Bisphosphonate-related osteonecrosis of the jaw: specificities

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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.

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

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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.

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

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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.)

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

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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.

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.

[Orthodontic treatment of patients medicated with bisphosphonates-a clinical case report].

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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.

Bisphosphonates and osteonecrosis of the jaw.

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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

Pleiotropic effects of bisphosphonates on osteosarcoma.

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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.

Bisphosphonates for osteoporosis in primary biliary cirrhosis

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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...

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

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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

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

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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...

BISPHOSPHONATE - RELATED MUCOSITIS (BRM: A CASE REPORT

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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.

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

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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.

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.

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

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

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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

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

BISPHOSPHONATE INDUCED STRESS FRACTURE OF BILATERAL FEMUR: A CASE REPORT

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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

A review of the clinical implications of bisphosphonates in dentistry.

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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.

Treatment of bisphosphonate related osteonecrosis following root canal therapy at the 1-year follow-up: report of two cases

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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

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

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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.

Psychometric evaluation of the Osteoporosis Patient Treatment Satisfaction Questionnaire (OPSAT-Q™, a novel measure to assess satisfaction with bisphosphonate treatment in postmenopausal women

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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

Atypical form of active melorheostosis and its treatment with bisphosphonate

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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.)

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

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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.

Characteristics of patients initiating raloxifene compared to those initiating bisphosphonates

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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

Bisphosphonate Treatment in Osteoporosis: Optimal Duration of Therapy and the Incorporation of a Drug Holiday.

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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.

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

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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...

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

The bisphosphonates: risks and benefits of long term use

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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...

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

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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.

Current state of orthodontic patients under Bisphosphonate therapy

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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

Inflammatory eye reactions with bisphosphonates and other osteoporosis medications

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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...

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

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

2004-01-01

To identify evidence for the role of bisphosphonates in malignancy for the treatment of hypercalcaemia, prevention of skeletal morbidity and use in the adjuvant setting. To perform an economic review of current literature and model the cost effectiveness of bisphosphonates in the treatment of hypercalcaemia and prevention of skeletal morbidity. Electronic databases (1966-June 2001). Cochrane register. Pharmaceutical companies. Experts in the field. Handsearching of abstracts and leading oncology journals (1999-2001). Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. Overall event rates were pooled in a meta-analysis, odds ratios (OR) were given with 95% confidence intervals (CI). Where data could not be combined, studies were reported individually and proportions compared using chi-squared analysis. Cost and cost-effectiveness were assessed by a decision analytic model comparing different bisphosphonate regimens for the treatment of hypercalcaemia; Markov models were employed to evaluate the use of bisphosphonates to prevent skeletal-related events (SRE) in patients with breast cancer and multiple myeloma. For acute hypercalcaemia of malignancy, bisphosphonates normalised serum calcium in >70% of patients within 2-6 days. Pamidronate was more effective than control, etidronate, mithramycin and low-dose clodronate, but equal to high dose clodronate, in achieving normocalcaemia. Pamidronate prolongs (doubles) the median time to relapse compared with clodronate or etidronate. For prevention of skeletal morbidity, bisphosphonates compared with placebo, significantly reduced the OR for fractures (OR [95% CI], vertebral, 0.69 [0.57-0.84], non-vertebral, 0.65 [0.54-0.79], combined, 0.65 [0.55-0.78]) radiotherapy 0.67 [0.57-0.79] and hypercalcaemia 0.54 [0.36-0.81] but not orthopaedic surgery 0.70 [0.46-1.05] or spinal cord compression 0.71 [0.47-1.08]. However, reduction in orthopaedic surgery was

Tooth alterations in areas of bisphosphonate-induced osteonecrosis.

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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.

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

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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.

Use of bisphosphonate therapy for osteoporosis in childhood and adolescence.

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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.

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

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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

The dental implications of bisphosphonates and bone disease.

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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.

Eliminating the need for fasting with oral administration of bisphosphonates

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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...

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.

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

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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.

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

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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.

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

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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.

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

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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

Do bisphosphonates inhibit direct fracture healing?: A laboratory investigation using an animal model.

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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.

BISPHOSPHONATES IN LANGERHANS CELL HISTIOCYTOSIS: AN INTERNATIONAL RETROSPECTIVE CASE SERIES

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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.

3-Keto-1,5-bisphosphonates Alleviate Serum-Oxidative Stress in the High-fat Diet Induced Obesity in Rats.

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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.

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

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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.

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.

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

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

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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

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

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

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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...

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.

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

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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

Future of bisphosphonates and denosumab for men with advanced prostate cancer

International Nuclear Information System (INIS)

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

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.

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.

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

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

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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

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.

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

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.

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.

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.

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).

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.

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

. Alendronate (60 μg/kg/d subcutaneously [s.c.]) or zoledronate (3 mg/kg/d orally) treatment for 28 days, started at the time of fracture, completely inhibited the development of hindpaw allodynia and reduced hindpaw unweighting by 44% ± 13% and 58% ± 5%, respectively. Orally administered zoledronate (3 mg/kg/d for 21 days) treatment also completely reversed established allodynia and unweighting when started at 4 weeks postfracture. Histomorphometric and microcomputed tomography analysis demonstrated that both the 3 and 60 μg/kg/d alendronate treatments reversed trabecular bone loss (an 88% ± 25% and 188% ± 39% increase in the ipsilateral distal femur BV/TV, respectively) and blocked the increase in osteoclast numbers and erosion surface observed in bilateral distal femurs and in L5 vertebra of the fracture rats. Alendronate treatment inhibited fracture-induced increases in hindpaw inflammatory mediators, reducing postfracture levels of tumor necrosis factor by 43% ± 9%, IL-1 by 60% ± 9%, IL-6 by 56% ± 14%, and NGF by 37% ± 14%, but had no effect on increased spinal cord Fos expression, or skin and sciatic nerve immunocomplex deposition. Collectively, these results indicate that bisphosphonate therapy inhibits pain, osteoclast activation, trabecular bone loss, and cutaneous inflammation in the rat fracture model of CRPS, data supporting the hypothesis that bisphosphonate therapy can provide effective multimodal treatment for CRPS.

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

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

Radiographic features of bisphosphonate therapy in pediatric patients

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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.)

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.)

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.

Treatment of bisphosphonate related osteonecrosis following root canal therapy at the 1-year follow-up: report of two cases

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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...

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

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;

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....

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.

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...

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

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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.)

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

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.

Healing of extraction sockets and augmented alveolar defects following 1-year treatment with bisphosphonate.

Science.gov (United States)

Khojasteh, Arash; Behnia, Hossein; Morad, Golnaz; Dashti, Seyedeh Ghazaleh; Dehghan, Mohammad Mehdi; Shahab, Shahriyar; Abbas, Fatemeh Mashhadi

2013-01-01

To assess the effect of bisphosphonates on healing of extraction sockets and augmented alveolar defects, 12 adult female mongrel dogs were assigned to 2 experimental groups and a control group. The experimental groups received oral alendronate (ALN, 3.5 mg/kg/wk) or IV pamidronate (PAM, 1 mg/kg/wk) for 12 months. Animals were randomly tested for serum C-terminal telopeptide of collagen I (CTx). The right first and second premolars were extracted. After 8 weeks, extraction sites were evaluated for healing. Subsequently, 3-wall defects were created in ridges and filled with human mineralized cortical particulate bone. Two months post-augmentation, animals were sacrificed and mandibles were collected for cone-beam computed tomography (CBCT) and histomorphometric appraisal. The obtained data were compared using 1-way ANOVA test. CTx test results in both experimental groups were comparable (alveolar bone in the PAM group and the upper rim of the alveoli in the ALN group. Histologically, bone sequestra from the PAM group demonstrated empty osteocyte lacunae, while in the ALN group areas of necrotic bone along with evidence of active bone remodeling was distinguished. Eight weeks post-augmentation, the experimental groups showed no evidence of bone formation in the augmented area, while bone formation ratio was measured to be 18.32% in the control group. The mean amount of pixel intensity calculated from the CBCT images of the ALN, PAM, and control group was 113.69 ± 11.04, 124.94 ± 4.72, and 113.69 ± 6.63, respectively. Pixel intensity in PAM-treated group was significantly higher than both other groups. This study demonstrated that 1-year treatment with ALN/PAM was associated with impairment of post-extraction and post-augmentation bone healing in dogs.

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.

Differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates

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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

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.

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...

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...

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

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.

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

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.

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...

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.

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

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)

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

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.

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.

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.

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

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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.

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...

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

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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.

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.

Bisphosphonates and osteonecrosis of jaws

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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.

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

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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.

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.

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.

Additive effects of nutritional supplementation, together with bisphosphonates, on bone mineral density after hip fracture: a 12-month randomized controlled study

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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

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...

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

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

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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.

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.

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.

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.

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

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....

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...

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 ...

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

Science.gov (United States)

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

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.

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.

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

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.

Osteoporosis treatment

DEFF Research Database (Denmark)

Pazianas, Michael; Abrahamsen, Bo

2016-01-01

The findings of the Women's Health Initiative study in 2002 marginalized the use of hormone replacement therapy and established bisphosphonates as the first line of treatment for osteoporosis. Denosumab could be used in selected patients. Although bisphosphonates only maintain the structure of bone...... to their benefits/harm ratio. Treatment of osteoporosis is a long process, and many patients will require treatment with more than one type of drug over their lifetime....

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.

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.

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

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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.

Leucocyte-rich and platelet-rich fibrin for the treatment of bisphosphonate-related osteonecrosis of the jaw: a prospective feasibility study.

Science.gov (United States)

Kim, Jin-Woo; Kim, Sun-Jong; Kim, Myung-Rae

2014-11-01

Our aim was to assess the feasibility of using leucocyte-rich and platelet-rich fibrin (L-PRF) for the treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in a single group study. After treatment with L-PRF, the response of each patient was recorded 1 month and 4 months postoperatively. Further assessments were made of the site, stage, concentration of c-terminal crosslinked telopepide of type 1 collagen, and actinomycosis. Among the total of 34 patients, 26 (77%) showed complete resolution, 6 (18%) had delayed resolution, and 2 (6%) showed no resolution. There was a significant association between the response to treatment and the stage of BRONJ (p=0.002) but no other significant associations were detected. This study has shown that it is feasible to use L-PRF for the treatment of BRONJ, but the effectiveness cannot be judged with this study design. Randomised prospective trials are needed to confirm this. Copyright © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

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

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...

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

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

for patients to be informed of the risk of this complication, so that they have the oppor-tunity to assess the need for dental treatment before starting therapy. Preventive measures must be taken before, during, and after treatment with bisphosphonates. Surgical treatment should be reserved for those patients who are symptomatic. Further investigation is needed to completely elucidate this complication.

Atypical femoral fractures related to bisphosphonate therapy

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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.

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

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

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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.

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

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

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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.

Osteonecrosis de los maxilares asociada al uso de bifosfonatos: revisión de ocho casos Bisphosphonate-related jaw osteonecrosis: Review of eight cases

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J. Joshi Otero

2011-03-01

cancer. Material and methods: A prospective study was made of patients from Hospital Virgen Macarena who presented bisphosphonate associated jaw lesions from 2006 to the present. The patient variables examined were: sex, age, bisphosphonate treatment, onset of osteonecrosis and its relation to dental treatment, treatment, and outcome. Results: Eight patients with osteonecrosis of the jaw secondary to treatment with intravenous or oral bisphosphonates for oncologic or osteoporotic pathology were treated according to their clinical and radiological findings with antibiotics and curettage and/or excision of sequestered bone, as needed. Results with a minimum follow up of 15 months are reported. Conclusions: The increased incidence of maxillary osteomyelitis in patients treated with bisphosphonates and the difficulty of treatment make it necessary to establish standard therapeutic guidelines. In the authors' experience, conservative treatment based on antibiotic therapy and/or curettage of the area under local anesthesia can adequately control and resolve the process in some patients with stage II BRJO.

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 ...

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

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...

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

International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates

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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....

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.

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.

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

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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.

Bisphosphonate-associated osteonecrosis of the jaws

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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.

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

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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.

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.

Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features.

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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.

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

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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.

Osteonecrose dos maxilares associada ao uso de bisfosfonatos: importante complicação do tratamento oncológico Bisphosphonate-associated jaws osteonecrosis: an important complication of oncology treatment

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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

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

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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.

Bisphosphonates as potential adjuvants for patients with cancers of the digestive system.

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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.

Bisphosphonate: Brief Review of Its Development for Usage in Dentistry

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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

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

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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.

Vitamin D insufficiency reduces the protective effect of bisphosphonate on ovariectomy-induced bone loss in rats.

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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.

Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.

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Bernard, Louis; Dinh, Aurélien; Ghout, Idir; Simo, David; Zeller, Valerie; Issartel, Bertrand; Le Moing, Vincent; Belmatoug, Nadia; Lesprit, Philippe; Bru, Jean-Pierre; Therby, Audrey; Bouhour, Damien; Dénes, Eric; Debard, Alexa; Chirouze, Catherine; Fèvre, Karine; Dupon, Michel; Aegerter, Philippe; Mulleman, Denis

2015-03-07

Duration of treatment for patients with vertebral osteomyelitis is mainly based on expert recommendation rather than evidence. We aimed to establish whether 6 weeks of antibiotic treatment is non-inferior to 12 weeks in patients with pyogenic vertebral osteomyelitis. In this open-label, non-inferiority, randomised controlled trial, we enrolled patients aged 18 years or older with microbiologically confirmed pyogenic vertebral osteomyelitis and typical radiological features from 71 medical care centres across France. Patients were randomly assigned to either 6 weeks or 12 weeks of antibiotic treatment (physician's choice in accordance with French guidelines) by a computer-generated randomisation list of permuted blocks, stratified by centre. The primary endpoint was the proportion of patients who were classified as cured at 1 year by a masked independent validation committee, analysed by intention to treat. Non-inferiority would be declared if the proportion of cured patients assigned to 6 weeks of treatment was not less than the proportion of cured patients assigned to 12 weeks of treatment, within statistical variability, by an absolute margin of 10%. This trial is registered with EudraCT, number 2006-000951-18, and Clinical Trials.gov, number NCT00764114. Between Nov 15, 2006, and March 15, 2011, 359 patients were randomly assigned, of whom six in the 6-week group and two in the 12-week group were excluded after randomisation. 176 patients assigned to the 6-week treatment regimen and 175 to the 12-week treatment regimen were analysed by intention to treat. 160 (90·9%) of 176 patients in the 6-week group and 159 (90·9%) of 175 of those in the 12-week group met the criteria for clinical cure. The difference between the groups (0·05%, 95% CI -6·2 to 6·3) showed the non-inferiority of the 6-week regimen when compared with the 12-week regimen. 50 patients in the 6-week group and 51 in the 12-week group had adverse events, the most common being death (14 [8%] in

A comparison of twice-weekly MPD-PUVA and three times-weekly skin typing-PUVA regimens for the treatment of psoriasis

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Buckley, D.A.; Rogers, S. [City of Dublin Skin and Cancer Hospital, Dublin (Ireland); Healy, E. [Royal Victoria Infirmary, Newcastle upon Tyne (United Kingdom)

1995-09-01

The most frequent PUVA treatment regimen in current use is three times weekly, using skin typing to estimate the starting dose. Recently, it was suggested that twice-weekly treatment, using the minimal phototoxic dose- (MPD) to calculate suberythmal starting doses of UVA, achieved similar clearance rates with fewer treatments and a lower cumulative UVA dose. We have carried out a trial on 83 patients, comparing twice-weekly MPD-PUVA with three times-weekly skin typing-PUVA, in order to test this hypothesis. Although clearance rates were comparable between the two regimens, there was no overall significant difference in the number of treatments or in the cumulative UVA doses at clearance. However, for patients with skin types I and II the cumulative UVA dose was significantly higher using the twice-weekly MPD regimen (70.OJ/cm{sup 2} vs. 55.8J/cm{sup 2}; P<0.05). Our results do not confirm that there is a reduction in cumulative UVA dosage with twice-weekly MPD-PUVA. (Author).

