Nuclear, Universidade Tecnica de Lisboa, Sacavem (Portugal); Duarte, M. Teresa; Andre, Vania; Teixeira, Antonio P.S. [Centro de Quimica Estrutural, Instituto Superior Tecnico, Universidade Tecnica de Lisboa (Portugal)

    2013-07-15

    A number of 1H-pyrazolo[3,4-b]pyridine derivatives, starting from 2-chloro-3-formyl pyridine, was synthesized to obtain new 1-hydroxybisphosphonates, a class of compounds with potential biological interest. Spectroscopic data were used to characterize all compounds and to identify N-1 and N-2 regioisomers, and mono- and bisphosphonates derivatives. X-ray diffractometry studies of compound 7a confirmed the proposed structure. (author)

  1. Assessing the feasibility of the Effectiveness of Discontinuing Bisphosphonates trial: a pilot study.

    Science.gov (United States)

    Wright, N C; Foster, P J; Mudano, A S; Melnick, J A; Lewiecki, M E; Shergy, W J; Curtis, J R; Cutter, G R; Danila, M I; Kilgore, M L; Lewis, E C; Morgan, S L; Redden, D T; Warriner, A H; Saag, K G

    2017-08-01

    The Effectiveness of Discontinuing Bisphosphonates (EDGE) study is a planned pragmatic clinical trial to guide "drug holiday" clinical decision making. This pilot study assessed work flow and feasibility of such a study. While participant recruitment and treatment adherence were suboptimal, administrative procedures were generally feasible and minimally disrupted clinic flow. The comparative effectiveness of continuing or discontinuing long-term alendronate (ALN) on fractures is unknown. A large pragmatic ALN discontinuation study has potential to answer this question. We conducted a 6-month pilot study of the planned the EDGE study among current long-term ALN users (women aged ≥65 with ≥3 years of ALN use) to determine study work flow and feasibility including evaluating the administrative aspects of trial conduct (e.g., time to contract, institutional review board (IRB) approval), assessing rates of site and participant recruitment, and evaluating post-randomization outcomes, including adherence, bisphosphonate-associated adverse events, and participant and site satisfaction. We assessed outcomes 1 and 6 months after randomization. Nine sites participated, including seven community-based medical practices and two academic medical centers. On average (SD), contract execution took 3.4 (2.3) months and IRB approval took 13.9 (4.1) days. Sites recruited 27 participants (13 to continue ALN and 14 to discontinue ALN). Over follow-up, 22% of participants did not adhere to their randomization assignment: 30.8% in the continuation arm and 14.3% in the discontinuation arm. No fractures or adverse events were reported. Sites reported no issues regarding work flow, and participants were highly satisfied with the study. Administrative procedures of the EDGE study were generally feasible, with minimal disruption to clinic flow. In this convenience sample, participant recruitment was suboptimal across most practice sites. Accounting for low treatment arm adherence, a

  2. Bisphosphonate: Brief Review of Its Development for Usage in Dentistry

    Directory of Open Access Journals (Sweden)

    Tita Ratya Utari

    2013-05-01

    Full Text Available Bisphosphonate (BP is a class of drug that prevent the loss of bone mass. It inhibits the resorption of bone by encouraging osteoclast to undergo apoptosis. Considering that oral diseases and dental procedures may lead to teeth instability whereas alveolar bone is the main tooth supporting tissue, forceful indication of this drug is for preventing and minimizing bone resorption following oral surgery and relapse movement in orthodontic treatment. Clinical use of BP in dentistry is limited by risk of osteonecrosis of the jaw (ONJ and of its systemic effects such as an increase of the bone mineral density in another bone area. Topical application with local effect would seem the choice of administration route for usage in dentistry. Until recently, no clinical usage of topical BP has been studied, however some experimental laboratory studies proved that this drug would be beneficial in a wide scope of dental treatments.DOI: 10.14693/jdi.v18i1.154

  3. United Kingdom nationwide study of avascular necrosis of the jaws including bisphosphonate-related necrosis.

    Science.gov (United States)

    Rogers, S N; Palmer, N O A; Lowe, D; Randall, C

    2015-02-01

    We aimed to record all new patients who presented to departments of oral surgery, oral medicine, and oral and maxillofacial surgery, and to dental hospitals in the UK, with avascular necrosis of the jaws including bisphosphonate-related necrosis (BRONJ) over a 2-year period (1 June 2009-31 May 2011). They were eligible irrespective of age, cause, or coexisting conditions. Data on incidence, clinical characteristics, risk factors, and coexisting conditions were collected. A total of 383 cases were registered: 369 were described as BRONJ, 5 as avascular necrosis, and 9 were unknown. Bisphosphonates had been given orally in 207 (56%), intravenously in 125 (34%), both orally and intravenously in 27 (7%), and was unknown in 9 (2%); one had been given denosumab. The main risk factor was dental extraction, and the mandible was commonly affected. The median duration of administration until onset of BRONJ was 3 years in those treated intravenously and 4 years in those treated orally. Levels of engagement with the study varied between regions, and extrapolation from the 2 most involved (Merseyside and Northern Ireland) found around 8.2-12.8 cases/million/year, which is 508-793 patients/year across the UK. To our knowledge this is one of the first studies to estimate national rates of BRONJ. It confirms that the risk and incidence are low. With changes in trends for antiresorptive bone medication, and increasing numbers of elderly people, it would be useful to repeat the registration in the future. Copyright © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  4. Bisphosphonates, atherosclerosis and vascular calcification: update and systematic review of clinical studies

    Directory of Open Access Journals (Sweden)

    Caffarelli C

    2017-10-01

    Full Text Available Carla Caffarelli,1 Andrea Montagnani,2 Ranuccio Nuti,1 Stefano Gonnelli1 1Department of Medicine, Surgery and Neuroscience, University of Siena, Italy; 2Division of Internal Medicine, General Hospital Misericordia, Grosseto, Italy Background: Epidemiologic and clinical data have suggested the existence of a biologic linkage between the bone system and the vascular system. Bisphosphonates (BPs are effective inhibitors of bone resorption and are currently considered the drugs of choice for the prevention and treatment of osteoporosis and related fractures. Data from several publications have suggested that BPs may also be effective in reducing the atherosclerotic process and vascular calcification, but the results of these studies are contrasting. This review aimed to allow a better understanding of the relationships between BPs and atherosclerosis in humans.Materials and methods: Electronic databases of Pubmed-Medline, Cochrane Library and SCOPUS from inception to June 30, 2016 were searched. The full texts of the articles potentially eligible were carefully assessed and reviewed. Finally, 20 studies were found to be eligible and were included in the systematic review. All included studies were published between 2000 and 2014.Results: In several studies, etidronate limited the progression of aortic and coronary calcification in hemodialysis patients, whereas the nitrogen-containing-BPs given orally did not significantly reduce vascular calcifications in patients with chronic kidney disease, kidney trasplant or in those with osteoporosis. Nitrogen-containing-BPs present favorable effects both on vessel wall thickness and on arterial elasticity due to both a reduction in serum lipids and the interaction of BPs with the bone tissue, with the consequent release of bone turnover markers and cytokines into the bloodstream.Conclusion: To sum up, the BPs seem to have the potential of influencing atherosclerosis and calcium homeostasis at the level of

  5. Bisphosphonates as potential adjuvants for patients with cancers of the digestive system.

    Science.gov (United States)

    Ang, Celina; Doyle, Erin; Branch, Andrea

    2016-01-21

    Best known for their anti-resorptive activity in bone, bisphosphonates (BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor (HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.

  6. Cost effectiveness of denosumab compared with oral bisphosphonates in the treatment of post-menopausal osteoporotic women in Belgium.

    Science.gov (United States)

    Hiligsmann, Mickaël; Reginster, Jean-Yves

    2011-10-01

    Denosumab has recently been shown to be well tolerated, to increase bone mineral density (BMD) and to significantly reduce the risk of hip, vertebral and non-vertebral fractures in the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial. It is becoming increasingly important to evaluate not only the therapeutic value of a new drug but also the cost effectiveness compared with the most relevant treatment alternatives. The objective of this study was to estimate the cost effectiveness of denosumab compared with oral bisphosphonates (branded and generic drugs) in the treatment of post-menopausal osteoporotic women in Belgium. Cost effectiveness of 3 years of treatment with denosumab was compared with branded risedronate and branded and generic alendronate using an updated version of a previously validated Markov microsimulation model. The model was populated with relevant cost, adherence and epidemiological data for Belgium from a payer perspective and the results were presented as costs per QALY gained (&U20AC;, year 2009 values). Analyses were performed in populations (aged ≥60 years) in which osteoporosis medications are currently reimbursed in many European countries, i.e. those with BMD T-score of -2.5 or less or prevalent vertebral fracture. Patients receiving denosumab were assumed to have a 46% lower risk of discontinuation than those receiving oral bisphosphonates, and the effect of denosumab after treatment cessation was assumed to decline linearly to zero over a maximum of 1 year. Denosumab was cost effective compared with all other therapies, assuming a willingness to pay of &U20AC;40 000 per QALY gained. In particular, denosumab was found to be cost effective compared with branded alendronate and risedronate at a threshold value of &U20AC;30 000 per QALY and denosumab was dominant (i.e. lower cost and greater effectiveness) compared with risedronate from the age of 70 years in women with a T-score of -2.5 or

  7. Bisphosphonate Drug Holiday and Fracture Risk: A Population-Based Cohort Study.

    Science.gov (United States)

    Adams, Annette L; Adams, John L; Raebel, Marsha A; Tang, Beth T; Kuntz, Jennifer L; Vijayadeva, Vinutha; McGlynn, Elizabeth A; Gozansky, Wendolyn S

    2018-03-12

    Holidays from bisphosphonates (BPs) may help to prevent rare adverse events like atypical femoral fractures, but may be appropriate only if risk of osteoporosis-related fractures does not increase. Our objective was to compare the incidence of osteoporosis-related fractures among women who had a bisphosphonate (BP) holiday to those who continued use BPs. This retrospective cohort study, conducted within 4 Kaiser Permanente integrated health system regions, included 39,502 women aged ≥45 years with ≥3 years exposure to BP. Participants with a BP holiday (≥12 months with no use) were compared to persistent (use with ≥50% adherence) and non-persistent (use with holiday (n = 11,497), non-persistent user (n = 10,882), and persistent user groups (n = 17,123) were observed for 156,657 person-years. A total of 5,199 osteoporosis-related fractures (including 1,515 hip fractures and 2,147 vertebral fractures) were observed. Compared to the persistent use group, there was a slight difference in overall osteoporosis-related fracture risk (HR 0.92, 95% CI 0.84-0.99)and no difference in hip fracture risk (HR 0.95, 95% CI 0.83-1.10) for the BP holiday group. A slight reduction in risk of vertebral fracture was observed (HR 0.83, 95% CI 0.74-0.95). Compared to the non-persistent user group, the BP holiday group was at decreased risk for osteoporosis-related fractures (HR 0.71, 95% CI 0.65-0.79), vertebral fractures (HR 0.68, 95% CI 0.59-0.78), and hip fractures (HR 0.59; 95% CI 0.50-0.70). Women who undertake a BP holiday from BP of ≥12 months duration for any reason after ≥3 years of BP use do not appear to be at greater risk of osteoporosis-related fragility fracture, hip, or vertebral fractures compared to ongoing BP users. In our cohort, BP holiday remains a viable strategy for balancing the benefits and potential harms associated with long-term BP use. This article is protected by copyright. All rights reserved. This article is protected by copyright

  8. Molecular mechanism and potential targets for bone metastasis

    International Nuclear Information System (INIS)

    Iguchi, Haruo

    2007-01-01

    The incidence of bone metastasis has been increasing in all cancers in recent years. Bone metastasis is associated with substantial morbidity, including bone pain, pathological fracture, neurological deficit and/or hypercalcemia. Thus, the management of bone metastasis in patients is a clinically significant issue. In the process of bone metastasis, the primary mechanism responsible for bone destruction is cancer cell-mediated stimulation of osteoclastic bone resorption, which results in osteolysis and release of various growth factors from the bone matrix. These growth factors are prerequisites for successful colonization and subsequent invasive growth of cancer cells in bone, which is called a 'vicious cycle.' Thus, it is important to elucidate what molecules are involved in this step of bone destruction, and the understanding of these molecular mechanisms could lead to develop molecular-target therapies for bone metastasis. Bisphosphonates introduced in the treatment for bone metastasis have been shown to reduce skeletal morbidity. In Japan, the most potent bisphosphonate, zoledronate (ZOMETA), was introduced in this past April, and a phase III clinical trial of humanized anti-receptor activator of NF-κB ligand (RANKL) monoclonal antibody (Denosumab) against bone metastasis is under way as a global study. These new agents, which are targeted to osteoclasts, are considered to be standard management in the care of bone metastasis patients in combination with chemotherapy and/or hormone therapy. (author)

  9. Assessment of a gel-type chelating preparation containing 1-hydroxyethylidene-1, 1-bisphosphonate.

    Science.gov (United States)

    Girard, S; Paqué, F; Badertscher, M; Sener, B; Zehnder, M

    2005-11-01

    To test an aqueous gel containing 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) regarding its interactions with sodium hypochlorite, its calcium binding capacity, and its potential in preventing the formation of a smear layer when used in conjunction with rotary root canal preparation. The experimental aqueous gel consisted of (w/v) 2% alginate, 3% aerosil, 10% Tween 80 and 18% HEBP. Interactions of gel components with hypochlorite were assessed using iodometric titration and monochromatic ultraviolet spectrometry. Two commercial paste-type chelators containing ethylenediaminetetraacetic acid (EDTA) and peroxide (RC-Prep and Glyde) served as controls. Calcium-binding capacities were measured in mixtures with a Ca2+ standard solution buffered at pH 10 using a calcium-selective measuring chain. Finally, root canals of 16 extracted single-rooted premolars per group were instrumented using ProFile instruments dipped in the experimental gel, RC-Prep, or nothing. Additionally, canals were rinsed with 10 mL of a 1% NaOCl solution during/after preparation. Smear scores in instrumented teeth were monitored using scanning electron microscopy. None of the experimental gel components showed short-term interactions with hypochlorite, whilst EDTA, peroxide, RC-Prep and Glyde immediately reduced the hypochlorite in solution. The experimental gel chelated 30 mg Ca2+ g-1, compared with 16 mg Ca2+ g-1 and 11 mg Ca2+ g-1 chelated by RC-Prep and Glyde respectively. Smear scores obtained with the experimental gel were significantly (P<0.05) lower than with RC-Prep in coronal and middle root thirds, whilst no differences were observed in apical root thirds. Under the conditions of this study, an HEBP gel appeared advantageous over currently available products.

  10. Influence of bone affinity on the skeletal distribution of fluorescently labeled bisphosphonates in vivo.

    Science.gov (United States)

    Roelofs, Anke J; Stewart, Charlotte A; Sun, Shuting; Błażewska, Katarzyna M; Kashemirov, Boris A; McKenna, Charles E; Russell, R Graham G; Rogers, Michael J; Lundy, Mark W; Ebetino, Frank H; Coxon, Fraser P

    2012-04-01

    Bisphosphonates are widely used antiresorptive drugs that bind to calcium. It has become evident that these drugs have differing affinities for bone mineral; however, it is unclear whether such differences affect their distribution on mineral surfaces. In this study, fluorescent conjugates of risedronate, and its lower-affinity analogues deoxy-risedronate and 3-PEHPC, were used to compare the localization of compounds with differing mineral affinities in vivo. Binding to dentine in vitro confirmed differences in mineral binding between compounds, which was influenced predominantly by the characteristics of the parent compound but also by the choice of fluorescent tag. In growing rats, all compounds preferentially bound to forming endocortical as opposed to resorbing periosteal surfaces in cortical bone, 1 day after administration. At resorbing surfaces, lower-affinity compounds showed preferential binding to resorption lacunae, whereas the highest-affinity compound showed more uniform labeling. At forming surfaces, penetration into the mineralizing osteoid was found to inversely correlate with mineral affinity. These differences in distribution at resorbing and forming surfaces were not observed at quiescent surfaces. Lower-affinity compounds also showed a relatively higher degree of labeling of osteocyte lacunar walls and labeled lacunae deeper within cortical bone, indicating increased penetration of the osteocyte canalicular network. Similar differences in mineralizing surface and osteocyte network penetration between high- and low-affinity compounds were evident 7 days after administration, with fluorescent conjugates at forming surfaces buried under a new layer of bone. Fluorescent compounds were incorporated into these areas of newly formed bone, indicating that "recycling" had occurred, albeit at very low levels. Taken together, these findings indicate that the bone mineral affinity of bisphosphonates is likely to influence their distribution within the

  11. Preparation and biodistribution of 131I labeled 3-Amino-1-hydroxypropylidene-1, 1-bisphosphonate

    International Nuclear Information System (INIS)

    Lin Rushan; Yang Yuanyou; Liu Ning; Liao Jiali; Jin Jiannan; Pu Manfei

    2008-01-01

    3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (ABP) was synthesized and labeled with 131 I using N-succinimidyl-5-(tri-butylstannyl)-3-pyridinecarboxylate (SPC) as a bi-functional linker. 131 I could be coupled to ABP via a 131 I-SIPC intermediate with a labeling yield of more than 64%, and a radiochemical purity of more than 99% after HPLC purification. After 72 h at room temperature, the radiochemical purity was still more than 98.8%, implying that the 131 I-SIPC-ABP is stable in vitro. Biodistribution experiments in mice show that 131 I-SIPC-ABP has high affinity to bone and high stability in vivo as well as in vitro. (authors)

  12. Adenosine Receptor Stimulation Improves Glucocorticoid-Induced Osteoporosis in a Rat Model

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    Gabriele Pizzino

    2017-09-01

    Full Text Available Glucocorticoid-induced osteoporosis (GIO is a secondary cause of bone loss. Bisphosphonates approved for GIO, might induce jaw osteonecrosis; thus additional therapeutics are required. Adenosine receptor agonists are positive regulators of bone remodeling, thus the efficacy of adenosine receptor stimulation for treating GIO was tested. In a preventive study GIO was induced in Sprague-Dawley rats by methylprednisolone (MP for 60 days. Animals were randomly assigned to receive polydeoxyribonucleotide (PDRN, an adenosine A2 receptor agonist, or PDRN and DMPX (3,7-dimethyl-1-propargylxanthine, an A2 antagonist, or vehicle (0.9% NaCl. Another set of animals was used for a treatment study, following the 60 days of MP-induction rats were randomized to receive (for additional 60 days PDRN, or PDRN and DMPX (an adenosine A2 receptor antagonist, or zoledronate (as control for gold standard treatment, or vehicle. Control animals were administered with vehicle for either 60 or 120 days. Femurs were analyzed after treatments for histology, imaging, and breaking strength analysis. MP treatment induced severe bone loss, the concomitant use of PDRN prevented the developing of osteoporosis. In rats treated for 120 days, PDRN restored bone architecture and bone strength; increased b-ALP, osteocalcin, osteoprotegerin and stimulated the Wnt canonical and non-canonical pathway. Zoledronate reduced bone resorption and ameliorated the histological features, without significant effects on bone formation. Our results suggest that adenosine receptor stimulation might be useful for preventing and treating GIO.