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

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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.

Is Bisphosphonate-Related Osteonecrosis of the Jaw an Infection? A Histological and Microbiological Ten-Year Summary

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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.

Osteomalacia: the missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws?

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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.

Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications - cohort analysis using a national prescription database

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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...

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.

Pharmacokinetic and tolerability of i.m. disodium clodronate 200 mg/lidocaine 1%, given twice monthly, in comparison with i.m. disodium clodronate 100 mg/lidocaine 1%, given weekly, in healthy postmenopausal female patients.

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Radicioni, Milko; Cremonesi, Giovanni; Baraldi, Enrica; Leuratti, Chiara; Mariotti, Fabrizia

2013-04-01

Clodronate is a bisphosphonate effective in the prevention and treatment of osteoporosis in postmenopausal women. Non-adherence to bisphosphonates, however, is a major issue in clinical practice. Simplifying dose regimens may increase compliance. To assess bioequivalence between an intramuscular (i.m.) clodronate 200 mg/lidocaine 1% twice-a-month formulation and a clodronate 100 mg/lidocaine 1% weekly formulation in 32 postmenopausal women. In this double-blind, randomized, two-way crossover study, test and reference formulations were administered in single dose, with a 2-week wash-out between administrations. The primary endpoint was clodronic acid cumulative excretion in the first 24 hours after injection (Xu0-24h). Cumulative excretion in the 72 hours post-dose (Xu0-72h) and maximum excretion rate (Ratemax) were also evaluated. Bioequivalence was assumed if the 90% confidence intervals (CIs) of the geometric means ratios of the dose-normalized parameters were within the 80.00 - 125.00% range. Local tolerability was evaluated. Mean Xu0-24h values were 114.03 ±23.13 mg and 55.22 ±9.73 mg for clodronate 200 mg and 100 mg. The 90% CIs for dose-normalized Xu0-24h, Xu0-72h and Ratemax ere 95 -110%, 94 -107% and 95 - 113%. Local tolerability of both treatments was good. The differences in pain intensity between formulations were not sigificantly different at most assessment times. Headache was the only treatment-related adverse event. Bioequivalence of the two formulations was confirmed in terms of dose-normalized rate and amount of clodronic acid excretion. This result, together with the favorable tolerability of the novel 200 mg formulation, suggests the possibility of reducing the number of i.m. administrations from once-a-week to twice-a-month.

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 ...

[Ibandronate in the treatment of postmenopausal osteoporosis].

Science.gov (United States)

Lakatos, Péter

2008-10-01

Postmenopausal osteoporosis affects 7-10% of the population of developed countries. During the past decade, a number of new therapeutical modalities have been made available. Among these, bisphosphonates mean the mainstay of medical treatment. Ibandronate belongs to the amino-bisphosphonate group of these drugs. Amino-bisphosphonates act via the mevalonate metabolic pathway, thus, inhibiting protein prenylation. Several clinical studies have shown a significant reduction in the fracture risk of osteoporotic patients treated with ibandronate. This compound can be administered orally once a month or intravenously once in every 3 months. Longer dosing intervals stimulate patient compliance, and consequently increase efficacy and cost effectiveness.

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

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.

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.

Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features

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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

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

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).

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...

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

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.

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.

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

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.

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.

Oral cutaneous sinus tract, vertical root fracture, and bisphosphonate-related osteonecrosis: a case report.

Science.gov (United States)

Wigler, Ronald; Steinbock, Nelly; Berg, Tal

2013-08-01

Oral cutaneous sinus tracts (OCSTs) of dental origin are often initially misdiagnosed and inappropriately treated. Accurate diagnosis is especially important in cases of bisphosphonate (BP) therapy because extraction may lead to a risk of osteonecrosis. A case report of misdiagnosis related to a tooth with a vertical root fracture in an oncologic patient treated with BPs is reported here. In 2011, a 75-year-old woman was examined at the oral medicine clinic because of pain and swelling of the left submandibular area. The patient's medical history included oral and intravenous BP therapy because she was diagnosed with metastatic breast cancer and left maxillary stage 1 antiresorptive agent-induced osteonecrosis of the jaw. The lower left odontogenic region showed no signs or symptoms, and no apical pathosis was observed on imaging. Although antibiotics were applied, clinical symptoms worsened and an OCST appeared. Intravenous antibiotic treatment was pursued. Biopsy and direct smear from fistula were not conclusive. A diagnosis of a nonexposed variant of stage 3 antiresorptive agent-induced osteonecrosis of the jaw was established. Symptoms resolved after 2 weeks of antibiotic treatment and reappeared a month later. Endodontic examination revealed that the origin of the OCST was tooth no. 18 caused by a vertical root fracture, and the tooth was extracted. The patient was scheduled for routine checkups because of the fact that osteonecrosis may occur in intravenous BP-treated patients. Early correct diagnosis can prevent unnecessary and ineffective antibiotic therapy and surgical intervention, which is not recommended in intravenous BP cases. Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation

Directory of Open Access Journals (Sweden)

Diefenbach K

2013-04-01

Full Text Available Konstanze Diefenbach,1 Dietmar Trummer,1 Frank Ebert,1 Michael Lissy,2 Manuela Koch,2 Beate Rohde,1 Hartmut Blode3 1Bayer HealthCare Pharmaceuticals, Berlin, Germany; 2Nuvisan GmbH, Neu-Ulm, Germany; 3Bayer HealthCare Pharmaceuticals Global R&D Center, Beijing, People's Republic of China Background: Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid. Methods: This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18–40 years received ethinylestradiol (EE-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase, and EE-drospirenone for an additional 20 weeks (folate elimination phase. The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ≥ 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium. Results: Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma or 24 weeks (RBC. After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8–12 weeks after cessation

Osteogenesis imperfecta: diagnosis and treatment.

Science.gov (United States)

Palomo, Telma; Vilaça, Tatiane; Lazaretti-Castro, Marise

2017-12-01

Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in osteogenesis imperfecta, and review the management of this disease in children and adults. Mutations in the two genes coding for collagen type I, COL1A1 and COL1A2, are the most common cause of osteogenesis imperfecta. In the past 10 years, defects in at least 17 other genes have been identified as responsible for osteogenesis imperfecta phenotypes, with either dominant or recessive transmission. Intravenous bisphosphonate infusions are the most widely used medical treatment. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures. However, bisphosphonates are less effective for preventing long-bone fractures. At the moment, new therapies are under investigation. Despite advances in the diagnosis and treatment of osteogenesis imperfecta, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice.

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.

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...

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

Successful treatment of chronic recurrent multifocal osteomyelitis using low-dose radiotherapy. A case report

International Nuclear Information System (INIS)

Dietzel, Christian T.; Vordermark, Dirk; Schaefer, Christoph

2017-01-01

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disease, which lacks an infectious genesis and predominantly involves the metaphysis of long bones. Common treatments range from nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids at first onset of disease, to immunosuppressive drugs and bisphosphonates in cases of insufficient remission. The therapeutic use of low-dose radiotherapy for CRMO constitutes a novelty. A 67-year-old female patient presented with radiologically proven CRMO affecting the right tibia/talus and no response to immunosuppressive therapy. Two treatment series of radiation therapy were applied with an interval of 6 weeks. Each series contained six fractions (three fractions per week) with single doses of 0.5 Gy, thus the total applied dose was 6 Gy. Ten months later, pain and symptoms of osteomyelitis had completely vanished. Radiotherapy seems to be an efficient and feasible complementary treatment option for conventional treatment refractory CRMO in adulthood. The application of low doses per fraction is justified by the inflammatory pathomechanism of disease. (orig.) [de

Bilateral Incomplete Atypical Femoral Fracture due to Long-Term Bisphosphonate Use: A Case Report

Directory of Open Access Journals (Sweden)

Sibel Başaran

2017-08-01

Full Text Available Although the overall safety profile of bisphosphonates (BP is favorable, adverse effects associated with long-term use have came up during recent years. In this report, a case of bilateral incomplete atypical femoral fracture (AFF due to prolonged BP use was presented. A 69-year-old patient, who has been in surgical menopause for 20 years and was started on BP following vertebral fracture almost 10 years ago, was admitted with thigh pain, which was increased two weeks ago. On physical examination, she had antalgic gait, increased thoracic kyphosis and tenderness to percussion over the thoracolumbar region. Lateral cortical thickness in the subtrochanteric region of both femurs and cortical radiolucency on the left femur were observed on plain radiography. Loss of height in L3 and L4 vertebrae was detected on vertebral radiography. Serum 25-hydroxy vitamin D [25(OHD], parathyroid hormone, alkaline phosphatase and calcium levels, along with osteoporosis markers were all within the normal ranges. As the patient was diagnosed with AFF, BP therapy was terminated and vitamin D-calcium supplementation was continued. Since she did not have severe pain, conservative management (limited weight bearing, using a walking stick was recommended for 3 months. Teriparatide therapy was started and she was discharged with recommendations. AFF, which is a rare disorder, should be kept in mind in patients on long-term BP treatment who are admitted with thigh pain and, necessary interventions should be tailored before the occurrence of complete fracture.

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

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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.

Prevention and Treatment of Bone Metastases in Breast Cancer

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Ripamonti Carla

2013-09-01

Full Text Available In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression. Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach.

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.

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

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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.

Paget's disease of the bone after treatment with Denosumab

DEFF Research Database (Denmark)

Schwarz, Peter; Rasmussen, Anne Qvist; Kvist, Torben M

2012-01-01

Bone affection in Paget's disease is characterized by increased bone turnover localised at one or more sites of the skeleton. Bisphosphonates are the drugs of choice when treating the increased bone turnover in Paget's disease. However, in cases of decreased kidney function only less effective tr...... treatments that are available as bisphosphonates are contraindicated in these patients. We present a case of a male patient aged 86 years with GFR of 11 mL/min and Paget's disease successfully treated by Denosumab. The bone turnover and pain decreased upon treatment....

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

Heartburn treatment in primary care: randomised, double blind study for 8 weeks

Science.gov (United States)

Hatlebakk, Jan G; Hyggen, Arild; Madsen, Per H; Walle, Per O; Schulz, Tom; Mowinckel, Petter; Bernklev, Tomm; Berstad, Arnold

1999-01-01

Objective To compare the effects and tolerability of omeprazole and cisapride with that of placebo for control of heartburn in primary care patients. Design Randomised, double blind, placebo controlled study. Setting 65 primary care practices in Norway. Participants 483 untreated patients with complaints of heartburn ⩾3 days a week, with at most grade 1 reflux oesophagitis. Interventions Omeprazole 20 mg once daily, cisapride 20 mg twice daily, or placebo for 8 weeks. Main outcome measures Adequate control of heartburn, defined as ⩽1 day of the past 7 days with no more than mild heartburn, after 4 weeks of treatment. Results In the all patients treated analysis, adequate control of heartburn was achieved in 71% of patients taking omeprazole, 22% taking cisapride, and 18% taking placebo after 4 weeks of treatment (omeprazole v cisapride and placebo, Pheartburn whereas cisapride 20 mg twice daily was not significantly more effective than placebo. Key messagesIn primary care patients, heartburn is commonly treated empiricallyMost randomised clinical trials of treatment for heartburn have been conducted in specialist care, and documentation for empirical treatment is limitedOmeprazole was significantly more effective than cisapride or placebo in controlling heartburn and other symptoms of gastro-oesophageal reflux after 2, 4, and 8 weeks, whereas cisapride did not differ significantly from placeboOmeprazole should be considered as a first choice for empirical treatment of heartburn in primary care PMID:10463897

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

International Nuclear Information System (INIS)

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.

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

Energy Technology Data Exchange (ETDEWEB)

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.

Targeted ultraviolet B phototherapy in vitiligo: A comparison between once-weekly and twice-weekly treatment regimens

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Imran Majid

2015-01-01

Full Text Available Background: Targeted ultraviolet B (T-UVB phototherapy in vitiligo is usually administered twice or thrice a week on non-consecutive days. It is difficult for many patients to adhere to this regimen, forcing them to discontinue treatment. Aim: The study aimed to compare the efficacy of twice-weekly and once-weekly targeted ultraviolet B phototherapy regimens in vitiligo. Methods: Sixty patients with non-segmental vitiligo on the face, neck or trunk were divided into two groups of 30 patients each. The patients in group A received targeted ultraviolet B twice weekly, while those in group B received targeted ultraviolet B once weekly. Repigmentation was monitored and graded as excellent (≥75% repigmentation, good (50−74% repigmentation and poor (<50% repigmentation. The extent of repigmentation at each body site (primary outcome measure, the number of doses required for initiation of pigmentation, and the cumulative dose of targeted ultraviolet B administered was calculated and compared between both groups. Results: A total of 90 lesions (48 in the twice weeklygroup and 42 in the once weekly group were treated on the face, neck and trunk. Excellent results were obtained in 62.5% (30/48 of lesions treated twice weekly, and 64.3% (27/42 in lesions treated once weekly. The mean number of doses required for initiation of pigmentation was 4.69 in the twice weekly group, and 4.35 in the once weekly group. The patients in the twice weekly group received a mean cumulative dose of 8.26 J/cm 2, while the once weekly group received 7.69 J/cm 2. No statistically significant differences were observed between the two groups with respect to the outcome, with respect to the total repigmentation, the number of doses till onset of pigmentation, as well as the cumulative dose of targeted UVB. Conclusion: Once-weekly targeted ultraviolet B phototherapy appears to be as efficacious as the twice-weekly regimen in vitiligo.

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.

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

Science.gov (United States)

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.

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

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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.

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

Directory of Open Access Journals (Sweden)

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.

Opsismodysplasia: Phosphate wasting osteodystrophy responds to bisphosphonate therapy

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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.

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.

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.

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.

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.

Report of a Rare Case of Gorham-Stout Disease of Both Shoulders: Bisphosphonate Treatment and Shoulder Replacement

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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.

Malignant pilomatricoma in a dog with local and distant metastases treated with chemotherapy and bisphosphonates

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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.

A prospective randomized cohort study evaluating 3 weeks vs 6 weeks of oral antibiotic treatment in the setting of "maximal medical therapy" for chronic rhinosinusitis.