  13. Quantitative ultrasound at the hand phalanges in patients with bisphosphonate-related osteonecrosis of the jaws

    Directory of Open Access Journals (Sweden)

    Ana Carolina Fragoso MOTTA

    2015-01-01

    Full Text Available Patients with bisphosphonate-related osteonecrosis of the jaws (BRONJ who received intravenous or oral bisphosphonates (BP were selected for determination of their bone microarchitecture as a risk predictor of BRONJ development. The diagnosis of BRONJ was made based on clinical and radiographic findings. The control group consisted of healthy patients. All patients underwent quantitative and qualitative ultrasound measurements of bone at the hand phalanges carried out using the DBM Sonic BP. Ultrasound bone profile index (UBPI, amplitude-dependent speed of sound (AD-SoS, bone biophysics profile (BBP, and bone transmission time (BTT were measured. The BRONJ group consisted of 17 patients (62 ± 4.24; range: 45-82; 10 (58.8% were male and seven (41.1% were female, of whom 11 (64.7% suffered from multiple myeloma, three (17.6% from osteoporosis, one (5.8% from prostate cancer, one (5.8% from kidney cancer, and one (5.8% from leukemia. Fourteen (82.3% of them received intravenous BP whereas three (17.6% received oral BP. Nine (9/17; 52.9% patients developed bone exposure: two in the maxilla and seven in the mandible. Regarding quantitative parameters, Ad-SoS was low in the BRONJ group, but not significant. The UBPI score was significantly reduced in BRONJ patients with exposed bone when compared to controls (0.47 ± 0.12 vs. 0.70 ± 0.15; p = 0.004. The present study demonstrated that quantitative ultrasound was able to show bone microarchitecture alterations in BRONJ patients, and suggests that these analyses may be an important tool for early detection of bone degeneration associated with BRONJ.

  14. Treatment of bisphosphonate related osteonecrosis following root canal therapy at the 1-year follow-up: report of two cases

    OpenAIRE

    Kaptan, Figen; Kazandag, Meric Karapinar; Iseri, Ufuk

    2013-01-01

    Figen Kaptan,1 Meric Karapinar Kazandag,1 Ufuk Iseri21Yeditepe University, Faculty of Dentistry, Department of Endodontics, 2Department of Prosthodontics, Istanbul, TurkeyAbstract: The objective of this report was to use topical gaseous ozone as an adjunct to conventional treatment methods and to describe the multidisciplinary management of bisphosphonate associated bone necrosis, which developed following endodontic treatment. No complaints were noted by the patients at their 1-year follow-u...

  15. Osteonecrosis de los maxilares inducida por bifosfonatos: prevención y actitud terapéutica Bisphosphonate induced osteonecrosis of the jaws: prevention and therapeutic approach

    Directory of Open Access Journals (Sweden)

    F.J. Barrientos Lezcano

    2007-10-01

    Full Text Available Introducción. La osteonecrosis maxilar o mandibular por bifosfonatos puede convertirse en una epidemia debido a la amplia difusión de estos fármacos entre la población. Material y método. Se muestra un protocolo para la prevención y el tratamiento de esta enfermedad. Se presentan tres casos de osteonecrosis maxilar/mandibular. Resultados. Es difícil lograr una curación completa; sin embargo es posible detener la progresión de la enfermedad. Discusión. La cirugía y la suspensión de la terapia con bifosfonatos han demostrado poca utilidad. Los antibióticos y los enjuagues con clorhexidina son las únicas medidas eficaces. Conclusiones. Es imprescindible una planificación adecuada previa a la instauración del tratamiento con bifosfonatos. Ante una osteonecrosis establecida, la actitud debe ser conservadora.Introduction. Bisphosphonate-induced osteonecrosis of the jaws might reach epidemic proportions due to the widespread use of this therapy. Materials and methods. A protocol for prevention and treatment of this pathology is shown. Three clinical cases are reported. Results. It is quite difficult to reach restitutio ad integrum, but stopping the progress of the disease is possible. Discussion. Surgical treatment and cessation of bisphosphonate therapy are of no use. Only antibiotics and oral chlorhexidine have shown some benefits. Conclusions. An accurate preventive attitude is mandatory prior to undergoing bisphosphonate therapy. If osteonecrosis of the jaws is present, management should be conservative.

  16. Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human farnesyl pyrophosphate synthase.

    Directory of Open Access Journals (Sweden)

    Jaeok Park

    Full Text Available Human farnesyl pyrophosphate synthase (hFPPS catalyzes the production of the 15-carbon isoprenoid farnesyl pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (PNP-BPs that have bulky hydrophobic side chains through a structure-based approach. Some of these compounds have proven to be more potent than the current clinical drugs in a number of antiproliferation assays using multiple myeloma cell lines. In the present work, we characterized the binding of our most potent PNP-BPs to the target enzyme, hFPPS. Co-crystal structures demonstrate that the molecular interactions designed to elicit tighter binding are indeed established. We carried out thermodynamic studies as well; the newly introduced protein-ligand interactions are clearly reflected in the enthalpy of binding measured, which is more favorable for the new PNP-BPs than for the lead compound. These studies also indicate that the affinity of the PNP-BPs to hFPPS is comparable to that of the current drug risedronate. Risedronate forms additional polar interactions via its hydroxyl functional group and thus exhibits more favorable binding enthalpy; however, the entropy of binding is more favorable for the PNP-BPs, owing to the greater desolvation effects resulting from their large hydrophobic side chains. These results therefore confirm the overall validity of our drug design strategy. With a distinctly different molecular scaffold, the PNP-BPs described in this report represent an interesting new group of future drug candidates. Further investigation should follow to

  17. Eleven years of experience with bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I

    Directory of Open Access Journals (Sweden)

    Iwamoto J

    2012-12-01

    Full Text Available Jun Iwamoto,1 Yoshihiro Sato,2 Mitsuyoshi Uzawa,3 Hideo Matsumoto11Institute for Integrated Sports Medicine, Keio University School of Medicine, Tokyo, 2Department of Neurology, Mitate Hospital, Fukuoka, 3Department of Orthopaedic Surgery, Keiyu Orthopaedic Hospital, Gunma, JapanAbstract: We report the 11-year follow-up of a man with osteogenesis imperfecta type I who was treated with bisphosphonates and alfacalcidol. A 36-year-old Japanese man with osteogenesis imperfecta type I who had frequently experienced painful fragility fractures consulted our clinic because of chronic back pain. The patient had multiple morphometric vertebral fractures and a low bone mineral density (BMD at the lumbar spine. The patient was treated with cyclical etidronate 200 mg, for 2 weeks every 3 months, plus alfacalcidol 1 µg daily, for 2 years; and alendronate 5 mg daily or 35 mg weekly, plus alfacalcidol 1 µg daily for 9 years. After 11 years of treatment, BMD at the lumbar spine increased by 6.4%, following a 20.3% reduction in serum alkaline phosphatase. Serum calcium, phosphorus, and intact parathyroid hormone levels remained within the normal ranges. Three clinical fractures occurred at two ribs and the metacarpus, and two morphometric vertebral fractures occurred at the thoracic spine during the 11-year treatment period, but the patient experienced no adverse effects. Thus, the present case report shows the long-term outcome and safety of bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I.Keywords: etidronate, alendronate, fragility fracture, bone mineral density, osteogenesis imperfecta

  18. Anchoring of self-assembled plasmid DNA/ anti-DNA antibody/cationic lipid micelles on bisphosphonate-modified stent for cardiovascular gene delivery

    Directory of Open Access Journals (Sweden)

    Ma G

    2013-03-01

    Full Text Available Guilei Ma,1,# Yong Wang,1,# Ilia Fishbein,2 Mei Yu,1 Linhua Zhang,1 Ivan S Alferiev,2 Jing Yang,1 Cunxian Song,1 Robert J Levy2 1Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, People's Republic of China; 2Children's Hospital of Philadelphia, Abramson Research Building, Philadelphia, PA, USA #These authors contributed equally to this work Purpose: To investigate the anchoring of plasmid DNA/anti-DNA antibody/cationic lipid tri-complex (DAC micelles onto bisphosphonate-modified 316 L coronary stents for cardiovascular site-specific gene delivery. Methods: Stents were first modified with polyallylamine bisphosphonate (PAA-BP, thereby enabling the retention of a PAA-BP molecular monolayer that permits the anchoring (via vector-binding molecules of DAC micelles. DAC micelles were then chemically linked onto the PAA-BP-modified stents by using N-succinimidyl-3-(2-pyridyldithiol-propionate (SPDP as a crosslinker. Rhodamine-labeled DNA was used to assess the anchoring of DAC micelles, and radioactive-labeled antibody was used to evaluate binding capacity and stability. DAC micelles (encoding green fluorescent protein were tethered onto the PAA-BP-modified stents, which were assessed in cell culture. The presence of a PAA-BP molecular monolayer on the steel surface was confirmed by X-ray photoelectron spectroscopy and atomic force microscope analysis. Results: The anchoring of DAC micelles was generally uniform and devoid of large-scale patches of defects. Isotopic quantification confirmed that the amount of antibody chemically linked on the stents was 17-fold higher than that of the physical adsorbed control stents and its retention time was also significantly longer. In cell culture, numerous green fluorescent protein-positive cells were found on the PAA-BP modified stents, which demonstrated high localization and efficiency of gene delivery. Conclusion: The DAC micelle

  19. Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α.

    Science.gov (United States)

    Brunetti, G; Papadia, F; Tummolo, A; Fischetto, R; Nicastro, F; Piacente, L; Ventura, A; Mori, G; Oranger, A; Gigante, I; Colucci, S; Ciccarelli, M; Grano, M; Cavallo, L; Delvecchio, M; Faienza, M F

    2016-07-01

    In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI. Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate. Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls. DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients. Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects

  20. Cell number and transfection volume dependent peptide nucleic acid antisense activity by cationic delivery methods

    DEFF Research Database (Denmark)

    Llovera Nadal, Laia; Berthold, Peter; Nielsen, Peter E

    2012-01-01

    have now quantitatively compared the cellular activity (in the pLuc705 HeLa cell splice correction system) of PNA antisense oligomers using lipoplex delivery of cholesterol- and bisphosphonate-PNA conjugates, polyplex delivery via a PNA-polyethyleneimine conjugate and CPP delivery via a PNA......Efficient intracellular delivery is essential for high activity of nucleic acids based therapeutics, including antisense agents. Several strategies have been developed and practically all rely on auxiliary transfection reagents such as cationic lipids, cationic polymers and cell penetrating...... peptides as complexing agents and carriers of the nucleic acids. However, uptake mechanisms remain rather poorly understood, and protocols always require optimization of transfection parameters. Considering that cationic transfection complexes bind to and thus may up-concentrate on the cell surface, we...

  1. Duration of treatment with bisphosphonates at the time of osteonecrosis of the jaw onset in patients with rheumatoid arthritis. Review.

    Science.gov (United States)

    Compain, H; Berquet, A; Loison-Robert, L-S; Ahossi, V; Zwetyenga, N

    2018-06-01

    Rheumatoid arthritis (RA) is a frequent and co-morbid condition. One of the main complications is induced osteoporosis. Treatments related to this complication significantly modify oral and implant management. Affected patients represent a population at intermediate risk of osteonecrosis of the jaw (ONJ). The objective was to search the literature for durations of treatment with bisphosphonates at the time of ONJ occurrence in patients with RA in order to obtain an average duration. A bibliographic search in the PubMed/Medline database was carried out using the following equation "(osteonecrosis and jaw) and rheumatoid arthritis" with no time limitation. The primary study endpoint was the duration of treatment with bisphosphonates (BP) at the time of ONJ onset in patients with RA. Twelve articles accounting for 50 patients were included. Patients had had a median of 46.8 months of treatment with BP before ONJ occurred. Mean, minimum and maximum treatment times were 48.68, 6 and 120 months, respectively. The standard deviation was 27.77 months. The median treatment duration in our cohort of patients with RA was less than that reported for osteoporosis. We therefore, recommend that practitioners take additional precautions regarding oral surgery or implant procedures, particularly in patients with RA who have been treated with BP for more than 4 years. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  2. Oral manifestations of McCune-Albright syndrome

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    Konidena Aravinda

    2013-01-01

    Full Text Available McCune- Albright Syndrome (MAS is a rare fibrosseous lesion, characterized by a classic triad of polyostotic fibrous dysplasia (PFD, cafι -au-lait macules (CALM and underlying endocrinopathies. We present the oral findings of an interesting case of MAS with relevant review of literature. A 30-year-old male presented to us with swelling of both jaws over a period of two years. Cutaneous examination revealed cafι - au - lait macule over the back, crossing the midline. Skeletal survey showed expansile, osteolytic, mixed radiolucent- radiopaque lesions in skull and jaw bones. Serum alkaline phosphatase was elevated (388 IU/L, with normal calcium, phosphorus, parathyroid hormone and 25 hydroxy vitamin D levels. Diagnosis of McCune- Albright syndrome was made and he was treated with parenteral bisphosphonates (intravenous Zoledronate 4 mg and is under follow up for surgical recontouring of the jaws. Early recognition facilitates better treatment and improves prognosis by reducing the morbidity.

  3. Impact of bisphosphonate-related osteonecrosis of the jaw on osteoporotic patients after dental extraction: a population-based cohort study.

    Directory of Open Access Journals (Sweden)

    Yi Fang Huang

    Full Text Available Little is currently known about the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ. This study sought to determine the incidence of BRONJ in osteoporotic patients. We also sought to identify the nature and types of risk factors of osteonecrosis of jaw (ONJ related to the use of oral bisphosphonates (BPs.Data from the National Health Insurance system of Taiwan. This cohort study included 19,399 adult osteoporosis patients received dental extraction in 2000-2010 (osteoporosis cohort and 38,669 age and gender matched comparisons selected from dental extraction people without osteoporosis and osteonecrosis history (comparison cohort. All study subjects were followed from the date of their dental extraction (index date to the development of ONJ and were included in the study up to 2011 or were lost to the study, whichever occurred first. Cox proportional hazard regression was used to estimate the hazard ratio and 95% confidence intervals for the two cohorts.Patients with osteoporosis had a significantly higher risk to develop ONJ than healthy persons (adjusted HR, 2.05; 95% confidence interval, 1.58-2.65. The risk of ONJ increased with the severity of osteoporosis, no matter whether patient with cancer or not. A cumulative effect of dental extraction frequency may increase the risk of ONJ.We concluded that ONJ is caused by a number of factors. Osteoporosis and past dental history play the very important roles, while BPs play the synergistic effect.

  4. Psychometric evaluation of the Osteoporosis Patient Treatment Satisfaction Questionnaire (OPSAT-Q™, a novel measure to assess satisfaction with bisphosphonate treatment in postmenopausal women

    Directory of Open Access Journals (Sweden)

    Shikiar Richard

    2006-07-01

    Full Text Available Abstract Background The Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q is a new measure of patient satisfaction with bisphosphonate treatment for osteoporosis. The objective of this study was to evaluate the psychometric characteristics of the OPSAT-Q. Methods The OPSAT-Q contains 16 items in four subscales: Convenience, Confidence with Daily Activities, Side Effects, and Overall Satisfaction. All four subscale scores and an overall composite satisfaction score (CSS can be computed. The OPSAT-Q, Osteoporosis Targeted Quality of Life (OPTQoL, and sociodemographic/clinical questionnaires, including 3 global items on convenience, functioning and side effects, were self-administered to women with osteoporosis or osteopenia recruited from four US clinics. Analyses included item and scale performance, internal consistency reliability, reproducibility, and construct validity. Reproducibility was measured using the intraclass correlation coefficient (ICC via a follow-up questionnaire completed by participants 2 weeks post baseline. Results 104 women with a mean age of 65.1 years participated. The majority were Caucasian (64.4%, living with someone (74%, and not currently employed (58.7%. 73% had osteoporosis and 27% had osteopenia. 80% were taking weekly bisphosphonates and 18% were taking daily medication (2% missing data. On a scale of 0–100, individual patient subscale scores ranged from 17 to 100 and CSS scores ranged from 44 to 100. All scores showed acceptable internal consistency reliability (Cronbach's alpha > 0.70 (range 0.72 to 0.89. Reproducibility ranged from 0.62 (Daily Activities to 0.79 (Side Effects for the subscales; reproducibility for the CSS was 0.81. Significant correlations were found between the OPSAT-Q subscales and conceptually similar global measures (p Conclusion The findings from this study confirm the validity and reliability of the OPSAT-Q and support the proposed composition of four subscales and a composite

  5. Evaluation of dental implants as a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw in breast cancer patients.

    Science.gov (United States)

    Matsuo, Akira; Hamada, Hayato; Takahashi, Hidetoshi; Okamoto, Ayako; Kaise, Hiroshi; Chikazu, Daichi

    2016-09-01

    It remains unclear whether dental implants are a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We retrospectively evaluated the status of dental implants in patients given intravenous bisphosphonates (BPs) in a breast cancer cohort to elucidate the risk for BRONJ at the implant site. We established a BRONJ oral monitoring program for 247 breast cancer patients given intravenous BP in our institution. The 3-year cumulative incidence rate was determined. The systemic and local risk factors of 44 patients who completed comprehensive oral examinations were evaluated by logistic regression analysis. The 3-year cumulative incidence rate of the 247 patients was 0.074 % (8/247, 95 % CI 0.0081-0.014). In the 44 orally examined patients, 6 (13.6 %: 6/44) had dental implants. Of these 6 patients, 1 developed BRONJ at the implant site. There were no significant differences in the age, total BP treatment period, number of residual teeth, time of regular oral monitoring, oral hygiene level, or dental implant insertion. Although a case of ONJ was identified, dental implants which were inserted before intravenous BP administration were not a risk factor for the development of ONJ in breast cancer patients.

  6. Intraoperative efficiency of fluorescence imaging by Visually Enhanced Lesion Scope (VELscope) in patients with bisphosphonate related osteonecrosis of the jaw (BRONJ).