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Sreenath, Satyan B; Taylor, Robert J; Miller, Justin D; Ambrose, Emily C; Rawal, Rounak B; Ebert, Charles S; Senior, Brent A; Zanation, Adam M

2015-09-01

Surprisingly, little literature exists evaluating the optimal duration of antibiotic treatment in "maximal medical therapy" for chronic rhinosinusitis (CRS). As such, we investigated whether 3 weeks vs 6 weeks of antibiotic therapy resulted in significant differences in clinical response. A prospective, randomized cohort study was performed with patients assigned to 3-week or 6-week cohorts. Our primary outcome was failure of "maximal medical therapy" and surgical recommendation. Secondary outcomes included changes in pretherapy and posttherapy scores for the Rhinosinusitis Disability Index (RSDI), Chronic Sinusitis Survey (CSS), and computed tomography (CT)-based Lund-Mackay (LM) evaluation. Analyses were substratified based on presence of nasal polyps. Forty patients were randomized to the 3-week or 6-week treatment cohorts, with near-complete clinical follow-up achieved. No significant difference was found between the proportion of patients who failed medical therapy and were deemed surgical candidates between the 2 cohorts (71% vs 68%, p = 1.000). No significant difference was found in the change of RSDI or CSS scores in the 3 vs 6 weeks of treatment groups (mean ± standard error of the mean [SEM]; RSDI: 9.62 ± 4.14 vs 1.53 ± 4.01, p = 0.868; CSS: 5.75 ± 4.36 vs 9.65 ± 5.34, p = 0.573). Last, no significant difference was found in the change of LM scores (3.35 ± 1.11 vs 1.53 ± 0.81, p = 0.829). Based on this data, there is little difference in clinical outcomes between 3 weeks vs 6 weeks of antibiotic treatment as part of "maximal medical therapy" for CRS. Increased duration of antibiotic treatment theoretically may increase risk from side effects and creates higher healthcare costs. © 2015 ARS-AAOA, LLC.

Subtrochanteric Fracture In A Chinese Woman With Paget’s Disease Of Bone And On Long Term Bisphosphonate Therapy: Could It Be An Insufficiency Fracture?

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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.

Osteogenesis Imperfecta in Adult Twins Responded To Treatment With Pamidronate

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Mehtap Çakır; Mine Öztürk

2011-01-01

Bisphosphonates are strong inhibitors of bone resorption and are used in the treatment of osteoporosis. Bisphosphonates are known to be effective in prevention of fractures, improvement of bone mineral density as well as in relieving bone pain in osteogenesis imperfecta (OI) patients. Recent studies have shown that especially intravenous pamidronate may be more effective when given in childhood and adolescence. This effect was also shown in adult OI patients in some clinical trials.22-year-ol...

Intravenous pamidronate in combination with calcium and vitamin D: highly effective in the treatment of low bone mineral density in inflammatory bowel disease

NARCIS (Netherlands)

Stokkers, Pieter C. F.; Deley, Maartje; van der Spek, Mirjam; Verberne, Hein J.; van Deventer, Sander J. H.; Hommes, Daniel W.

2006-01-01

OBJECTIVE: Decreased bone mineral density (BMD) is common in inflammatory bowel disease (IBD) and an increased risk of fractures has been reported. Guidelines state bisphosphonate treatment for IBD patients with decreased BMD, but orally available bisphosphonates have been associated with

The cost effectiveness of teriparatide as a first-line treatment for glucocorticoid-induced and postmenopausal osteoporosis patients in Sweden

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Murphy Daniel R

2012-10-01

Full Text Available Abstract Background This paper presents the model and results to evaluate the use of teriparatide as a first-line treatment of severe postmenopausal osteoporosis (PMO and Glucocorticoid-induced osteoporosis (GIOP. The study’s objective was to determine if teriparatide is cost effective against oral bisphosphonates for two large and high risk cohorts. Methods A computer simulation model was created to model treatment, osteoporosis related fractures, and the remaining life of PMO and GIOP patients. Natural mortality and additional mortality from osteoporosis related fractures were included in the model. Costs for treatment with both teriparatide and oral bisphosphonates were included. Drug efficacy was modeled as a reduction to the relative fracture risk for subsequent osteoporosis related fractures. Patient health utilities associated with age, gender, and osteoporosis related fractures were included in the model. Patient costs and utilities were summarized and incremental cost-effectiveness ratios (ICERs for teriparatide versus oral bisphosphonates and teriparatide versus no treatment were estimated. For each of the PMO and GIOP populations, two cohorts differentiated by fracture history were simulated. The first contained patients with both a historical vertebral fracture and an incident vertebral fracture. The second contained patients with only an incident vertebral fracture. The PMO cohorts simulated had an initial Bone Mineral Density (BMD T-Score of −3.0. The GIOP cohorts simulated had an initial BMD T-Score of −2.5. Results The ICERs for teriparatide versus bisphosphonate use for the one and two fracture PMO cohorts were €36,995 per QALY and €19,371 per QALY. The ICERs for teriparatide versus bisphosphonate use for the one and two fracture GIOP cohorts were €20,826 per QALY and €15,155 per QALY, respectively. Conclusions The selection of teriparatide versus oral bisphosphonates as a first-line treatment for the high risk PMO

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

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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.

Bisphosphonates, atherosclerosis and vascular calcification: update and systematic review of clinical studies

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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

Bis-phosphonate sequestering agents. Synthesis and preliminary evaluation for in vitro and in vivo uranium(VI) chelation

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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)

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

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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

Cortical Reorganisation during a 30-Week Tinnitus Treatment Program.

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Catherine M McMahon

Full Text Available Subjective tinnitus is characterised by the conscious perception of a phantom sound. Previous studies have shown that individuals with chronic tinnitus have disrupted sound-evoked cortical tonotopic maps, time-shifted evoked auditory responses, and altered oscillatory cortical activity. The main objectives of this study were to: (i compare sound-evoked brain responses and cortical tonotopic maps in individuals with bilateral tinnitus and those without tinnitus; and (ii investigate whether changes in these sound-evoked responses occur with amelioration of the tinnitus percept during a 30-week tinnitus treatment program. Magnetoencephalography (MEG recordings of 12 bilateral tinnitus participants and 10 control normal-hearing subjects reporting no tinnitus were recorded at baseline, using 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz tones presented monaurally at 70 dBSPL through insert tube phones. For the tinnitus participants, MEG recordings were obtained at 5-, 10-, 20- and 30- week time points during tinnitus treatment. Results for the 500 Hz and 1000 Hz sources (where hearing thresholds were within normal limits for all participants showed that the tinnitus participants had a significantly larger and more anteriorly located source strengths when compared to the non-tinnitus participants. During the 30-week tinnitus treatment, the participants' 500 Hz and 1000 Hz source strengths remained higher than the non-tinnitus participants; however, the source locations shifted towards the direction recorded from the non-tinnitus control group. Further, in the left hemisphere, there was a time-shifted association between the trajectory of change of the individual's objective (source strength and anterior-posterior source location and subjective measures (using tinnitus reaction questionnaire, TRQ. The differences in source strength between the two groups suggest that individuals with tinnitus have enhanced central gain which is not significantly influenced by

Cortical Reorganisation during a 30-Week Tinnitus Treatment Program

Science.gov (United States)

McMahon, Catherine M.; Ibrahim, Ronny K.; Mathur, Ankit

2016-01-01

Subjective tinnitus is characterised by the conscious perception of a phantom sound. Previous studies have shown that individuals with chronic tinnitus have disrupted sound-evoked cortical tonotopic maps, time-shifted evoked auditory responses, and altered oscillatory cortical activity. The main objectives of this study were to: (i) compare sound-evoked brain responses and cortical tonotopic maps in individuals with bilateral tinnitus and those without tinnitus; and (ii) investigate whether changes in these sound-evoked responses occur with amelioration of the tinnitus percept during a 30-week tinnitus treatment program. Magnetoencephalography (MEG) recordings of 12 bilateral tinnitus participants and 10 control normal-hearing subjects reporting no tinnitus were recorded at baseline, using 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz tones presented monaurally at 70 dBSPL through insert tube phones. For the tinnitus participants, MEG recordings were obtained at 5-, 10-, 20- and 30- week time points during tinnitus treatment. Results for the 500 Hz and 1000 Hz sources (where hearing thresholds were within normal limits for all participants) showed that the tinnitus participants had a significantly larger and more anteriorly located source strengths when compared to the non-tinnitus participants. During the 30-week tinnitus treatment, the participants’ 500 Hz and 1000 Hz source strengths remained higher than the non-tinnitus participants; however, the source locations shifted towards the direction recorded from the non-tinnitus control group. Further, in the left hemisphere, there was a time-shifted association between the trajectory of change of the individual’s objective (source strength and anterior-posterior source location) and subjective measures (using tinnitus reaction questionnaire, TRQ). The differences in source strength between the two groups suggest that individuals with tinnitus have enhanced central gain which is not significantly influenced by the

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.

Short, frequent, 5-days-per-week, in-center hemodialysis versus 3-days-per week treatment: a randomized crossover pilot trial through the Midwest Pediatric Nephrology Consortium.

Science.gov (United States)

Laskin, Benjamin L; Huang, Guixia; King, Eileen; Geary, Denis F; Licht, Christoph; Metlay, Joshua P; Furth, Susan L; Kimball, Tom; Mitsnefes, Mark

2017-08-01

No controlled trials in children with end-stage kidney disease have assessed the benefits of more frequently administered hemodialysis (HD). We conducted a multicenter, crossover pilot trial to determine if short, more frequent (5 days per week) in-center HD was feasible and associated with improvements in blood pressure compared with three conventional HD treatments per week. Because adult studies have not controlled for the weekly duration of dialysis, we fixed the total treatment time at 12 h a week of dialysis during two 3-month study periods; only frequency varied from 5 to 3 days per week between study periods. Eight children (median age 16.7 years) consented at three children's hospitals. The prespecified primary composite outcome was a sustained 10% decrease in systolic blood pressure and/or a decrease in antihypertensive medications relative to each study period's baseline. Among the six patients completing both study periods, five (83.3%) experienced the primary outcome during HD performed 5 days per week but not 3 days per week; one of the six (16.7%) achieved that outcome during 3-day but not 5-day (p = 0.22) per week HD. During 5-day HD, all patients had significantly more treatments during which their pre-HD systolic (p = 0.01) or diastolic (p = 0.01) blood pressure was 10% lower than baseline. We observed that more frequent HD sessions per week was feasible and associated with improved blood pressure control, but barriers to changing thrice-weekly standard of care include financial reimbursement and the time demands associated with more frequent treatments.

The Electroporation as a Tool for Studying the Role of Plasma Membrane in the Mechanism of Cytotoxicity of Bisphosphonates and Menadione.

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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

Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis.

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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.

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.

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.

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.

Macrofilaricidal Activity in Wuchereria bancrofti after 2 Weeks Treatment with a Combination of Rifampicin plus Doxycycline

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Alexander Yaw Debrah

2011-01-01

Full Text Available Infection with the filarial nematode Wuchereria bancrofti can lead to lymphedema, hydrocele, and elephantiasis. Since adult worms cause pathology in lymphatic filariasis (LF, it is imperative to discover macrofilaricidal drugs for the treatment of the infection. Endosymbiotic Wolbachia in filariae have emerged as a new target for antibiotics which can lead to macrofilaricidal effects. In Ghana, a pilot study was carried out with 39 LF-infected men; 12 were treated with 200 mg doxycycline/day for 4 weeks, 16 were treated with a combination of 200 mg doxycycline/day + 10 mg/kg/day rifampicin for 2 weeks, and 11 patients received placebo. Patients were monitored for Wolbachia and microfilaria loads, antigenaemia, and filarial dance sign (FDS. Both 4-week doxycycline and the 2-week combination treatment reduced Wolbachia load significantly. At 18 months posttreatment, four-week doxycycline resulted in 100% adult worm loss, and the 2-week combination treatment resulted in a 50% adult worm loss. In conclusion, this pilot study with a combination of 2-week doxycycline and rifampicin demonstrates moderate macrofilaricidal activity against W. bancrofti.

Utility of radius bone densitometry for the treatment of osteoporosis with once-weekly teriparatide therapy

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Harumi Nakayama

2018-03-01

Full Text Available Objectives: As clinics that treat patients with osteoporosis do not usually have central dual-energy X-ray absorptiometry (DXA, bone density is often measured with radial DXA. However, no long-term evidence exists for radius bone density outcomes following treatment with once-weekly teriparatide in actual medical treatment. Methods: We evaluated changes in bone density at 6-, 12-, and 18-month intervals using radial DXA in patients treated with once-weekly teriparatide for more than 6 months. Results: A significant increase in bone mineral density (BMD was observed at the 1/3 and 1/10 radius sites 12 months after the initiation of once-weekly teriparatide. We also observed that the rate of change in BMD was greater at the distal 1/10 radius than at the 1/3 radius. Conclusions: Considering these points, the effect of once-weekly teriparatide therapy can be observed at the radius. In clinics that do not have central DXA, but instead have radial DXA, these findings can help to evaluate the effect of once-weekly teriparatide treatment on osteoporosis. Keywords: Once-weekly teriparatide, Osteoporosis, Radius, Dual-energy X-ray absorptiometry

Updated recommendations for managing the care of patients receiving oral bisphosphonate therapy: an advisory statement from the American Dental Association Council on Scientific Affairs.

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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.

Evaluation of a four- versus six-week length of stay in the Navy's alcohol treatment program.

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Trent, L K

1998-05-01

Attempts to balance escalating health care costs with resource downsizing have prompted alcohol treatment directors in the U.S. Navy to consider reducing the standard length of stay in treatment. The objectives of this study were to (1) determine whether a 4-week inpatient treatment program is as effective as a 6-week program, and (2) explore the potential for matching patients to a 4- or 6-week program according to the severity of their condition at intake. A total of 2,823 active-duty alcohol-dependent inpatients (2,685 men, 138 women) at 12 Navy treatment facilities participated in the evaluation. All facilities conducted a 6-week program until data had been collected for 1,380 participants; they then switched to a 4-week program (n = 1,443). Background information and clinical profile were obtained when patients entered treatment; 1-year outcome data (e.g., alcohol use, behavior problems, job performance, quality of life) were obtained from participants, work supervisors and aftercare advisors. Hierarchical multiple regression analyses were used to assess the effect of length of stay on outcome and to examine patient-program interactions. The single best predictor of success at 1 year was months of aftercare attendance. Program membership failed to explain any of the observed differences in the criterion measures, once the effects of other predictors had been taken into account. Severity of condition and patient-program interactions were likewise nonsignificant. It was concluded that a reduction in length of stay from 6 weeks to 4 weeks in the Navy's inpatient alcohol treatment program would not have an adverse effect on outcome.

Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up.