    Science.gov (United States)

    Assaf, Alexandre T; Zrnc, Tomislav A; Riecke, Björn; Wikner, Johannes; Zustin, Jozef; Friedrich, Reinhard E; Heiland, Max; Smeets, Ralf; Gröbe, Alexander

    2014-07-01

    The purpose of this study was to determine the potential of tissue fluorescence imaging by using Visually Enhanced Lesion Scope (VELscope) for the detection of osteonecrosis of the jaw induced by bisphosphonates (BRONJ). We investigated 20 patients (11 females and 9 males; mean age 74 years, standard deviation ± 6.4 years), over a period of 18 month with the diagnosis of BRONJ in this prospective cohort study. All patients received doxycycline as a fluorescending marker for osseous structures. VELscope has been used intraoperatively using the loss of fluorescence to detect presence of osteonecrosis. Osseous biopsies were taken to confirm definite histopathological diagnosis of BRONJ in each case. Diagnosis of BRONJ was confirmed for every patient. In all patients except one, VELscope was sufficient to differentiate between healthy and necrotic bone by visual fluorescence retention (VFR) and visual fluorescence loss (VFL). 19 cases out of a total of 20 showed no signs of recurrence of BRONJ during follow-up (mean 12 months, range 4-18 months). VELscope examination is a suitable tool to visualize necrotic areas of the bone in patients with bisphosphonate related osteonecrosis of the jaw. Loss of fluorescence in necrotic bone areas is useful intraoperatively as a tool for fluorescence-guided bone resection with relevant clinical interpretation. Copyright © 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  7. Activation of Src kinase by protein-tyrosine phosphatase-PEST in osteoclasts: comparative analysis of the effects of bisphosphonate and protein-tyrosine phosphatase inhibitor on Src activation in vitro.

    Science.gov (United States)

    Chellaiah, Meenakshi A; Schaller, Michael D

    2009-08-01

    PTP-PEST is involved in the regulation of sealing ring formation in osteoclasts. In this article, we have shown a regulatory role for PTP-PEST on dephosphorylation of c-Src at Y527 and phosphorylation at Y418 in the catalytic site. Activation of Src in osteoclasts by over-expression of PTP-PEST resulted in the phosphorylation of cortactin at Y421 and WASP at Y294. Also enhanced as a result, is the interaction of Src, cortactin, and Arp2 with WASP. Moreover, the number of osteoclasts displaying sealing ring and bone resorbing activity was increased in response to PTP-PEST over-expression as compared with control osteoclasts. Cells expressing constitutively active-Src (527YDeltaF) simulate the effects mediated by PTP-PEST. Treatment of osteoclasts with a bisphosphonate alendronate or a potent PTP inhibitor PAO decreased the activity and phosphorylation of Src at Y418 due to reduced dephosphorylation state at Y527. Therefore, Src-mediated phosphorylation of cortactin and WASP as well as the formation of WASP.cortactin.Arp2 complex and sealing ring were reduced in these osteoclasts. Similar effects were observed in osteoclasts treated with an Src inhibitor PP2. We have shown that bisphosphonates could modulate the function of osteoclasts by inhibiting downstream signaling mediated by PTP-PEST/Src, in addition to its effect on the inhibition of the post-translational modification of small GTP-binding proteins such as Rab, Rho, and Rac as shown by others. The promising effects of the inhibitors PP2 and PAO on osteoclast function suggest a therapeutic approach for patients with bone metastases and osteoporosis as an alternative to bisphosphonates.

  8. Viewpoints of dentists on the use of bisphosphonates in rheumatology patients.

    Science.gov (United States)

    Daron, Coline; Deschaumes, Christophe; Soubrier, Martin; Mathieu, Sylvain

    2018-02-15

    Alhough typically prescribed in oncology, bisphosphonates (BPs) are also employed in rheumatology, particularly for the treatment of osteoporosis, sometimes resulting in complications, such as osteonecrosis of the jaw. Because of different opinions between rheumatologists and dentists on BP use, this study aimed to assess the views of dentists regarding administration of BPs in rheumatology. A questionnaire was sent to 880 dentists from the Auvergne region of France to determine their views on BP treatment. We obtained 382 (43.4%) responses and analysed 376 (58.7% men). In total, 156 (41.5%) of the responders analysed had attended an in-service training course (ISTC) on the topic. A total of 237 (63.0%) systematically inquired as to whether their patients were undergoing BP treatment; this proportion was higher among those who had been practicing for fewer than 10 years (P ISTC (62.6% vs. 50.7%; P < 0.03). Dentists feel ill at ease providing dental surgery to patients receiving BPs. Closer collaboration and better information-sharing between rheumatologists and dentists is necessary to facilitate the administration of BPs in rheumatology. © 2018 FDI World Dental Federation.

  9. Nonuremic calciphylaxis precipitated by teriparatide [rhPTH(1-34)] therapy in the setting of chronic warfarin and glucocorticoid treatment.

    Science.gov (United States)

    Spanakis, E K; Sellmeyer, D E

    2014-04-01

    Calciphylaxis occurs rarely in the absence of end stage renal disease. Predisposing factors for nonuremic calciphylaxis (NUC) include hyperparathyroidism, coagulopathies, connective tissue disease, liver disease, glucocorticoid use, and malignancy. Warfarin can facilitate vascular calcification by reducing vitamin K-dependent carboxylation of matrix-Gla proteins. An 86-year-old Caucasian woman with a history of polymyalgia rheumatica, two spontaneous deep venous thromboses (DVTs) and multiple fractures was treated with calcium, vitamin D, prednisone, and warfarin. The patient's low bone density was treated initially with estrogen, then oral bisphosphonate, which was discontinued due to upper gastrointestinal symptoms. Nasal calcitonin was initiated. After 10 years of calcitonin treatment, she was changed to teriparatide. Two months after initiating teriparatide, she developed lower extremity edema and painful erythematous nodular lesions on her calves bilaterally, that progressed to necrotic ulcers despite antibiotic therapy. Biopsy of the lesions showed calcification in the media of small blood vessels and subcutaneous fat with fat necrosis, consistent with calciphylaxis. Teriparatide was discontinued. Aggressive wound care, antibiotics, and intravenous zoledronic acid were initiated. With cessation of teriparatide therapy and intensive wound care, the patient's lesions resolved over 8 months. We report the first case of NUC precipitated by teriparatide therapy. Our patient had multiple underlying predisposing factors including a connective tissue disorder, glucocorticoid therapy, warfarin use, and possible underlying coagulopathy given her history of multiple DVTs. In such patients, alternative osteoporosis therapies may be preferred.

  10. Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications - cohort analysis using a national prescription database

    DEFF Research Database (Denmark)

    Pazianas, Michael; Clark, Emma M; Eiken, Pia Agnete

    2013-01-01

    Ocular inflammatory reactions have been described in patients on bisphosphonate treatment. We estimated the incidence rate of ocular inflammation at 3 and 12 months in patients treated for osteoporosis using a register based cohort linked to prescription data (hospitals and private practice.......4%) of patients on osteoporosis therapy filled one or more prescriptions for TES. TES treatment rates (per 1000 patient years) in the first year of osteoporosis treatment were 44 (95% confidence interval (CI) 42-46) for alendronate, 40 (95% CI 38-43) for etidronate, 45 (95% CI 35-57) for risedronate, 32 (95% CI...

  11. [Amplification of γδ T cells in PBMCs of healthy donors and osteosarcoma patients stimulated by zoledronate].

    Science.gov (United States)

    Li, Zhao-xu; Sun, Ling-ling; Cheng, Rui-lin; Sun, Zheng-wang; Ye, Zhao-ming

    2012-08-01

    To investigate the amplification and cytotoxicity of γδ T cells in peripheral blood mononuclear cells (PBMCs) of healthy donors and osteosarcoma patients stimulated by zoledronate (Zol) and IL-2. PBMCs from healthy donors and osteosarcoma patients were stimulated with IL-2 and Zol+IL-2, respectively. After 14-day culture, the purity of γδ T cells was assessed by flow cytometry. The cytotoxicity of γδ T cells against target cells was analyzed using a standard lactate dehydrogenase release assay with γδ T lymphocyte-sensitive Daudi cells, γδ T lymphocyte-resistant Raji cells and human osteoblast cell line, hFOB, as the target cells. After 2-week culture ex vivo of PBMCs from healthy donors and osteosarcoma patients, compared with stimulation of IL-2, Zol+IL-2 significantly promoted the amplification of γδ T cells. In addition, γδ T cells showed the higher cytotoxicity against Daudi cells, but no cytotoxic effect on normal cells like hFOB. γδ T cells of high purity and high cytotoxicity can be obtained by the stimulation of Zol combined with IL-2 on PBMCs from healthy donors and osteosarcoma patients.

  12. Delayed healing of lower limb fractures with bisphosphonate therapy.

    Science.gov (United States)

    Yue, B; Ng, A; Tang, H; Joseph, S; Richardson, M

    2015-07-01

    Bisphosphonate therapy (BT) is used commonly in the management of osteoporosis. A systematic review was conducted investigating delayed union of lower limb, long bone fractures in patients on BT. We specifically assessed whether BT increases the risk of delayed union or non-union in lower limb, long bone fractures. A literature search was conducted in the PubMed and Embase™ on 4 November 2014. Articles that investigated lower limb fractures, history of BT and fracture union were included in the review. A total of 9,809 papers were retrieved and 14 were deemed suitable for this review. The mean time to union in patients on BT was 8.5 months. A longer time to union was reported in a study investigating BT users versus controls (6.5 vs 4.8 months respectively). The mean rate of delayed or non-union for BT associated atypical fractures was 20% per fracture. Specifically in one study, delayed union was more common in the cohort with more than three years of BT (67%) than in the group with less than three years of BT (26%). Surgical fixation was associated with improved outcomes compared with non-operative management. BT has been described to be associated with multiple adverse outcomes related to atypical fractures. Current evidence recommends operative management for this patient group. Further investigation is required to evaluate the exact effects of BT on lower limb fractures, in particular typical femoral fractures.

  13. Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis.

    Science.gov (United States)

    Katsumi, Hidemasa; Tanaka, Yutaro; Hitomi, Kaori; Liu, Shu; Quan, Ying-Shu; Kamiyama, Fumio; Sakane, Toshiyasu; Yamamoto, Akira

    2017-08-17

    To improve the transdermal bioavailability and safety of alendronate (ALN), a nitrogen-containing bisphosphonate, we developed self-dissolving microneedle arrays (MNs), in which ALN is loaded only at the tip portion of micron-scale needles by a dip-coating method (ALN(TIP)-MN). We observed micron-scale pores in rat skin just after application of ALN(TIP)-MN, indicating that transdermal pathways for ALN were created by MN. ALN was rapidly released from the tip of MNs as observed in an in vitro release study. The tip portions of MNs completely dissolved in the rat skin within 5 min after application in vivo. After application of ALN(TIP)-MN in mice, the plasma concentration of ALN rapidly increased, and the bioavailability of ALN was approximately 96%. In addition, the decrease in growth plate was effectively suppressed by this efficient delivery of ALN in a rat model of osteoporosis. Furthermore, no skin irritation was observed after application of ALN(TIP)-MN and subcutaneous injection of ALN, while mild skin irritation was induced by whole-ALN-loaded MN (ALN-MN)-in which ALN is contained in the whole of the micron-scale needles fabricated from hyaluronic acid-and intradermal injection of ALN. These findings indicate that ALN(TIP)-MN is a promising transdermal formulation for the treatment of osteoporosis without skin irritation.

  14. Cost-effectiveness of zoledronic acid in the prevention of skeletal-related events in patients with bone metastases secondary to advanced renal cell carcinoma: application to France, Germany, and the United Kingdom.

    Science.gov (United States)

    Botteman, M F; Meijboom, M; Foley, I; Stephens, J M; Chen, Y M; Kaura, S

    2011-12-01

    The use of zoledronic acid (ZOL) has recently been shown to significantly reduce the risk of new skeletal-related events (SREs) in renal cell carcinoma (RCC) patients with bone metastases. The present exploratory study assessed the cost-effectiveness of ZOL in this population, adopting a French, German, and United Kingdom (UK) government payer perspective. This cost-effectiveness model was based on a post hoc retrospective analysis of a subset of patients with RCC who were included in a larger randomized clinical trial of patients with bone metastases secondary to a variety of cancers. In the trial, patients were randomized to receive ZOL (n = 27) or placebo (n = 19) with concomitant antineoplastic therapy every 3 weeks for 9 months (core study) plus 12 months during a study extension. Since the trial did not collect costs or data on the quality-adjusted life years (QALYs) of the patients, these outcomes had to be assumed via modeling exercises. The costs of SREs were estimated using hospital DRG tariffs. These estimates were supplemented with literature-based costs where possible. Drug, administration, and supply costs were obtained from published and internet sources. Consistent with similar economic analyses, patients were assumed to experience quality of life decrements lasting 1 month for each SRE. Uncertainty surrounding outcomes was addressed via multivariate sensitivity analyses. Patients receiving ZOL experienced 1.07 fewer SREs than patients on placebo. Patients on ZOL experienced a gain in discounted QALYs of approximately 0.1563 in France and Germany and 0.1575 in the UK. Discounted SRE-related costs were substantially lower among ZOL than placebo patients (-€ 4,196 in France, - € 3,880 in Germany, and -€ 3,355 in the UK). After taking into consideration the drug therapy costs, ZOL saved € 1,358, € 1,223, and € 719 in France, Germany, and the UK, respectively. In the multivariate sensitivity analyses, therapy with ZOL saved costs in 67

  15. Incidence of bisphosphonate-related osteonecrosis of the jaw in high-risk patients undergoing surgical tooth extraction.

    Science.gov (United States)

    Bodem, Jens Philipp; Kargus, Steffen; Eckstein, Stefanie; Saure, Daniel; Engel, Michael; Hoffmann, Jürgen; Freudlsperger, Christian

    2015-05-01

    As the most suitable approach for preventing bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients undergoing surgical tooth extraction is still under discussion, the present study evaluates the incidence of BRONJ after surgical tooth extraction using a standardized surgical protocol in combination with an adjuvant perioperative treatment setting in patients who are at high-risk for developing BRONJ. High-risk patients were defined as patients who received intravenous bisphosphonate (BP) due to a malignant disease. All teeth were removed using a standardized surgical protocol. The perioperative adjuvant treatment included intravenous antibiotic prophylaxis starting at least 24 h before surgery, a gastric feeding tube and mouth rinses with chlorhexidine (0.12%) three times a day. In the follow-up period patients were examined every 4 weeks for the development of BRONJ. Minimum follow-up was 12 weeks. In 61 patients a total number of 184 teeth were removed from 102 separate extraction sites. In eight patients (13.1%) BRONJ developed during the follow-up. A higher risk for developing BRONJ was found in patients where an additional osteotomy was necessary (21.4% vs. 8.0%; p = 0.0577), especially for an osteotomy of the mandible (33.3% vs. 7.3%; p = 0.0268). Parameters including duration of intravenous antibiotic prophylaxis, the use of a gastric feeding tube and the duration of intravenous BP therapy showed no statistical impact on the development of BRONJ. Furthermore, patients currently undergoing intravenous BP therapy showed no higher risk for BRONJ compared with patients who have paused or completed their intravenous BP therapy (p = 0.4232). This study presents a protocol for surgical tooth extraction in high-risk BP patients in combination with a perioperative adjuvant treatment setting, which reduced the risk for postoperative BRONJ to a minimum. However, the risk for BRONJ increases significantly if an additional osteotomy is necessary

  16. Vitamin D insufficiency reduces the protective effect of bisphosphonate on ovariectomy-induced bone loss in rats.

    Science.gov (United States)

    Mastaglia, Silvina R; Pellegrini, Gretel G; Mandalunis, Patricia M; Gonzales Chaves, Macarena M; Friedman, Silvia M; Zeni, Susana N

    2006-10-01

    The present study was carried out to obtain an experimental model of vitamin D (vit D) insufficiency and established osteopenia (experiment 1) to then investigate whether vit D status, i.e. normal or insufficient, interferes with bone mass recovery resulting from bisphosphonate therapy (experiment 2). Rats (n = 40) underwent OVX (n = 32) or a sham operation (n = 8). The first 15 days post-surgery, all groups were kept under fluorescent tube lighting and fed a diet containing 200 IU% vit D (+D). They were then assigned during an additional 45 days to receive either +D or a diet lacking vit D (-D) and kept under 12 h light/dark cycles using fluorescent or red lighting. Serum 25HOD was significantly lower in -D rats (P < 0.0001). The type of lighting did not induce differences in 25OHD, calcium (sCa), phosphorus (sP), bone alkaline phosphatase (b-AL), CTX, bone density or histology. No osteoid was observed in undecalcified bone sections. Experiment 2 (105 days): rats were fed either +D or -D according to experiment 1 and were treated with either placebo or 16 mug olpadronate (OPD)/100 g rat/week during the last 45 days. Whereas 25HOD was significantly lower (P < 0.0001) in -D/OPD than in +D/OPD rats, no significant differences in sCa, sP, b-AL or CTX were observed. OPD prevented the loss of lumbar spine (LS) and proximal tibia (PT) BMD and the decrease in bone volume (BV/TV) (P < 0.05) and in the number of trabeculae observed in untreated rats. However, +D/OPD animals presented significantly higher values of LS BMD, PT BMD and BV/TV than -D/OPD rats (P < 0.05). No osteoid was observed in undecalcified sections of bone. In summary, this is the first experimental study to provide evidence that differences in vit D status may affect the anticatabolic response to bisphosphonate treatment. However, the molecular mechanism through which vit D insufficiency reduces the effect of the aminobisphosphonate remains to be defined.

  17. Osseointegration of biochemically modified implants in an osteoporosis rodent model

    Directory of Open Access Journals (Sweden)

    B Stadlinger

    2013-07-01

    Full Text Available The present study examined the impact of implant surface modifications on osseointegration in an osteoporotic rodent model. Sandblasted, acid-etched titanium implants were either used directly (control or were further modified by surface conditioning with NaOH or by coating with one of the following active agents: collagen/chondroitin sulphate, simvastatin, or zoledronic acid. Control and modified implants were inserted into the proximal tibia of aged ovariectomised (OVX osteoporotic rats (n = 32/group. In addition, aged oestrogen competent animals received either control or NaOH conditioned implants. Animals were sacrificed 2 and 4 weeks post-implantation. The excised tibiae were utilised for biomechanical and morphometric readouts (n = 8/group/readout. Biomechanical testing revealed at both time points dramatically reduced osseointegration in the tibia of oestrogen deprived osteoporotic animals compared to intact controls irrespective of NaOH exposure. Consistently, histomorphometric and microCT analyses demonstrated diminished bone-implant contact (BIC, peri-implant bone area (BA, bone volume/tissue volume (BV/TV and bone-mineral density (BMD in OVX animals. Surface coating with collagen/chondroitin sulphate had no detectable impact on osseointegration. Interestingly, statin coating resulted in a transient increase in BIC 2 weeks post-implantation; which, however, did not correspond to improvement of biomechanical readouts. Local exposure to zoledronic acid increased BIC, BA, BV/TV and BMD at 4 weeks. Yet this translated only into a non-significant improvement of biomechanical properties. In conclusion, this study presents a rodent model mimicking severely osteoporotic bone. Contrary to the other bioactive agents, locally released zoledronic acid had a positive impact on osseointegration albeit to a lesser extent than reported in less challenging models.