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Wilson, Darrell M; Abrams, Stephanie H; Aye, Tandy; Lee, Phillip D K; Lenders, Carine; Lustig, Robert H; Osganian, Stavroula V; Feldman, Henry A

2010-02-01

Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported. To test the hypothesis that 48 weeks of daily metformin hydrochloride extended release (XR) therapy will reduce body mass index (BMI) in obese adolescents, as compared with placebo. Multicenter, randomized, double-blind, placebo-controlled clinical trial. The 6 centers of the Glaser Pediatric Research Network from October 2003 to August 2007. Obese (BMI > or = 95th percentile) adolescents (aged 13-18 years) were randomly assigned to the intervention (n = 39) or placebo groups. Intervention Following a 1-month run-in period, subjects following a lifestyle intervention program were randomized 1:1 to 48 weeks' treatment with metformin hydrochloride XR, 2000 mg once daily, or an identical placebo. Subjects were monitored for an additional 48 weeks. Main Outcome Measure Change in BMI, adjusted for site, sex, race, ethnicity, and age and metformin vs placebo. After 48 weeks, mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment. No significant effects of metformin on body composition, abdominal fat, or insulin indices were observed. Metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program. clinicaltrials.gov Identifiers: NCT00209482 and NCT00120146.

Bisphosphonate-associated osteonecrosis of jaw reoccurrence after methotrexate therapy: a case report.

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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.

Osteonecrose maxilar em pacientes portadores de doenças neoplásicas sob uso de bisfosfonatos Jaw osteonecrosis in patients with neoplastic diseases taking bisphosphonates

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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

Synergistic effects of bisphosphonate and calcium phosphate nanoparticles on peri-implant bone responses in osteoporotic rats.

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Alghamdi, Hamdan S; Bosco, Ruggero; Both, Sanne K; Iafisco, Michele; Leeuwenburgh, Sander C G; Jansen, John A; van den Beucken, Jeroen J J P

2014-07-01

The prevalence of osteoporosis will increase within the next decades due to the aging world population, which can affect the bone healing response to dental and orthopedic implants. Consequently, local drug targeting of peri-implant bone has been proposed as a strategy for the enhancement of bone-implant integration in osteoporotic conditions. In the present study, an established in-vivo femoral condyle implantation model in osteoporotic and healthy bone is used to analyze the osteogenic capacity of titanium implants coated with bisphosphonate (BP)-loaded calcium phosphate nanoparticles (nCaP) under compromised medical conditions. After 4 weeks of implantation, peri-implant bone volume (%BV; by μCT) and bone area (%BA; by histomorphometry) were significantly increased within a distance of 500 μm from implant surfaces functionalized with BP compared to control implants in osteoporotic and healthy conditions. Interestingly, the deposition of nCaP/BP coatings onto implant surfaces increased both peri-implant bone contact (%BIC) and volume (%BV) compared to the deposition of nCaP or BP coatings individually, in osteoporotic and healthy conditions. The results of real-time PCR revealed similar osteogenic gene expression levels to all implant surfaces at 4-weeks post-implantation. In conclusion, simultaneous targeting of bone formation (by nCaP) and bone resorption (by BP) using nCaP/BP surface coatings represents an effective strategy for synergistically improvement of bone-implant integration, especially in osteoporotic conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

The case of David: on the couch for sixty minutes, nine years of once-a-week treatment.

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Kavaler-Adler, Susan

2005-06-01

This paper illustrates a unique case of object relations psychoanalytic psychotherapy on a once-a-week treatment basis. The work of developmental mourning that would be thought to require two to five sessions a week was accomplished on a once-a-week basis. The analyst adjusted the treatment hour, in this one case, to 60 minutes, as opposed to the 45- or 50-minute hour. When treatment began, the analyst made an intuitive judgment to increase the patient's one session a week--which the patient made clear was all he was ready to do--to 60 minutes. The analyst made time in her practice for this 60-minute session and has continued with the patient using this format for 9 years of treatment. This had led up to the current stage of treatment, which has been so critical to the patient's self-integration process.

Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α.

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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

Tratamiento con bisfosfonatos y fracturas atípicas Treatment with bisphosphonates and atypical fractures

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Francisco R. Spivacow

2009-12-01

remodeling could be the microdamage accumulation, and paradoxically the occurrence of new and atypical fractures. Until now, few cases of these unusual fractures have been reported in the international literature. All these patients shared some common characteristics, apart from the chronic use of bisphosphonates for the treatment of osteoporosis. The more frequent is the atypical location of the fractures. Since the majority happened in one or both femoral shafts, others bones such as sacrum, ischium, ribs and pubic rami could be affected. The fractures were atraumatic or caused by minimal trauma and, in some cases, it was preceded by a prodromal pain in the affected area. All cases had biochemical or histomorphometric evidence of low bone turnover. The aim of this paper is to report three new cases of patients that fulfill with the diagnostic criteria of this new entity, two of them with femoral shaft fractures and the remainder with a pelvis one.

A Comparison of Daily Versus Weekly Electronic Cigarette Users in Treatment for Substance Abuse.

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Gubner, Noah R; Pagano, Anna; Tajima, Barbara; Guydish, Joseph

2018-04-02

This research examined electronic cigarette (e-cigarette) use by individuals in treatment for substance abuse, a population with a high prevalence of tobacco use and poor smoking cessation outcomes. We surveyed 1127 individuals from 24 substance abuse treatment centers across the United States. Bivariate analyses and logistic regression were used to examine factors associated with daily (N = 87) versus weekly (N = 81) e-cigarette use. Among the full sample, 59.8% reported any lifetime use of e-cigarettes, with 23.6% reporting past 30-day use. Daily e-cigarette users were more likely to have used second-generation, tank-type e-cigarettes, χ2(1,N = 165) = 11.54, p = .001, used more flavors overall, t(168) = 2.15, p = .03, and were more likely to report using their e-cigarette continuously throughout the day, χ2(4,N = 168) = 16.7, p = .002, compared to weekly e-cigarette users. Over half (57.7%) of the daily and weekly e-cigarette users reported having an e-cigarette device that broke. The logistic regression model adjusting for clinic type and days with poor mental health found that daily e-cigarette users were significantly more likely than weekly e-cigarette users to be from methadone clinics (adjusted odds ratio [AOR] = 2.40, p = .04), and former smokers (AOR = 6.37, p users in substance abuse treatment were more likely to be from methadone clinics and former cigarette smokers. However, the majority (73.6%) of daily e-cigarette users were current cigarette smokers. E-cigarette device type reliability (eg, breakage) may be an important factor to consider among drug treatment and other populations with lower socioeconomic status. This study found several differences in the device type, flavors, and use characteristics of daily versus weekly e-cigarette users. While majority of e-cigarette users in substance abuse treatment were current cigarette smokers, daily e-cigarette users were more likely to be former cigarette smokers. Administrators of substance abuse

Current options for the treatment of Paget’s disease of the bone

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Daniela Merlotti

2009-07-01

Full Text Available Daniela Merlotti, Luigi Gennari, Giuseppe Martini, Ranuccio NutiDepartment of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena, Siena, ItalyAbstract: Paget’s disease of bone (PDB is a chronic bone remodeling disorder characterized by increased osteoclast-mediated bone resorption, with subsequent compensatory increases in new bone formation, resulting in a disorganized mosaic of woven and lamellar bone at affected skeletal sites. This disease is most often asymptomatic but can be associated with bone pain or deformity, fractures, secondary arthritis, neurological complications, deafness, contributing to substantial morbidity and reduced quality of life. Neoplastic degeneration of pagetic bone is a relatively rare event, occurring with an incidence of less than 1%, but has a grave prognosis. Specific therapy for PDB is aimed at decreasing the abnormal bone turnover and bisphosphonates are currently considered the treatment of choice. These treatments are associated with a reduction in plasma alkaline phosphatase (ALP activity and an improvement in radiological and scintigraphic appearance and with a reduction in bone pain and bone deformity, Recently, the availability of newer, more potent nitrogen-containing bisphosphonates has improved treatment outcomes, allowing a more effective and convenient management of this debilitating disorder.Keywords: Paget’s disease of bone, bisphosphonates, aminobisphosphonates, bone remodeling

Therapies for treatment of osteoporosis in US women: cost-effectiveness and budget impact considerations.

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Tosteson, Anna N A; Burge, Russel T; Marshall, Deborah A; Lindsay, Robert

2008-09-01

To evaluate the cost-effectiveness of osteoporosis treatments for women at high fracture risk and estimate the population-level impact of providing bisphosphonate therapy to all eligible high-risk US women. Fractures, healthcare costs, and quality-adjusted life-years (QALYs) were estimated over 10 years using a Markov model. No therapy, risedronate, alendronate, ibandronate, and teriperatide (PTH) were compared among 4 risk groups. Sensitivity analyses examined the robustness of model results for 65-year-old women with low bone density and previous vertebral fracture. Women treated with a bisphosphonate experienced fewer fractures and more QALYs compared with no therapy or PTH. Total costs were lowest for the untreated cohort, followed by risedronate, alendronate, ibandronate, and PTH in all risk groups except women aged 75 years with previous fracture. The incremental cost-effectiveness of risedronate compared with no therapy ranged from cost saving for the base case to $66,722 per QALY for women aged 65 years with no previous fracture. Ibandronate and PTH were dominated in all risk groups. (A dominated treatment has a higher cost and poorer outcome.) Treating all eligible women with a bisphosphonate would cost an estimated additional $5563 million (21% total increase) and would result in 390,049 fewer fractures (35% decrease). In the highest risk group, the additional cost of therapy was offset by other healthcare cost savings. Osteoporosis treatment of high-risk women is cost-effective, with bisphosphonates providing the most benefit at lowest cost. For highest risk women, costs are offset by savings from fracture prevention.

Effect of risedronate on bone in renal transplant recipients.

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Coco, Maria; Pullman, James; Cohen, Hillel W; Lee, Sally; Shapiro, Craig; Solorzano, Clemencia; Greenstein, Stuart; Glicklich, Daniel

2012-08-01

Bisphosphonates may prevent or treat the bone loss promoted by the immunosuppressive regimens used in renal transplantation. Risedronate is a commonly used third-generation amino-bisphosphonate, but little is known about its effects on the bone health of renal transplant recipients. We randomly assigned 42 new living-donor kidney recipients to either 35 mg of risedronate weekly or placebo for 12 months. We obtained bone biopsies at the time of renal transplant and after 12 months of protocol treatment. Treatment with risedronate did not affect bone mineral density (BMD) in the overall cohort. In subgroup analyses, it tended to preserve BMD in female participants but did not significantly affect the BMD of male participants. Risedronate did associate with increased osteoid volume and trabecular thickness in male participants, however. There was no evidence for the development of adynamic bone disease. In summary, further study is needed before the use of prophylactic bisphosphonates to attenuate bone loss can be recommended in renal transplant recipients.

Implications of bisphosphonate calcium ion depletion interfering with desmosome epithelial seal in osseointegrated implants and pressure ulcers.

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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.

Pamidronate treatment for osteogenesis imperfecta in black South Africans.

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Henderson, B D; Isaac, N; Mabele, O; Khiba, S; Nkayi, A; Mokoena, T

2016-05-25

Osteogenesis imperfecta is a heritable disorder of bone connective tissue. Type III has a high incidence in the black pop-ulation of South Africa. Affected people experience numerous fractures, bone pain and progressive disability. Until the introduction of bisphosphonates to reduce fracture incidence, treatment revolved around orthopaedic and supportive care. Objective. To assess the subjective attitude of patients towards pamidronate treatment. Thirty black patients with osteogenesis imperfecta type III treated at Universitas Hospital were approached and 26 were included in this study. Patients or their parents were interviewed using a standardised researcher-administered questionnaire, either in person or by telephone. Most patients reported a reduction in symptoms, a feeling of increased wellbeing, increased strength and rated the pamidronate treatment highly. The intravenous route of administration and the side-effects experienced were bearable. Overall all patients would recommend this treatment to other affected persons. This is first study to look at bisphosphonate treatment for osteogenesis imperfecta type III in black South Africans. The treatment is well tolerated and highly rated by the patients. Reported improvements and side-effects are similar to those reported in other populations. Using this form of treatment in this population is supported by these findings.

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.

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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.

Bisphosphonate-Related Osteonecrosis of the Jaw Bone: Radiological Pattern and the Potential Role of CBCT in Early Diagnosis

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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.

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

Limited cognitive benefits in Stage +2 postmenopausal women after 6 weeks of treatment with Ginkgo biloba.

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Elsabagh, Sarah; Hartley, David E; File, Sandra E

2005-03-01

Gingko biloba has cognitive benefits both in populations suffering from dementia and after acute treatment in healthy volunteers, with some evidence indicating that those with poorer cognitive performance show greater benefit. We have previously found that 1 week of treatment with ginkgo improved attention, memory and mental flexibility in post-menopausal women, but the evidence for any beneficial effects of longer treatment is less well-established. The present study aimed to determine whether cognitive benefits, similar to those previously found after 1 week of treatment, would persist after 6 weeks of treatment, and whether those with poorer cognitive performance would benefit more. In a placebo-controlled, double-blind study, postmenopausal women (aged 51-67 years) were randomly allocated to receive a standardized extract of ginkgo (LI 1370, Lichtwer Pharma, Marlow, UK) (one capsule/day of 120 mg, n = 45) or matching placebo (n = 42) for 6 weeks. According to an established reproductive staging system, subjects were divided into those in the early (Stage +1; mean age 55 years) and late (Stage +2: mean age 61 years) stages of menopause. At baseline and after 6 weeks of treatment, subjects completed tests of mental flexibility, planning, memory and sustained attention, and ratings of mood, sleepiness, bodily and menopausal symptoms. The only significant effects of ginkgo were in the test of mental flexibility, in which there were significant menopausal stage-ginkgo interactions. This was because subjects in Stage +2 required fewer trials to complete the task and made fewer errors after ginkgo treatment, whereas those in Stage +1 showed no benefits. Subjects in Stage +2 had poorer performance at baseline compared to those in Stage +1 both in this task and the test of planning ability. The beneficial effects of ginkgo were limited to the test of mental flexibility and to those with poorer performance.

Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection

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Belknap, Robert; Holland, David; Feng, Pei-Jean; Millet, Joan-Pau; Caylà, Joan A.; Martinson, Neil A.; Wright, Alicia; Chen, Michael P.; Moro, Ruth N.; Scott, Nigel A.; Arevalo, Bert; Miró, José M.; Villarino, Margarita E.; Weiner, Marc; Borisov, Andrey S.

2017-01-01

Background Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation. Objective To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation. Design An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711) Setting Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa. Participants 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection. Intervention Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring. Measurements The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event–monitoring devices for self-administration. The main secondary outcome was adverse events. Results Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration–with–reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met

Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone.

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Acevedo, Claire; Bale, Hrishikesh; Gludovatz, Bernd; Wat, Amy; Tang, Simon Y; Wang, Mingyue; Busse, Björn; Zimmermann, Elizabeth A; Schaible, Eric; Allen, Matthew R; Burr, David B; Ritchie, Robert O

2015-12-01

Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1 mL/kg/day, 3 years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3 years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length-scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue-like) fractures. Published by Elsevier Inc.

Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study.

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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.

Bisphosphonate-Induced Osteonecrosis of the Maxilla Resembling a Persistent Endodontic Lesion.

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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.

Bisphosphonate-induced zebra lines in fibrous dysplasia of bone: histo-radiographic correlation in a case of McCune-Albright syndrome

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Corsi, Alessandro; Riminucci, Mara [Sapienza University, Department of Molecular Medicine, Rome (Italy); Ippolito, Ernesto [University of Rome Tor Vergata, Department of Orthopaedic Surgery, Rome (Italy); Robey, Pamela G. [Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (United States); Boyde, Alan [Queen Mary University of London, Dental Physical Sciences, London (United Kingdom)

2017-10-15

Bisphosphonates (BPs) are currently used in the treatment of diverse bone diseases including fibrous dysplasia of bone (FD). In pediatric patients, a radiographic consequence of cyclical administration of BPs is the development of apo-, epi-, and meta-physeal sclerotic bands, otherwise known as zebra lines, which result from the temporary inhibition of osteoclastic activity at the time of drug treatment. We report here on a child with McCune-Albright syndrome (FD in addition to hyperfunctioning endocrinopathies and skin hyperpigmentation) treated with cyclical intravenous infusions of pamidronate in which conventional radiography, contact microradiography, histology, and backscattered electron image analysis demonstrated that zebra lines formed only where bone was normal, were arrested at the boundary between FD-unaffected and FD-affected bone where bone is sclerotic, and were absent within the undermineralized FD bone. Moreover, in spite of the treatment, the FD lesions continued to expand. This case report is unique because no previously published studies correlated the radiographic and the histologic features of BP-induced zebra lines in the metaphysis of an FD-affected long bone of the limbs. (orig.)

Bisphosphonate-induced zebra lines in fibrous dysplasia of bone: histo-radiographic correlation in a case of McCune-Albright syndrome

International Nuclear Information System (INIS)

Corsi, Alessandro; Riminucci, Mara; Ippolito, Ernesto; Robey, Pamela G.; Boyde, Alan

2017-01-01

Bisphosphonates (BPs) are currently used in the treatment of diverse bone diseases including fibrous dysplasia of bone (FD). In pediatric patients, a radiographic consequence of cyclical administration of BPs is the development of apo-, epi-, and meta-physeal sclerotic bands, otherwise known as zebra lines, which result from the temporary inhibition of osteoclastic activity at the time of drug treatment. We report here on a child with McCune-Albright syndrome (FD in addition to hyperfunctioning endocrinopathies and skin hyperpigmentation) treated with cyclical intravenous infusions of pamidronate in which conventional radiography, contact microradiography, histology, and backscattered electron image analysis demonstrated that zebra lines formed only where bone was normal, were arrested at the boundary between FD-unaffected and FD-affected bone where bone is sclerotic, and were absent within the undermineralized FD bone. Moreover, in spite of the treatment, the FD lesions continued to expand. This case report is unique because no previously published studies correlated the radiographic and the histologic features of BP-induced zebra lines in the metaphysis of an FD-affected long bone of the limbs. (orig.)

[Neonatal meningitis due to Listeria monocytogenes after 3 weeks of maternal treatment during pregnancy].

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Fayol, L; Beizig, S; Le Monnier, A; Lacroze, V; Simeoni, U

2009-04-01

We report the case of a pregnant woman with listeriosis at 26 gestational weeks followed by premature labor at 30 gestational weeks. Bacterial meningitis was suspected in the neonate with ventriculitis on sonography, a high level of protein in the cerebrospinal fluid (CSF), and an identified specific bacterial genome of Listeria monocytogenes (PCR 16S rDNA and sequencing and specific amplification of L. monocytogenes hly gene) in CSF. Neonatal meningitis was complicated with cerebral venous sinus thrombosis and ventriculomegaly. Listeriosis during pregnancy can lead to severe complications in the neonate. Thus, listeriosis should be a diagnostic concern in febrile pregnant women at any stage of pregnancy. First-line treatment is based on high-dose amoxicillin (> or =6g/day) and must be used for at least 3 weeks for treatment of listeriosis during pregnancy. If the fetus survives, longer therapy until delivery can be discussed.

Poor medication adherence to bisphosphonates and high self-perception of aging in elderly female patients with osteoporosis.

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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.

Alendronate sodium hydrate (oral jelly for the treatment of osteoporosis: review of a novel, easy to swallow formulation

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Imai K

2013-06-01

Full Text Available Kazuhiro Imai Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan Abstract: Osteoporosis is a skeletal disorder characterized by loss of bone mass, decreased bone strength, and an increased risk of bone fracture. The disease progresses with age, especially in postmenopausal women. Japan is one of the most rapidly aging societies worldwide. Japanese individuals over 65 years of age constituted 23.0% of the population in 2010 and 25.1% to 25.2% as of 2013. The estimated number of people with osteoporosis in Japan is currently 13 million. Bisphosphonates increase bone mineral density by inhibiting osteoclast-mediated bone resorption, thereby reducing the risk of fractures. Alendronate sodium hydrate (alendronate is a bisphosphonate that potently inhibits bone resorption and is used to treat osteoporosis. Sufficient water is required to take an alendronate oral tablet; insufficient water could result in digestive system diseases, such as esophageal ulceration. Elderly patients with swallowing difficulty may choke on the tablet. Taking a tablet with oral jelly is a method to prevent digestive system disease and reduce the choking hazard. Once-weekly alendronate oral jelly was approved in 2012 by the Ministry of Health, Labour, and Welfare of Japan as the world's first drug for osteoporosis in a jelly formulation. It consists of a jelly portion and an air portion. The jelly formulation is smoothly discharged by pushing the air portion. Therefore, elderly patients with physical disabilities are able to easily take all of the jelly formulation from the package. In this review, this new formulation of alendronate sodium hydrate (oral jelly is introduced and discussed in terms of osteoporosis treatment. This new formulation provides an alternative so that patients may select a method of dosing tailored to their preferences. Management of osteoporosis involves assessing fracture risk and preventing

Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta.

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Grafe, Ingo; Alexander, Stefanie; Yang, Tao; Lietman, Caressa; Homan, Erica P; Munivez, Elda; Chen, Yuqing; Jiang, Ming Ming; Bertin, Terry; Dawson, Brian; Asuncion, Franklin; Ke, Hua Zhu; Ominsky, Michael S; Lee, Brendan

2016-05-01

Osteogenesis imperfecta (OI) is characterized by low bone mass, poor bone quality, and fractures. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely correct the bone phenotype, and seem to be less effective in adults. Sclerostin-neutralizing antibodies (Scl-Ab) have been shown to be beneficial in animal models of osteoporosis, and dominant OI resulting from mutations in the genes encoding type I collagen. However, Scl-Ab treatment has not been studied in models of recessive OI. Cartilage-associated protein (CRTAP) is involved in posttranslational type I collagen modification, and its loss of function results in recessive OI. In this study, we treated 1-week-old and 6-week-old Crtap(-/-) mice with Scl-Ab for 6 weeks (25 mg/kg, s.c., twice per week), to determine the effects on the bone phenotype in models of "pediatric" and "young adult" recessive OI. Vehicle-treated Crtap(-/-) and wild-type (WT) mice served as controls. Compared with control Crtap(-/-) mice, micro-computed tomography (μCT) analyses showed significant increases in bone volume and improved trabecular microarchitecture in Scl-Ab-treated Crtap(-/-) mice in both age cohorts, in both vertebrae and femurs. Additionally, Scl-Ab improved femoral cortical parameters in both age cohorts. Biomechanical testing showed that Scl-Ab improved parameters of whole-bone strength in Crtap(-/-) mice, with more robust effects in the week 6 to 12 cohort, but did not affect the increased bone brittleness. Additionally, Scl-Ab normalized the increased osteoclast numbers, stimulated bone formation rate (week 6 to 12 cohort only), but did not affect osteocyte density. Overall, our findings suggest that Scl-Ab treatment may be beneficial in the treatment of recessive OI caused by defects in collagen posttranslational modification. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.

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...

Use of bisphosphonate might be important to improve bone mineral density in patients with rheumatoid arthritis even under tight control: the TOMORROW study.

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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.

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

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

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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.

Comparison of the efficacy of 4- and 8-week lansoprazole treatment for ESD-induced gastric ulcers: a randomized, prospective, controlled study.

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Park, Ji Hoon; Baek, Eun Kyung; Choi, Chang Hwan; Lee, Kyung Hun; Kim, Beom Jin; Kim, Jeong Wook; Kim, Jae Gyu; Chang, Sae Kyung

2014-01-01

Although endoscopic submucosal dissection (ESD) is widely used to treat gastric neoplasms, there is no consensus for the optimal treatment for ESD-induced ulcers. We compared efficacy between 4 and 8 weeks of lansoprazole treatment for iatrogenic gastric ulcers that developed after ESD. Eighty-four patients who were diagnosed with gastric adenoma or early gastric cancer were enrolled and randomly assigned to treatment with lansoprazole (30 mg/day) for 4 or 8 weeks. Eight weeks after ESD, we conducted follow-up endoscopy to compare ulcer stage and ulcer reduction ratio (dividing the ulcer dimension at 8 weeks by the initial ulcer dimension) between the two groups. From the 84 patients, 69 patients were included in the final analysis, with 34 in the 4-week group and 35 in the 8-week group. Eight weeks after ESD, there were no significant difference observed between the two groups in terms of the ulcer stage (68 % in the scar stage in the 4-week group vs. 69 % in the 8-week group, P = 0.93) or the ulcer reduction ratio (0.0081 ± 0.015 in the 4-week group vs. 0.0037 ± 0.008 in the 8-week group, P = 0.15). Also, in the subgroup analysis among the patients with large ulcers (>30 mm), those parameters were not different. For ESD-induced gastric ulcers, treatment with lansoprazole for 4 weeks was as effective as treatment for 8 weeks. Considering cost-effectiveness, proton pump inhibitor therapy for 4 weeks may be sufficient for ESD-induced gastric ulcers.

Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults.

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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.

Absorption of silicon from artesian aquifer water and its impact on bone health in postmenopausal women: a 12 week pilot study

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Lee Tsz

2010-10-01

Full Text Available Abstract Background Decreased bone mineral density and osteoporosis in postmenopausal women represents a growing source of physical limitations and financial concerns in our aging population. While appropriate medical treatments such as bisphosphonate drugs and hormone replacement therapy exist, they are associated with serious side effects such as osteonecrosis of the jaw or increased cardiovascular risk. In addition to calcium and vitamin D supplementation, previous studies have demonstrated a beneficial effect of dietary silicon on bone health. This study evaluated the absorption of silicon from bottled artesian aquifer water and its effect on markers of bone metabolism. Methods Seventeen postmenopausal women with low bone mass, but without osteopenia or osteoporosis as determined by dual x-ray absorptiometry (DEXA were randomized to drink one liter daily of either purified water of low-silicon content (PW or silicon-rich artesian aquifer water (SW (86 mg/L silica for 12 weeks. Urinary silicon and serum markers of bone metabolism were measured at baseline and after 12 weeks and analyzed with two-sided t-tests with p Results The urinary silicon level increased significantly from 0.016 ± 0.010 mg/mg creatinine at baseline to 0.037 ± 0.014 mg/mg creatinine at week 12 in the SW group (p = 0.003, but there was no change for the PW group (0.010 ± 0.004 mg/mg creatinine at baseline vs. 0.009 ± 0.006 mg/mg creatinine at week 12, p = 0.679. The urinary silicon for the SW group was significantly higher in the silicon-rich water group compared to the purified water group (p Conclusions These findings indicate that bottled water from artesian aquifers is a safe and effective way of providing easily absorbed dietary silicon to the body. Although the silicon did not affect bone turnover markers in the short-term, the mineral's potential as an alternative prevention or treatment to drug therapy for osteoporosis warrants further longer-term investigation

Treatment with α-Lipoic Acid over 16 Weeks in Type 2 Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading

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Hector Garcia-Alcala

2015-01-01

Full Text Available Effective treatment of diabetic sensorimotor polyneuropathy remains a challenge. To assess the efficacy and safety of α-lipoic acid (ALA over 20 weeks, we conducted a multicenter randomized withdrawal open-label study, in which 45 patients with type 2 diabetes and symptomatic polyneuropathy were initially treated with ALA (600 mg tid for 4 weeks (phase 1. Subsequently, responders were randomized to receive ALA (600 mg qd; n=16 or to ALA withdrawal (n=17 for 16 weeks (phase 2. During phase 1, the Total Symptom Score (TSS decreased from 8.9 ± 1.8 points to 3.46 ± 2.0 points. During phase 2, TSS improved from 3.7 ± 1.9 points to 2.5 ± 2.5 points in the ALA treated group (p<0.05 and remained unchanged in the ALA withdrawal group. The use of analgesic rescue medication was higher in the ALA withdrawal group than ALA treated group (p<0.05. In conclusion, in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose (600 mg tid administration of ALA, subsequent treatment with ALA (600 mg qd over 16 weeks improved neuropathic symptoms, whereas ALA withdrawal was associated with a higher use of rescue analgesic drugs. This trial is registered with ClinicalTrials.gov Identifier: NCT02439879.

Collapsing focal segmental glomerulosclerosis following long-term treatment with oral ibandronate: case report and review of literature

International Nuclear Information System (INIS)

Jia, Ning; Cormack, Fionnuala C.; Xie, Bin; Shiue, Zita; Najafian, Behzad; Gralow, Julie R.

2015-01-01

Renal toxicity has been reported with bisphosphonates such as pamidronate and zolidronate but not with ibandronate, in the treatment of breast cancer patients with bone metastasis. One of the patterns of bisphosphonate-induced nephrotoxicity is focal segmental glomerulosclerosis (FSGS) or its morphological variant, collapsing focal segmental glomerulosclerosis (CFSGS). We describe a breast cancer patient who developed heavy proteinuria (protein/creatinine ratio 9.1) and nephrotic syndrome following treatment with oral ibandronate for 29 months. CFSGS was proven by biopsy. There was no improvement 1 month after ibandronate was discontinued. Prednisone and tacrolimus were started and she experienced a decreased in proteinuria. In patient who develops ibandronate-associated CFSGS, proteinuria appears to be at least partially reversible with the treatment of prednisone and/or tacrolimus if the syndrome is recognized early and ibandronate is stopped

Administration of cetuximab every 2 weeks in the treatment of metastatic colorectal cancer

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Tabernero, Josep; Pfeiffer, Per; Cervantes, Andrés

2008-01-01

The primary purpose of this paper is to present the available evidence for the administration of cetuximab on an every-2-weeks basis in combination with irinotecan in metastatic colorectal cancer (mCRC). Cetuximab is an epidermal growth factor receptor-targeted IgG(1) monoclonal antibody...... that is approved for use in combination with irinotecan or as monotherapy in the treatment of mCRC. The currently approved dosing regimen for cetuximab is a 400-mg/m(2) initial dose followed by 250 mg/m(2) weekly. Many commonly used chemotherapy agents for mCRC (including irinotecan alone or in combination with 5......-fluorouracil [5-FU]/folinic acid [FA] and oxaliplatin plus 5-FU/FA) are administered on an every-2-weeks basis. The ability to synchronize the administration of cetuximab and concomitant chemotherapy is desirable for both patients and health care workers. A cetuximab dose of 500 mg/m(2) every 2 weeks exhibited...