  18. Treatment of hemimandibular paresthesia in a patient with bisphosphonate-related osteonecrosis of the jaw (BRONJ) by combining surgical resection and PRGF-Endoret.

    Science.gov (United States)

    Anitua, E; Begoña, L; Orive, G

    2013-12-01

    We report a case of a 50-year-old patient with bisphosphonate-related osteonecrosis of the jaws (BRONJs) whose symptoms included severe pain and hemimandibular paraesthesia. The treatment included resection of necrotic bone and the application of plasma rich in growth factors (PRGF(®)-Endoret(®)). We closed the ulcer in the soft tissue and her pain and paraesthesia improved. One year postoperatively sensitivity was totally recovered, pain was absent and bone was partially regenerated. Copyright © 2012 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  19. Osteoporosebehandling kan pauseres efter individuel vurdering

    DEFF Research Database (Denmark)

    Eiken, Pia Agnete; Abrahamsen, Bo

    2017-01-01

    In most patients, treatment of osteoporosis is a long-term challenge. Because alendronate and zoledronic acid accumulate in bone with some persistent antifracture efficacy after therapy, it is reasonable to consider a "drug holiday" for low-risk patients. It is recommended that the duration...

  20. Positive effects of bisphosphonates on bone and muscle in a mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Yoon, Sung-Hee; Sugamori, Kim S; Grynpas, Marc D; Mitchell, Jane

    2016-01-01

    Patients with Duchenne muscular dystrophy are at increased risk of decreased bone mineral density and bone fracture as a result of inactivity. To determine if antiresorptive bisphosphonates could improve bone quality and their effects on muscle we studied the Mdx mouse, treated with pamidronate during peak bone growth at 5 and 6 weeks of age, and examined the outcome at 13 weeks of age. Pamidronate increased cortical bone architecture and strength in femurs with increased resistance to fracture. While overall long bone growth was not affected by pamidronate, there was significant inhibition of remodeling in metaphyseal trabecular bone with evidence of residual calcified cartilage. Pamidronate treatment had positive effects on skeletal muscle in the Mdx mice with decreased serum and muscle creatine kinase and evidence of improved muscle histology and grip strength. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Clinical and therapeutic aspects of osteoporosis

    Energy Technology Data Exchange (ETDEWEB)

    Compston, Juliet [University of Cambridge School of Clinical Medicine, Box 157, Department of Medicine, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ (United Kingdom)], E-mail: jec1001@cam.ac.uk

    2009-09-15

    Osteoporosis is characterized by reduced bone mass and alteration in bone architecture, resulting in increased fracture risk. These fractures are a major cause of morbidity and mortality in the elderly and impose a huge economic burden on health services. Oestrogen deficiency plays a major role in the pathogenesis of bone loss and fracture in both women and men. Other pathogenetic factors include reduced physical activity and vitamin D insufficiency. A range of options is available for the prevention of fractures in high risk postmenopausal women. These include the bisphosphonates, strontium ranelate, raloxifene and parathyroid hormone peptides. Because of their broad spectrum of demonstrated anti-fracture efficacy, alendronate, risedronate, zoledronate and strontium ranelate are generally considered as front-line options for most women. The optimum duration of treatment has not been established but re-evaluation of risk and the need for continued therapy after 5 years of treatment may be appropriate. Compliance and persistence with long-term treatment is poor but may be improved by less frequent dosing regimens.

  2. Clinical and therapeutic aspects of osteoporosis

    International Nuclear Information System (INIS)

    Compston, Juliet

    2009-01-01

    Osteoporosis is characterized by reduced bone mass and alteration in bone architecture, resulting in increased fracture risk. These fractures are a major cause of morbidity and mortality in the elderly and impose a huge economic burden on health services. Oestrogen deficiency plays a major role in the pathogenesis of bone loss and fracture in both women and men. Other pathogenetic factors include reduced physical activity and vitamin D insufficiency. A range of options is available for the prevention of fractures in high risk postmenopausal women. These include the bisphosphonates, strontium ranelate, raloxifene and parathyroid hormone peptides. Because of their broad spectrum of demonstrated anti-fracture efficacy, alendronate, risedronate, zoledronate and strontium ranelate are generally considered as front-line options for most women. The optimum duration of treatment has not been established but re-evaluation of risk and the need for continued therapy after 5 years of treatment may be appropriate. Compliance and persistence with long-term treatment is poor but may be improved by less frequent dosing regimens.

  3. Malignant pilomatricoma in a dog with local and distant metastases treated with chemotherapy and bisphosphonates

    Directory of Open Access Journals (Sweden)

    Elisabetta Treggiari

    2017-07-01

    Full Text Available A ten-year-old male neutered cross breed dog presented for evaluation of a mass associated with the left scapular bone, identified as a carcinoma. The dog had a malignant pilomatricoma removed from the left lateral thigh 6 months earlier. Histopathology review of the cutaneous and scapular mass identified the same tumour type, confirming metastatic disease; additional metastases to the inguinal lymph node, liver and lungs were identified. Chemotherapy resulted in partial responses/stable disease of very short duration. Bisphosphonates were administered due to lack of a measurable response and worsening of the associated lameness. The patient ultimately developed a symptomatic vertebral metastasis and was euthanased. The dog survived 255 days since medical treatment was started and 455 days since surgical removal of the primary tumour. This case report suggests that medical treatment with the addition of analgesia may be able to palliate clinical signs and possibly extend survival in dogs with metastatic epithelial cancer.

  4. [Orthodontic treatment of patients medicated with bisphosphonates-a clinical case report].

    Science.gov (United States)

    Krieger, Elena; d'Hoedt, Bernd; Scheller, Herbert; Jacobs, Collin; Walter, Christian; Wehrbein, Heinrich

    2013-01-01

    Bisphosphonates (BP) are an established medication, e.g., for the prevention/therapy of osteoporosis. The effects of the changed bone metabolism for orthodontic treatments are unknown. A 66-year-old woman underwent a total oral rehabilitation. The therapy included (1) tooth extractions, (2) periodontal treatment, (3) insertion of dental implants, (4) provisional implant restorations, (5) orthodontic treatment, and (6) definite implant restorations. The orthodontic tooth movements were in- and retrusion of the upper frontal teeth, intrusion of the lower front teeth, using the dental implants as skeletal anchorage. After implant insertion and one month before beginning the orthodontic treatment, osteoporosis was diagnosed in this patient and, without notification to our facility, BP treatment was initiated by her general practitioner (alendronate oral, 70 mg/week), with an overall duration of intake of 7 months. After 13 months, the orthodontic treatment was successfully accomplished; however enlarged periodontal gaps, sclerotic bone areas, and mild apical root resorptions of the upper frontal teeth were found in this patient. Currently, there are no recommendations for orthodontic patients undergoing BP therapy. Orthodontic tooth movement in this low-risk patient with a short duration of intake and a low-dose BP medication was possible. Because of the reduced bone metabolism and the higher amount of side effects, the treatment should be performed with extremely light forces and frequent monitoring.

  5. Impact of bone turnover markers and/or educational information on persistence to oral bisphosphonate therapy: a community setting-based trial.

    Science.gov (United States)

    Silverman, S L; Nasser, K; Nattrass, S; Drinkwater, B

    2012-03-01

    We examined how the use of bone turnover markers and educational information affects persistence of bisphosphonate use in osteoporotic patients. We found that reporting bone turnover results and/or educational information did not affect persistence. Long-term adherence and persistence to osteoporosis medication are poor. We examined whether reporting of bone turnover marker results, education about osteoporosis, or a combination of both would increase persistence to oral bisphosphonates. Two hundred and forty women who were 5 years postmenopausal with BMD at least 2.0 standard deviations below normal were recruited for the study. All women were given a new prescription for alendronate and randomly assigned to one of four groups: (1) bone marker results at baseline, 3 and 12 months; (2) educational materials every month and a membership in the National Osteoporosis Foundation; (3) bone marker and educational information; and (4) control, no information other than usual care. Persistence among randomization groups was tested using survival analysis adjusting for the delay between intervention methods. Of those filling their initial prescription, 95.5% refilled their prescription at the end of the first month, 87% at 3 months, 82% at 6 months, and 78% at 10 months. Overall persistence through 12 months was 54%. There was no difference found among the four groups for persistence time using (p > 0.58). Providing bone turnover marker results is not an effective way to enhance early compliance and persistence with drug therapy. While the women in our study felt that bone marker results and educational information were helpful to them, there was no difference in persistence between those who received either bone marker information and/or educational information and those who did not. Because of the unexpected rate of primary nonadherence, this study may be underpowered.

  6. Syntheses and evaluation of 68 Ga- and 153 Sm-labeled DOTA-conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases.

    Science.gov (United States)

    Chakraborty, Sudipta; Goswami, Dibakar; Chakravarty, Rubel; Mohammed, Sahiralam Khan; Sarma, Haladhar Deb; Dash, Ashutosh

    2018-05-05

    This article reports the syntheses and evaluation of 68 Ga- and 153 Sm-complexes of a new DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-conjugated geminal bisphosphonate, DOTA-Bn-SCN-BP, for their potential uses in the early detection of skeletal metastases by imaging and palliation of pain arising from skeletal metastases, respectively. The conjugate was synthesized in high purity following an easily adaptable three-step reaction scheme. Gallium-68- and 153 Sm-complexes were prepared in high yield (>98%) and showed excellent in vitro stability in phosphate-buffered saline (PBS) and human serum. Both the complexes showed high affinity for hydroxyapatite particles in in vitro binding study. In biodistribution studies carried out in normal Wistar rats, both the complexes exhibited rapid skeletal accumulation with almost no retention in any other major organ. The newly synthesized molecule DOTA-Bn-SCN-BP would therefore be a promising targeting ligand for the development of radiopharmaceuticals for both imaging skeletal metastases and palliation of pain arising out of it in patients with cancer when radiolabeled with 68 Ga and 153 Sm, respectively. A systematic comparative evaluation, however, showed that there was no significant improvement of skeletal accumulation of the 153 Sm-DOTA-Bn-SCN-BP complex over 153 Sm-DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid) as the later itself demonstrated optimal properties required for an agent for bone pain palliation. © 2018 John Wiley & Sons A/S.

  7. Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial.

    Science.gov (United States)

    Rossi, Emanuela; Morabito, Alessandro; Di Rella, Francesca; Esposito, Giuseppe; Gravina, Adriano; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Pacilio, Carmen; De Maio, Ermelinda; Di Maio, Massimo; Piccirillo, Maria Carmela; De Feo, Gianfranco; D'Aiuto, Giuseppe; Botti, Gerardo; Chiodini, Paolo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

    2009-07-01

    PURPOSE We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. PATIENTS AND METHODS Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. CONCLUSION Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

  8. How rebates, copayments, and administration costs affect the cost-effectiveness of osteoporosis therapies.

    Science.gov (United States)

    Ferko, Nicole C; Borisova, Natalie; Airia, Parisa; Grima, Daniel T; Thompson, Melissa F

    2012-11-01

    Because of rising drug expenditures, cost considerations have become essential, necessitating the requirement for cost-effectiveness analyses for managed care organizations (MCOs). The study objective is to examine the impact of various drug-cost components, in addition to wholesale acquisition cost (WAC), on the cost-effectiveness of osteoporosis therapies. A Markov model of osteoporosis was used to exemplify different drug cost scenarios. We examined the effect of varying rebates for oral bisphosphonates--risedronate and ibandronate--as well as considering the impact of varying copayments and administration costs for intravenous zoledronate. The population modeled was 1,000 American women, > or = 50 years with osteoporosis. Patients were followed for 1 year to reflect an annual budget review of formularies by MCOs. The cost of therapy was based on an adjusted WAC, and is referred to as net drug cost. The total annual cost incurred by an MCO for each drug regimen was calculated using the net drug cost and fracture cost. We estimated cost on a quality adjusted life year (QALY) basis. When considering different rebates, results for risedronate versus ibandronate vary from cost-savings (i.e., costs less and more effective) to approximately $70,000 per QALY. With no risedronate rebate, an ibandronate rebate of approximately 65% is required before cost per QALY surpasses $50,000. With rebates greater than 25% for risedronate, irrespective of ibandronate rebates, results become cost-saving. Results also showed the magnitude of cost savings to the MCO varied by as much as 65% when considering no administration cost and the highest coinsurance rate for zoledronate. Our study showed that cost-effectiveness varies considerably when factors in addition to the WAC are considered. This paper provides recommendations for pharmaceutical manufacturers and MCOs when developing and interpreting such analyses.

  9. The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases

    Directory of Open Access Journals (Sweden)

    Omoigui Sota

    2007-03-01

    Full Text Available Abstract We describe the inflammation pathway from Cholesterol to Aging. Interleukin 6 mediated inflammation is implicated in age-related disorders including Atherosclerosis, Peripheral Vascular Disease, Coronary Artery Disease, Osteoporosis, Type 2 Diabetes, Dementia and Alzheimer's disease and some forms of Arthritis and Cancer. Statins and Bisphosphonates inhibit Interleukin 6 mediated inflammation indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion. Polyphenolic compounds found in plants, fruits and vegetables inhibit Interleukin 6 mediated inflammation by direct inhibition of the signal transduction pathway. Therapeutic targets for the control of all the above diseases should include inhibition of Interleukin-6 mediated inflammation.

  10. Report of a Rare Case of Gorham-Stout Disease of Both Shoulders: Bisphosphonate Treatment and Shoulder Replacement

    Directory of Open Access Journals (Sweden)

    Eike Garbers

    2011-01-01

    Full Text Available Massive osteolysis known as Gorham-Stout disease is a rare idiopathic disorder typically affecting long bones in a unifocal pattern. Angiomatosis is strongly connected to the osteolysis. Weather angiomatosis is the cause or the result of osteolysis is subject of intense discussion (Kawasaki et al. (2003, Möller et al. (1999, Radhakrishnan and Rockson (2008. There are about 200 cases described since 1955. Our patient is a 77-year-old female patient with osteolyses of both shoulders involving the proximal humerus, lateral clavicle, and the glenoid. Under bisphosphonate therapy, the progressive osteolysis stopped on the right side and showed progression on the left. With the patient complaining about severe rest pain and impaired function, we performed surgical reconstruction by implantation of total shoulder prosthesis three months after onset of symptoms. Our case shows a possibility of primary and early surgical reconstruction with good clinical outcome.

  11. Osteonecrose dos maxilares associada ao uso de bisfosfonatos: importante complicação do tratamento oncológico Bisphosphonate-associated jaws osteonecrosis: an important complication of oncology treatment

    Directory of Open Access Journals (Sweden)

    Marco Antonio T. Martins

    2009-02-01

    Full Text Available Os bisfosfonatos são um grupo de medicamentos utilizados no tratamento de doenças malignas metastáticas e em outras doenças ósseas como osteoporose e doença de Paget. A despeito dos seus benefícios, uma importante complicação denominada de osteonecrose dos maxilares vem sendo observada nos pacientes usuários crônicos dos bisfosfonatos que se caracteriza clinicamente por exposições ósseas na região maxilofacial persistente, acompanhadas de osteomielite, geralmente sintomáticas e cujo tratamento é complexo. Este estudo tem por objetivo revisar a literatura sobre a osteonecrose associada ao uso dos bisfosfonatos, em especial, em oncologia, no período de 2003 a 2008. Serão apresentados e discutidos os fatores de risco, aspectos etiopatogênicos, clínicos, imagenológicos, terapêuticos e preventivos desta doença. Devido à dificuldade de tratamento da osteonecrose associada aos bisfosfonatos, o foco deve ser a prevenção, sendo o ideal a eliminação de quadros infecciosos orais antes da terapia com os bisfosfonatos ter sido iniciada e minimizar traumas em boca após o uso destes medicamentos.Bisphosphonates are drugs used in the treatment of malignant metastatic diseases and in other bone lesions such as osteoporosis and Paget´s disease. Besides their benefits, jaw osteonecrosis, an important side effect, has been observed in long-term users of these drugs. Jaw osteonecrosis is clinically characterized by prolonged maxillary and mandible bone exposure accompanied by osteomyelitis. These lesions are usually symptomatic and difficult to treat. This study has the objective of reviewing publications from 2003 to 2008 about bisphosphonate-associated jaw osteonecrosis, in particular in relation to oncology. Risk factors, and etiopathological, clinical, radiographic, therapeutic, and preventive aspects of this condition are presented and discussed. Due to the difficulty to treat this disease, the focus must be prevention, with the

  12. Synthesis and characterization of polyamidoamine conjugates of neridronic acid

    CSIR Research Space (South Africa)

    Aderibigbe, BA

    2015-10-01

    Full Text Available transform spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) and energy-dispersive X-ray analysis (EDX). NMR, TGA, XRD and FTIR confirmed the successful incorporation of the bisphosphonate on to the carriers. The mass percentage...

  13. Natural history of malignant bone disease in hepatocellular carcinoma: final results of a multicenter bone metastasis survey.

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    Daniele Santini

    Full Text Available BACKGROUND: Bone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC. Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC. PATIENTS AND METHODS: Data on clinicopathology, survival, skeletal-related events (SREs, and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed. RESULTS: The median age was 70 years; 172 patients were male (81.5%. The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis; 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%. Most of these lesions were osteolytic (82.4%; 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (p = 0.001, HR = 1.819. The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (p = 0.005, ECOG performance status (p = 0.002 and treatment with bisphosphonate (p = 0.024 were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE (p = 0.021 and OS (p = 0.001. CONCLUSIONS: This study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.

  14. Pharmacological interventions for the prevention of insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults.

    Science.gov (United States)

    van den Blink, Qurrat U; Garcez, Kate; Henson, Caroline C; Davidson, Susan E; Higham, Claire E

    2018-04-23

    obtain missing data. Data were to be pooled using the random-effects model if study comparisons were similar, otherwise results were to be reported narratively. We included two RCTs (1167 participants). The first RCT compared zoledronic acid with placebo in 96 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.The second RCT had four treatment arms, two of which evaluated zoledronic acid plus adjuvant androgen suppression compared with androgen suppression only in 1071 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.Both studies were at a moderate to high risk of bias and all evidence was judged to be of very low certainty.The studies provided no evidence on the primary outcomes of the review and provided limited data in relation to secondary outcomes, such that meta-analyses were not possible. Both studies focused on interventions to improve bone health in relation to androgen deprivation rather than radiation-related insufficiency fractures and avascular necrosis. Few fractures were described in each study and those described were not specific