Health state utilities associated with attributes of weekly injection devices for treatment of type 2 diabetes

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Louis S. Matza

2017-11-01

Full Text Available Abstract Background Glucagon-like peptide-1 (GLP-1 receptor agonists are often recommended as part of combination therapy for type 2 diabetes when oral medication does not result in sufficient glycemic control. Several GLP-1 receptor agonists are available as weekly injections. These medications vary in their injection delivery systems, and these differences could impact quality of life and treatment preference. The purpose of this study was to estimate utilities associated with attributes of injection delivery systems for weekly GLP-1 therapies. Methods Participants with type 2 diabetes in the UK valued health states in time trade-off interviews. The health states (drafted based on literature, device instructions for use, and clinician interviews had identical descriptions of type 2 diabetes, but differed in description of the treatment process. One health state described oral treatment, while six others described oral treatment plus a weekly injection. The injection health states varied in three aspects of the treatment administration process: requirements for reconstituting the medication (i.e., mixing the medication prior to the injection, waiting during medication preparation, and needle handling. Every participant valued all seven health states. Results A total of 209 participants completed interviews (57.4% male; mean age = 60.4y. The mean utility of the oral treatment health state was 0.89. All injection health states had significantly (p < 0.01 lower utilities ranging from 0.86 to 0.88. Differences among health state utilities suggest that each administration requirement had a small but measureable disutility: -0.004 (reconstitution, -0.004 (needle handling, -0.010 (reconstitution, needle handling, and -0.020 (reconstitution, waiting, needle handling. Conclusions Findings suggest it is feasible to use the TTO method to quantify preferences among injection treatment processes. It may be useful to incorporate these utility differences

Trends in the pharmacological treatment of osteoporosis in Spain from 2000 to 2008.

Science.gov (United States)

Salgueiro, M Esther; Manso, Gloria; Castells, Xavier; Jimeno, Francisco J; Ordoñez, Lucía; González, Verónica; Rodríguez, Alfonso; Capellà, Dolors

2013-01-01

To analyze the time trends in anti-osteoporosis medications consumption in Spain between 2000 and 2008 and the influence on such consumption induced by the Information Sheets related to the safety of menopausal hormone therapy and strontium ranelate published by the Spanish Agency of Medicines and Health Products (AEMPS). Purchase data of anti-osteoporosis medications from 2000 to 2008 were obtained from the Spanish Ministry of Health. This information includes the pharmacy sales data of medicinal products reimbursed by the Spanish National Health Service. Anti-osteoporosis medications consumption data were expressed as defined daily dose per 1 000 inhabitants per day in women aged 50 or more. During the study period, anti-osteoporosis medications consumption showed a continuous increase. The greatest increase was observed with bisphosphonates, particularly alendronate and risedronate in their weekly formulations. Strontium ranelate consumption was low but continuously increased and new information concerning its safety in 2007 had no effect on its consumption. The use of menopausal hormone therapy remained stable until 2003, and from then presented a continuous decrease until 2008. Raloxifene utilization increased from 2000 to 2004 and decreased thereafter. Calcitonin utilization decreased uninterruptedly and teriparatide was infrequently used. This study reports a marked change in osteoporosis treatment in Spain, which includes an important increase in anti-osteoporosis medication use, particularly of bisphosphonates and a decrease in menopausal hormone therapy use secondary to the new information about their safety. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A short 2 week dose titration regimen reduces the severity of flu-like symptoms with initial interferon gamma-1b treatment.

Science.gov (United States)

Devane, John G; Martin, Mary L; Matson, Mark A

2014-06-01

Flu-like symptoms (FLS) are commonly experienced by patients receiving interferon gamma-1b which may cause discontinuation or disruption of dosing during initial therapy or on re-initiation following a break in therapy. In contrast to Type I interferons, the impact of dose-titration on FLS has not been reported and is not a practice described or included in the approved prescribing information for interferon gamma-1b.The objective of this study was to assess the effect of a 2 week titration regimen on the severity of FLS during the initial 3 weeks of therapy with three times weekly subcutaneous injections of interferon gamma-1b. Healthy men and women were randomized into a double-blind, two-period, crossover study. Each study period was 3 weeks in duration and there was a minimum 15 day washout between treatment periods. Two treatment regimens were compared: No Titration dosing (full 50 mcg/m(2) subcutaneously [s.c.] three times weekly for 3 weeks) and Titration (15 mcg/m(2) s.c. three times weekly during week 1, 30 mcg/m(2) s.c. three times weekly during week 2 followed by the full dose of 50 mcg/m(2) s.c. three times weekly during week 3). Subjects remained in the clinic for at least 12 hours following each injection. FLS was based on a composite score for fever, chills, tiredness and muscle aches assessed at baseline and 4, 8 and 12 hours following each injection. Acetaminophen was allowed at the discretion of the PI. The primary endpoint was the change from baseline in FLS severity at 8 hours averaged over the 3 weeks of treatment. Additional endpoints included FLS at 4 and 12 hours, individual flu-like symptoms, rates of discontinuation, incidence of FLS and acetaminophen use. NCT 01929382. Of the 40 subjects randomized, there were 15 (37.5%) discontinuations. Titration resulted in a significant reduction in FLS severity at 8 hours (p = 0.023) averaged over the 3 week treatment period. The difference in 3 week FLS severity reflects differences

Sclerostin antibody treatment improves the bone phenotype of Crtap−/− mice, a model of recessive Osteogenesis Imperfecta

Science.gov (United States)

Grafe, Ingo; Alexander, Stefanie; Yang, Tao; Lietman, Caressa; Homan, Erica P; Munivez, Elda; Chen, Yuqing; Jiang, Ming Ming; Bertin, Terry; Dawson, Brian; Asuncion, Franklin; Ke, Hua Zhu; Ominsky, Michael S; Lee, Brendan

2016-01-01

Osteogenesis Imperfecta (OI) is characterized by low bone mass, poor bone quality and fractures. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely correct the bone phenotype, and seem to be less effective in adults. Sclerostin neutralizing antibodies (Scl-Ab) have been shown to be beneficial in animal models of osteoporosis, and dominant OI resulting from mutations in the genes encoding type I collagen. However, Scl-Ab treatment has not been studied in models of recessive OI. Cartilage associated protein (CRTAP) is involved in posttranslational type I collagen modification, and its loss of function results in recessive OI. In this study, we treated 1 and 6 week old Crtap−/− mice with Scl-Ab for 6 weeks (25 mg/kg, s.c., twice per week), to determine the effects on the bone phenotype in models of “pediatric” and “young adult” recessive OI. Vehicle treated Crtap−/− and wildtype (WT) mice served as controls. Compared with control Crtap−/− mice, microCT analyses showed significant increases in bone volume and improved trabecular microarchitecture in Scl-Ab treated Crtap−/− mice in both age cohorts, in both vertebrae and femurs. Additionally, Scl-Ab improved femoral cortical parameters in both age cohorts. Biomechanical testing showed that Scl-Ab improved parameters of whole bone strength in Crtap−/− mice, with more robust effects in the week 6–12 cohort, but did not affect the increased bone brittleness. Additionally, Scl-Ab normalized the increased osteoclast numbers, stimulated bone formation rate (week 6–12 cohort only), but did not affect osteocyte density. Overall, our findings suggest that Scl-Ab treatment may be beneficial in the treatment of recessive OI caused by defects in collagen post-translational modification. PMID:26716893

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....

Comparison of once-daily versus twice-weekly terbinafine administration for the treatment of canine Malassezia dermatitis - a pilot study.

Science.gov (United States)

Berger, Darren J; Lewis, Thomas P; Schick, Anthea E; Stone, Richard T

2012-10-01

Terbinafine, an allylamine antifungal, is used in pulsatile dose regimens for superficial mycoses in human medicine. To compare the clinical efficacy of twice-weekly versus once-daily terbinafine administration to determine whether preliminary proof-of-concept evidence exists for pulsatile administration of terbinafine in the treatment of canine Malassezia dermatitis and to determine whether twice-weekly treatment results in fewer clinical and owner-perceived adverse events. Twenty client-owned dogs with Malassezia dermatitis. In this randomized, single-blinded clinical trial, dogs were randomly assigned to receive terbinafine (30 mg/kg) either once daily for 21 days (n = 10) or once daily on two consecutive days per week for six doses (n = 10). On day 0 and day 21, a mean yeast count was calculated from eight anatomical locations via adhesive tape-strip cytology, clinical lesion scores were assigned to the same locations, and owners assessed pruritus using a visual analog scale. There was no significant difference between treatment groups with respect to the reduction in mean yeast count (P = 0.343) and clinical lesion scores (P = 0.887). Pruritus measured by visual analog scale was significantly decreased in the twice-weekly treatment group compared with the daily treatment group (P = 0.047). Seven of 20 dogs had a clinically measurable or owner-reported adverse event during treatment that included gastrointestinal disturbances, excessive panting and elevated hepatic enzymes, with no significant difference noted between treatment groups. This pilot study indicates that twice-weekly terbinafine administration may be an effective alternative treatment for canine Malassezia dermatitis and merits further investigation. © 2012 The Authors. Veterinary Dermatology © 2012 ESVD and ACVD.

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.

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

Darbepoetin alfa once every 2 weeks for treatment of anemia in dialysis patients

DEFF Research Database (Denmark)

Mann, J; Kessler, M; Villa, Giulio Palludan

2007-01-01

AIM: Darbepoetin alfa has a longer half-life than epoetin-(EPO) alfa or beta, allowing administration at less frequent intervals for the treatment of renal anemia. The aim of the present analysis was to evaluate the efficacy and tolerability of an every-2-week (Q2W) schedule of darbepoetin alfa...

Variability of skin autofluorescence measurement over 6 and 12 weeks and the influence of benfotiamine treatment.

Science.gov (United States)

Stirban, Alin; Pop, Alexandra; Fischer, Annelie; Heckermann, Sascha; Tschoepe, Diethelm

2013-09-01

Measurements of skin autofluorescence (SAF) allow for a simple and noninvasive quantification of tissue advanced glycation end-products (AGEs), a marker linked to the risk of diabetes complications. The aim of this study was to test the repeatability of SAF over 6 and 12 weeks and to test whether benfotiamine, a thiamine prodrug suggested to reduce AGEs formation under hyperglycemic conditions, is able to attenuate SAF when administered over 6 weeks. In a double-blind, placebo-controlled, randomized, crossover study, 22 patients with type 2 diabetes mellitus (T2DM) received 900 mg/day benfotiamine or placebo for 6 weeks (washout period of 6 weeks between). At the beginning and at the end of each treatment period, SAF was assessed in the fasting state, as well as 2, 4, and 6 h following a mixed test meal. The respective intra-individual and inter-individual variability of fasting SAF was 6.9% and 24.5% within 6 weeks and 10.9% and 23.1% within 12 weeks. The respective variability calculated for triplicate comparisons was 9.9% and 27.7%. A short-term therapy with benfotiamine did not influence SAF significantly, nor did we find a significant postprandial SAF increase. In patients with T2DM, repeated, timely spaced SAF measurements have an intra-subject variability of below 11%. Using these data, sample sizes were calculated for interventional studies aiming at reducing SAF. Benfotiamine treatment for 6 weeks did not significantly influence SAF; for this, a longer-term therapy is probably needed.

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

Effects of early surfactant treatment persisting for one week after lung transplantation in rats

NARCIS (Netherlands)

Erasmus, ME; Hofstede, GJH; Petersen, AH; Haagsman, HP; Oetomo, SB; Prop, J

We investigated whether pulmonary surfactant in rat lung transplants recovered during the first week post-transplantation, along with symptoms of the reimplantation response, and whether this recovery was affected by early surfactant treatment. The severity of pulmonary injury was varied by

Treatment with 4Jointz reduces knee pain over 12 weeks of treatment in patients with clinical knee osteoarthritis: a randomised controlled trial.

Science.gov (United States)

Laslett, L L; Quinn, S J; Darian-Smith, E; Kwok, M; Fedorova, T; Körner, H; Steels, E; March, L; Jones, G

2012-11-01

To assess the efficacy of thrice daily topical 4Jointz utilizing Acteev technology (a combination of a standardized comfrey extract and a pharmaceutical grade tannic acid, 3.5 g/day) on osteoarthritic knee pain, markers of inflammation and cartilage breakdown over 12 weeks. Adults aged 50-80 years (n = 133) with clinical knee OA were randomised to receive 4Jointz or placebo in addition to existing medications. Pain and function were measured using a visual analogue scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) scale at baseline, 4, 8 and 12 weeks. Inflammation was measured analysing IL-6 expression and CTX-2 presence as representative for cartilage breakdown using ELISA, at baseline and 12 weeks. Pain scores significantly reduced in the group who received 4Jointz compared to the group who received placebo after 12 weeks using both the VAS (-9.9 mm, P = 0.034) and the KOOS pain scale (+5.7, P = 0.047). Changes in IL-6 and CTX-2 were not significant (-0.04, P = 0.5; -0.01, P = 0.68). Post-hoc analyses suggested that treatment may be most effective in women (VAS -16.8 mm, P = 0.008) and those with milder radiographic osteoarthritis (OA) (VAS -16.1 mm, P = 0.009). Rates of adverse events were similar in both groups, excepting local rash that was more common amongst participants receiving 4Jointz (21% vs 1.6%, IRR 13.2, P = 0.013), but only 26% (n = 4) of participants with rashes discontinued treatment. There were no changes in systemic blood results. Topical treatment using 4Jointz reduced pain but had no effect on inflammation or cartilage breakdown over 12 weeks of treatment. Australia and New Zealand Clinical Trials registry ACTRN12610000877088. Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Bisfosfonatassocieret osteonekrose i kaeberne hos patienter med myelomatose

DEFF Research Database (Denmark)

Lund, Thomas; Gregersen, Henrik; Vangsted, Annette

2009-01-01

of bisphosphonate therapy and with the potency of the used bisphosphonate. BON usually develops after tooth extraction or other oral surgery, and has proven difficult to treat. Optimal dental hygiene should be ensured prior to treatment initiation where possible, and once bisphosphonate treatment is instituted...

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.

Prophylactic pamidronate partially protects from glucocorticoid-induced bone loss in the mdx mouse model of Duchenne muscular dystrophy.

Science.gov (United States)

Yoon, Sung-Hee; Chen, Jinghan; Grynpas, Marc D; Mitchell, Jane

2016-09-01

Glucocorticoids are extensively used to treat patients with Duchenne muscular dystrophy because of their ability to delay muscle damage, prolong ambulation and extend life. However, use of glucocorticoids significantly increases bone loss, fragility and fractures. To determine if antiresorptive bisphosphonates could prevent the effects of glucocorticoids on bone quality, we used dystrophic mdx mice treated with the glucocorticoid prednisone during 8weeks of rapid bone growth from 5 to 13weeks of age and treated some mice with the bisphosphonate pamidronate during the first two weeks of prednisone administration. Prednisone reduced long bone growth, decreased cortical bone thickness and area and decreased the strength of the femurs. Pamidronate treatment protected mice from cortical bone loss but did not increase bone strength. The combination of prednisone and pamidronate inhibited remodeling of metaphyseal trabecular bone with large numbers of trabeculae containing remnants of calcified cartilage. Prednisone improved muscle strength in the mdx mice and decreased serum creatine kinase with evidence of improved muscle histology and these effects were maintained in mice treated with pamidronate. Copyright © 2016. Published by Elsevier Inc.

The efficacy of 12 weeks non-surgical treatment for patients not eligible for total knee replacement

DEFF Research Database (Denmark)

Skou, Søren Thorgaard; Rasmussen, Sten; Laursen, Mogens Berg

2015-01-01

OBJECTIVE: To compare the efficacy of a 12-week non-surgical treatment program with usual care in patients with knee osteoarthritis (OA) not eligible for total knee replacement (TKR). METHOD: This two-arm parallel group assessor-blinded randomized controlled trial (RCT) included 100 adults from...... secondary care with knee OA, confirmed by radiography (Kellgren-Lawrence grade ≥1), but not eligible for a TKR. The 12-week non-surgical treatment program consisted of individualized progressed neuromuscular exercise, patient education, insoles, dietary advice and prescription of pain medication...... if indicated, while usual care comprised two leaflets with information and advice on knee OA and recommended treatments. The primary outcome was the change from baseline to 12 months in the Knee injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the KOOS subscales of pain...

A radiotherapeutic clinical trial of twice per week vs. five times per week in oral cancer

International Nuclear Information System (INIS)

Handa, K.; Edoliya, T.N.; Pandey, R.P.; Agarwal, Y.C.; Sinha, N.

1980-01-01

135 cases of oral cancer have been treated by two fractions per week, and the results are compared with 115 approximately identical cases treated by conventional five days a week schedule with other parameters being identical. Radical irradiation was done by 6000 to 6500 rd in 6-6 1/2 weeks (NSD 1800-1900 ret) and palliative dose was 4500 R4 weeks (NSD 1532 ret). Tumour regression was found markedly superior by conventional regime in radically irradiated cases but much less superior for palliative treatment. Acute and late reaction as well as tumour control at 1 year was better with daily treatment, more so in cases treated for radical cure, while in palliative treatment, the superiority of daily regime was less marked. Our study provides evidence that only for palliation in advanced cases, radiation therapy by 2 fractions a week can be alternatively used. (orig.) [de

Weekly, low-dose docetaxel combined with estramustine for Japanese castration-resistant prostate cancer: its efficacy and safety profile compared with tri-weekly standard-dose treatment.

Science.gov (United States)

Nakai, Yasutomo; Nishimura, Kazuo; Nakayama, Masashi; Uemura, Motohide; Takayama, Hitoshi; Nonomura, Norio; Tsujimura, Akira

2014-02-01

We retrospectively investigated the efficacy and safety profile of weekly low-dose docetaxel (DTX) with estramustine in comparison with triweekly standard-dose DTX treatment for Japanese patients with castration-resistant prostate cancer (CRPC). Between April 2002 and January 2011, 75 CRPC patients were treated with triweekly DTX (60-75 mg/m(2) every 3 weeks) (standard-dose group), and 76 CRPC patients were treated with weekly low-dose DTX (20-30 mg/m(2) on days 2 and 9 with estramustine 560 mg on days 1-3 and 8-10) every 3 weeks (low-dose group). Prostate-specific antigen (PSA) response and progression-free and overall survival were analyzed in each group. Median serum PSA level of the standard-dose group and low-dose group was 25.0 and 35.5 ng/ml, respectively. In the standard-dose and low-dose groups, 57.8 and 65.2 % of patients, respectively, achieved a PSA decline ≥ 50 %. There was no significant difference in either median time to progression between the standard-dose group (10.0 months) and low-dose group (7.1 months) or in median duration of survival between the standard-dose group (24.2 months) and low-dose group (30.6 months). Multivariate analysis with a Cox proportional hazards regression model showed that DTX treatment protocol did not influence the risk of death. Incidences of grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia were significantly higher in the standard-dose versus low-dose group (58.7 vs. 7.9 %, 16.0 vs. 3.9 %, and 8.0 vs. 0 %, respectively). For Japanese CRPC patients, weekly low-dose DTX combined with estramustine has similar efficacy to standard-dose DTX but with fewer adverse events.

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...

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)

Treatment of bone loss in osteopenic patients with Crohn's disease: a double-blind, randomised trial of oral risedronate 35 mg once weekly or placebo, concomitant with calcium and vitamin D supplementation.

Science.gov (United States)

van Bodegraven, Ad A; Bravenboer, Nathalie; Witte, Birgit I; Dijkstra, Gerard; van der Woude, C Janneke; Stokkers, Pieter C M; Russel, Maurice G; Oldenburg, Bas; Pierik, Marieke; Roos, Jan C; van Hogezand, Ruud A; Dik, Vincent K; Oostlander, Angela E; Netelenbos, J Coen; van de Langerijt, Lex; Hommes, Daniel W; Lips, Paul

2014-09-01

Osteoporosis and fractures are frequently encountered in patients with Crohn's disease. In order to prevent fractures, treatment with bone protecting drugs appears warranted early in the course of bone disease when bone loss is not yet prominent. We therefore aimed to demonstrate a beneficial effect on bone density of the bisphosphonate risedronate in osteopenic Crohn's disease patients. This double-blind, placebo-controlled randomised trial of risedronate with calcium and vitamin D supplementation was performed in osteopenic Crohn's disease patients. Patients were treated for 2 years with follow-up after 3 and after every 6 months. Disease characteristics and activity and bone turnover markers were assessed at all visits; dual x-ray absorptiometry was performed at baseline, 12 and 24 months; radiographs of the spine at baseline and 24 months. Of 132 consenting patients, 131 were randomised (67 placebo and 64 risedronate). Patient characteristics were similar in both groups, although the risedronate group was slightly heavier (body mass index 24.3 vs 23.0 kg/m(2)). Bone mineral density at lumbar spine increased 0.04 g/cm(2) on average in the risedronate group versus 0.01 g/cm(2) in the placebo group (p=0.007). The mean increase in total hip bone mineral density was 0.03 versus 0.01 g/cm(2), respectively (p=0.071). Fracture prevalence and incidence were similar. Change of T-scores and concentrations of bone turnover markers were consistent with a beneficial effect of risedronate when compared with placebo. The effect of risedronate was primarily demonstrated in the first 12 months of treatment. No serious unexpected suspected adverse events were observed. A 24-month treatment course with risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation, in osteopenic Crohn's disease patients improved bone density at lumbar spine. NTR 163 Dutch Trial Register. Published by the BMJ Publishing Group Limited. For permission to use

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.

Bisphosphonate Drug Holiday and Fracture Risk: A Population-Based Cohort Study.

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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

Bisfosfonatassocieret osteonekrose i kaeberne hos patienter med myelomatose

DEFF Research Database (Denmark)

Lund, Thomas; Gregersen, Henrik; Vangsted, Annette

2009-01-01

of bisphosphonate therapy and with the potency of the used bisphosphonate. BON usually develops after tooth extraction or other oral surgery, and has proven difficult to treat. Optimal dental hygiene should be ensured prior to treatment initiation where possible, and once bisphosphonate treatment is instituted......, oral surgery should be avoided if possible. Udgivelsesdato: 2009-Jan-5...

The effectiveness of non-surgical interventions in the treatment of Charcot foot.

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Smith, Caroline; Kumar, Saravana; Causby, Ryan

2007-12-01

Background  Charcot neuropathic osteoarthropathy is commonly known as 'Charcot foot'. It is a serious foot complication of diabetes mellitus that can frequently lead to foot ulceration, gangrene, hospital admission and foot amputation. A multidisciplinary approach to the management of Charcot foot is taken involving medical and allied health professionals. The management approach may also differ between different countries. To date, there is no systematic review of the literature undertaken to identify the clinical effectiveness of non-operative interventions in the treatment of acute Charcot foot. Objective  The objective of this review was to identify the effectiveness of non-surgical interventions with reducing lesions, ulceration, the rate of surgical intervention, reducing hospital admissions and improve the quality of life of subjects with Charcot foot. Search strategy  A comprehensive search strategy was undertaken on databases available from University of South Australia from their inception to November 2006. Selection criteria  Randomised controlled trials or clinical controlled trials were primarily sought. Critical appraisal of study quality and data extraction was undertaken using Joanna Briggs Institute instruments. Review Manager software was used to calculate comparative statistics. Results  This review identified 11 trials and five trials were included in the review. Three trials involved the use of bisphosphonate, a pharmacological agent. Two experimental treatments were also included, evaluating palliative radiology and magnetic fields. No trials were found using immobilisation and off-loading interventions for acute Charcot foot. The overall methodological quality score of the five studies was moderate. Owing to heterogeneous data, meta-analysis could not be performed. The trials did not report on reducing lesions, ulceration, rate of surgical intervention, hospital admissions and the quality of life of subjects with Charcot foot. The

Influence of bone affinity on the skeletal distribution of fluorescently labeled bisphosphonates in vivo.

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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

Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489

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Olaleye Joseph

2005-12-01

Full Text Available Abstract Background The aim of this study was to evaluate the long-term efficacy and tolerability of etoricoxib, a COX-2 selective inhibitor, in osteoarthritis (OA patients. Methods A double-blind, randomized, multicenter study was conducted in 617 patients with OA of the knee. The base study was 14 weeks in duration and consisted of 2 parts; in Part I (6 weeks, patients were allocated to once daily oral etoricoxib 5, 10, 30, 60, 90 mg or placebo. In Part II (8 weeks; the placebo, etoricoxib 5 and 10 mg groups were reallocated to etoricoxib 30, 60, or 90 mg qd or diclofenac 50 mg t.i.d. Treatment was continued for consecutive 12 and 26 week extensions. Primary efficacy endpoints were the WOMAC VA 3.0 pain subscale and investigator global assessment of disease status. Safety and tolerability were assessed by collecting adverse events throughout the study. Results Compared with placebo, the etoricoxib groups displayed significant (p Conclusion In this extension study, etoricoxib, at doses ranging from 30 to 90 mg, demonstrated a maintenance of significant clinical efficacy in patients with OA through 52 weeks of treatment. Etoricoxib displayed clinical efficacy similar to diclofenac 150 mg and was generally well tolerated.

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)

Live imaging of osteoclast inhibition by bisphosphonates in a medaka osteoporosis model

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Tingsheng Yu

2016-02-01

Full Text Available Osteoclasts are bone-resorbing cells derived from the monocyte/macrophage lineage. Excess osteoclast activity leads to reduced bone mineral density, a hallmark of diseases such as osteoporosis. Processes that regulate osteoclast activity are therefore targeted in current osteoporosis therapies. To identify and characterize drugs for treatment of bone diseases, suitable in vivo models are needed to complement cell-culture assays. We have previously reported transgenic medaka lines expressing the osteoclast-inducing factor receptor activator of nuclear factor κB ligand (Rankl under control of a heat shock-inducible promoter. Forced Rankl expression resulted in ectopic osteoclast formation, as visualized by live imaging in fluorescent reporter lines. This led to increased bone resorption and a dramatic reduction of mineralized matrix similar to the situation in humans with osteoporosis. In an attempt to establish the medaka as an in vivo model for osteoporosis drug screening, we treated Rankl-expressing larvae with etidronate and alendronate, two bisphosphonates commonly used in human osteoporosis therapy. Using live imaging, we observed an efficient, dose-dependent inhibition of osteoclast activity, which resulted in the maintenance of bone integrity despite an excess of osteoclast formation. Strikingly, we also found that bone recovery was efficiently promoted after inhibition of osteoclast activity and that osteoblast distribution was altered, suggesting effects on osteoblast-osteoclast coupling. Our data show that transgenic medaka lines are suitable in vivo models for the characterization of antiresorptive or bone-anabolic compounds by live imaging and for screening of novel osteoporosis drugs.

The effects of 2 weeks of statin treatment on mitochondrial respiratory capacity in middle-aged males

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Asping, Magnus; Stride, Nis; Sogaard, Ditte

2017-01-01

Background Statins are used to lower cholesterol in plasma and are one of the most used drugs in the world. Many statin users experience muscle pain, but the mechanisms are unknown at the moment. Many studies have hypothesized that mitochondrial function could be involved in these side effects. Aim...... treatment. Fasting glucose and insulin as well as VO2max were not changed after treatment. Conclusion Two weeks of statin (S or P) treatment have no major effect on mitochondrial function. The tendency for an increased mitochondrial substrate sensitivity after simvastatin treatment could be an early...... indication of the negative effects linked to statin treatment....

Quantitative ultrasound at the hand phalanges in patients with bisphosphonate-related osteonecrosis of the jaws

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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.

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

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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.

Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom's macroglobulinemia: a retrospective multicentric study

International Nuclear Information System (INIS)

Andriani, A; Petrucci, M T; Caravita, T; Montanaro, M; Villivà, N; Levi, A; Siniscalchi, A; Bongarzoni, V; Pisani, F; De Muro, M; Coppetelli, U; Avvisati, G; Zullo, A; Agrillo, A; Gaglioti, D

2012-01-01

Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4–15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstrom's macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O 2 therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O 2 /hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O 2 hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health

Weekly azathioprine pulse versus daily azathioprine in the treatment of Parthenium dermatitis: A non-inferiority randomized controlled study

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Kaushal K Verma

2015-01-01

Full Text Available Background: Azathioprine in daily doses has been shown to be effective and safe in the treatment of Parthenium dermatitis. Weekly pulses of azathioprine (WAP are also effective, but there are no reports comparing the effectiveness and safety of these two regimens in this condition. Aims: To study the efficacy and safety of WAP and daily azathioprine in Parthenium dermatitis. Methods: Sixty patients with Parthenium dermatitis were randomly assigned to treatment with azathioprine 300 mg weekly pulse or azathioprine 100 mg daily for 6 months. Patients were evaluated every month to assess the response to treatment and side effects. Results: The study included 32 patients in the weekly azathioprine group and 28 in the daily azathioprine group, of whom 25 and 22 patients respectively completed the study. Twenty-three (92% patients on WAP and 21 (96% on daily azathioprine had a good or excellent response. The mean pretreatment clinical severity score decreased from 26.4 ± 14.5 to 4.7 ± 5.1 in the WAP group, and from 36.1 ± 18.1 to 5.7 ± 6.0 in the daily azathioprine group, which was statistically significant and comparable (P = 0.366. Patients on WAP had a higher incidence of adverse effects (P = 0.02. Limitations: The study had a small sample size and the amount of clobetasol propionate used in each patient was not determined, though it may not have affected the study outcome due to its comparable use in both groups. Conclusions: Azathioprine 300 mg weekly pulse and 100 mg daily dose are equally effective and safe in the treatment of Parthenium dermatitis.

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.

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.

Modified Suanzaorentang Had the Treatment Effect for Generalized Anxiety Disorder for the First 4 Weeks of Paroxetine Medication: A Pragmatic Randomized Controlled Study

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Ming-Fen Song

2017-01-01

Full Text Available Background. Paroxetine does not show satisfactory therapeutic effect for generalized anxiety disorder (GAD patients for the first 2–4 weeks of medication. Diazepam is always concurrently used although it has some shortcomings such as physical dependence and withdrawal reactions. In this study, we aimed to identify whether modified Suanzaorentang (MSZRT, a combined Chinese formula including Suanzaorentang (SZRT and Zhizichitang (ZZCT, could control the anxiety of GAD for the first 4 weeks of paroxetine medication. Methods. 156 GAD patients were randomized to the treatment of paroxetine, paroxetine-diazepam, or paroxetine-MSZRT for 4 weeks. Hamilton Anxiety Scale (HAMA Test and Self-Rating Anxiety Scale (SAS Test were determined each week as the evaluation of clinical efficacy. Adverse events (AEs were also closely observed by performing the Treatment Emergent Symptom Scale (TESS Test. Results. Both paroxetine-MSZRT and paroxetine-diazepam decreased more HAMA and SAS total scores than paroxetine from weeks 1 to 3. Paroxetine-MSZRT as well as paroxetine-diazepam had an obviously higher onset rate than paroxetine in each week. After 4 weeks’ treatment, the overall effectiveness rate in the paroxetine-MSZRT group (90.00% was obviously higher than those of the paroxetine group (74.42% but did not significantly differ from the paroxetine-diazepam group (93.88%. Conclusion. MSZRT had the treatment effect for GAD when paroxetine was used for the first 4 weeks.

Physical comorbidity and 12-week treatment outcomes in Korean patients with depressive disorders: the CRESCEND study.

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Kim, Jae-Min; Stewart, Robert; Bae, Kyung-Yeol; Yang, Su-Jin; Yoon, Jin-Sang; Jung, Sung-Won; Lee, Min-Soo; Yim, Hyeon-Woo; Jun, Tae-Youn

2011-11-01

Physical and depressive disorders frequently co-occur, but effects of physical health on depression treatment outcomes have received little research. This study aimed to compare treatment outcomes between people with depressive disorder with and without comorbid physical disorders. A Korean nationwide sample of 723 people with depressive disorder initiated on antidepressant treatment, and re-evaluated at 1, 2, 4, 8, and 12 weeks later. Assessment scales for evaluating depressive symptoms (HAMD), anxiety (HAMA), global severity (CGI-s), and functioning (SOFAS) were administered at baseline and every follow-up visit. Achievement of remission or response was defined only when these were maintained to the 12 weeks study endpoint or to the last follow-up examination, if earlier, with the date of the first observed remission point applied as the timing of remission. Logistic regression and Cox proportional hazards models were used. Of the sample, 247 (34%) had at least one physical disorder. This was associated with lower socioeconomic status and more severe depressive symptoms at baseline, but was not associated with any treatment related characteristics including antidepressant type and regimen, concomitant medications, side effects, and duration of treatment period. After adjustment, patients with physical comorbidity responded more slowly and less often - particularly in domains of anxiety, global severity, and functioning (all p-values depressive disorders in people with physical comorbidity. Future comparative studies between conventional and integrated treatment approaches are indicated for depressive disorders with physical comorbidity. 2011 Elsevier Inc. All rights reserved.

Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human farnesyl pyrophosphate synthase.

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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

Eight weeks of citicoline treatment does not perturb sleep/wake cycles in cocaine-dependent adults.

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Bracken, Bethany K; Penetar, David M; Rodolico, John; Ryan, Elizabeth T; Lukas, Scott E

2011-06-01

Citicoline (cytidine-5'-diphosphate) is a mononucleotide composed of ribose, cytosine, pyrophosphate, and choline, and is involved in the biosynthesis of the structural phosopholipids of cell membranes. Treatment with citicoline, improves memory in patients with dementia, and reduces damage to the brain after traumatic brain injury or stroke. Recent research has been conducted to assess whether citicoline is an effective treatment for cocaine dependence. In cocaine-dependent individuals, withdrawal from cocaine is associated with disturbed sleep, which may contribute to the high rate of relapse to cocaine use. Therefore, it is important to know the impact of citicoline on the sleep/wake cycle in these individuals in order to rate its overall efficacy. In this double-blind, placebo-controlled trial, the effects of citicoline treatment on the sleep/wake cycles of cocaine dependent participants were assessed. The results of the current study are reported as part of a larger study, consisting of an eight-week treatment period to assess the efficacy of longer-term treatment with citicoline at decreasing cocaine consumption in cocaine-dependent polydrug using participants. In this non-abstinent, cocaine-dependent population, citicoline had no effect on any of the sleep parameters measured including sleep efficiency, sleep latency, total sleep time, number of waking episodes, time awake per episode, amount of time in bed spent moving, number of sleep episodes, time asleep per episode, and amount of time in bed spent immobile. These data suggest that eight weeks of citicoline administration does not disturb sleep/wake cycles of cocaine-dependent individuals. Copyright © 2011 Elsevier Inc. All rights reserved.

Intravenous immunoglobulin for maintenance treatment of multifocal motor neuropathy: A multi-center, open-label, 52-week phase 3 trial.

Science.gov (United States)

Kuwabara, Satoshi; Misawa, Sonoko; Mori, Masahiro; Iwai, Yuta; Ochi, Kazuhide; Suzuki, Hidekazu; Nodera, Hiroyuki; Tamaoka, Akira; Iijima, Masahiro; Toda, Tatsushi; Yoshikawa, Hiroo; Kanda, Takashi; Sakamoto, Ko; Kusunoki, Susumu; Sobue, Gen; Kaji, Ryuji

2018-04-10

Intravenous immunoglobulin (IVIg) therapy is currently the only established treatment in patients with multifocal motor neuropathy (MMN), and many patients have an IVIg-dependent fluctuation. We aimed to investigate the efficacy and safety of every 3 week IVIg (1.0 g/kg) for 52 weeks. This study was an open-label phase 3 clinical trial, enrolling 13 MMN patients. After an induction IVIg therapy (0.4 g/kg/d for 5 consecutive days), maintenance dose (1.0 g/kg) was given every 3 weeks for 52 weeks. The major outcome measures were the Medical Research Council (MRC) sum score and hand-grip strength at week 52. This trial is registered with ClinicalTrials.gov, number NCT01827072. At week 52, 11 of the 13 patients completed the study, and all 11 had a sustained improvement. The mean (SD) MRC sum score was 85.6 (8.7) at the baseline, and 90.6 (12.8) at week 52. The mean grip strength was 39.2 (30.0) kPa at the baseline and 45.2 (32.8) kPa at week 52. Two patients dropped out because of adverse event (dysphagia) and decision of an investigator, respectively. Three patients developed coronary spasm, dysphagia, or inguinal herniation, reported as the serious adverse events, but considered not related with the study drug. The other adverse effects were mild and resolved by the end of the study period. Our results show that maintenance treatment with 1.0 g/kg IVIg every 3 week is safe and efficacious for MMN patients up to 52 weeks. Further studies are required to investigate optimal dose and duration of maintenance IVIg for MMN. © 2018 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.

96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection.

Science.gov (United States)

Agarwal, Kosh; Brunetto, Maurizia; Seto, Wai Kay; Lim, Young-Suk; Fung, Scott; Marcellin, Patrick; Ahn, Sang Hoon; Izumi, Namiki; Chuang, Wan-Long; Bae, Ho; Sharma, Manoj; Janssen, Harry L A; Pan, Calvin Q; Çelen, Mustafa Kemal; Furusyo, Norihiro; Shalimar, Dr; Yoon, Ki Tae; Trinh, Huy; Flaherty, John F; Gaggar, Anuj; Lau, Audrey H; Cathcart, Andrea L; Lin, Lanjia; Bhardwaj, Neeru; Suri, Vithika; Mani Subramanian, G; Gane, Edward J; Buti, Maria; Chan, Henry L Y

2018-04-01

Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double-blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials. In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25 mg TAF or 300 mg TDF in a double-blinded fashion. One study enrolled HBeAg-positive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population. At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference -2.2% (95% CI -8.3 to 3.9%; p = 0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference -0.6% (95% CI -7.0 to 5.8%; p = 0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change -0.33% vs. -2.51%; p TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341. At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued

Increased Tumor Oxygenation and Drug Uptake During Anti-Angiogenic Weekly Low Dose Cyclophosphamide Enhances the Anti-Tumor Effect of Weekly Tirapazamine

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Doloff, J.C.; Khan, N.; Ma, J.; Demidenko, E.; Swartz, H.M.; Jounaidi, Y.

2010-01-01

Metronomic cyclophosphamide treatment is associated with anti-angiogenic activity and is anticipated to generate exploitable hypoxia using hypoxia-activated prodrugs. Weekly administration of tirapazamine (TPZ; 5 mg/kg body weight i.p.) failed to inhibit the growth of 9L gliosarcoma tumors grown s.c. in scid mice. However, the anti-tumor effect of weekly cyclophosphamide (CPA) treatment (140 mg/kg BW i.p.) was substantially enhanced by weekly TPZ administration. An extended tumor free period and increased frequency of tumor eradication without overt toxicity were observed when TPZ was given 3, 4 or 5 days after each weekly CPA treatment. Following the 2nd CPA injection, Electron Paramagnetic Resonance (EPR) Oximetry indicated significant increases in tumor pO2, starting at 48 hr, which further increased after the 3rd CPA injection. pO2 levels were, however, stable in growing untreated tumors. A strong negative correlation (−0.81) between tumor pO2 and tumor volume during 21 days of weekly CPA chemotherapy was observed, indicating increasing tumor pO2 with decreasing tumor volume. Furthermore, CPA treatment resulted in increased tumor uptake of activated CPA. CPA induced increases in VEGF RNA, which reached a maximum on day 1, and in PLGF RNA which was sustained throughout the treatment, while anti-angiogenic host thrombospondin-1 increased dramatically through day 7 post-CPA treatment. Weekly cyclophosphamide treatment was anticipated to generate exploitable hypoxia. However, our findings suggest that weekly CPA treatment induces a functional improvement of tumor vasculature, which is characterized by increased tumor oxygenation and drug uptake in tumors, thus counter-intuitively, benefiting intratumoral activation of TPZ and perhaps other bioreductive drugs. PMID:19754361

THE CHIMERIC ALT-VASTUS LATERALIS FREE FLAP IN RECONSTRUCTION OF ADVANCED BRONJ OF THE MAXILLA

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Francesca Toia

2015-04-01

Full Text Available ntroduction Bisphosphonate-related osteonecrosis of the jaw (BRONJ is a dangerous complication of bisphosphonates, a class of pharmaceutical agents used in numerous bone disorders. No gold standard therapy exists, but recent literature suggests that, in advanced stages, the best results are achieved with aggressive debridement. In this paper, we report our experience of treatment of stage 3 BRONJ of the maxilla with extensive surgical debridement and reconstruction with a chimeric ALT-Vastus lateralis flap. Methods Five selected patients with stage 3 BRONJ underwent partial maxillectomy with disease-free margins followed by immediate reconstruction with a chimeric ALT-Vastus lateralis free flap. Results Only two patients experienced minor complications. All other patients healed uneventfully within two weeks and donor site morbidity was minimal. Conclusions Our data suggest that aggressive debridement and reconstruction with a chimeric ALT -Vastus lateralis flap is an effective option for the treatment of stage III BRONJ of the maxilla.

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

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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.

Causes, consequences, and treatment of osteoporosis in men

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Banu J

2013-08-01

Full Text Available Jameela Banu Coordinated Program in Dietetics, College of Health Sciences and Human Services and Department of Biology, College of Science and Mathematics, University of Texas-Pan American, Edinburg, TX, USA Abstract: Men undergo gradual bone loss with aging, resulting in fragile bones. It is estimated that one in five men will suffer an osteoporotic fracture during their lifetime. The prognosis for men after a hip fracture is very grim. A major cause is reduction of free testosterone. Many other factors result in secondary osteoporosis, including treatment for other diseases such as cancer and diabetes. Patients should be screened not only for bone density but also assessed for their nutritional status, physical activity, and drug intake. Therapy should be chosen based on the type of osteoporosis. Available therapies include testosterone replacement, bisphosphonates, and nutritional supplementation with calcium, vitamin D, fatty acids, and isoflavones, as well as certain specific antibodies, like denosumab and odanacatib, and inhibitors of certain proteins. Keywords: risk factors, hormones, bisphosphonates, nutritional supplements, antibodies, protein inhibitors, male osteoporosis

Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial.

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Johannsson, Gudmundur; Feldt-Rasmussen, Ulla; Håkonsson, Ida Holme; Biering, Henrik; Rodien, Patrice; Tahara, Shigeyuki; Toogood, Andrew; Rasmussen, Michael Højby

2018-05-01

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin ® . Local tolerability and treatment satisfaction were also assessed. 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan ( n  = 61) or once-daily Norditropin ( n  = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin ( P  = 0.0171). In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin. © 2018 The authors.

Anchoring of self-assembled plasmid DNA/ anti-DNA antibody/cationic lipid micelles on bisphosphonate-modified stent for cardiovascular gene delivery

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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

Randomized clinical trial assessing whether additional massage treatments for chronic neck pain improve 12- and 26-week outcomes.

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Cook, Andrea J; Wellman, Robert D; Cherkin, Daniel C; Kahn, Janet R; Sherman, Karen J

2015-10-01

This is the first study to systematically evaluate the value of a longer treatment period for massage. We provide a framework of how to conceptualize an optimal dose in this challenging setting of nonpharmacologic treatments. The aim was to determine the optimal dose of massage for neck pain. Two-phase randomized trial for persons with chronic nonspecific neck pain. Primary randomization to one of five groups receiving 4 weeks of massage (30 minutes 2x/or 3x/wk or 60 minutes 1x, 2x, or 3x/wk). Booster randomization of participants to receive an additional six massages, 60 minutes 1x/wk, or no additional massage. A total of 179 participants from Group Health and the general population of Seattle, WA, USA recruited between June 2010 and August 2011 were included. Primary outcomes self-reported neck-related dysfunction (Neck Disability Index) and pain (0-10 scale) were assessed at baseline, 12, and 26 weeks. Clinically meaningful improvement was defined as greater than or equal to 5-point decrease in dysfunction and greater than or equal to 30% decrease in pain from baseline. Clinically meaningful improvement for each primary outcome with both follow-up times was analyzed using adjusted modified Poisson generalized estimating equations (GEEs). Secondary analyses for the continuous outcomes used linear GEEs. There were no observed differences by primary treatment group at 12 or 26 weeks. Those receiving booster dose had improvements in both dysfunction and pain at 12 weeks (dysfunction: relative risk [RR]=1.56 [1.08-2.25], p=.018; pain: RR=1.25 [0.98-1.61], p=.077), but those were nonsignificant at 26 weeks (dysfunction: RR=1.22 [0.85-1.74]; pain: RR=1.09 [0.82-1.43]). Subgroup analysis by primary and booster treatments found the booster dose only effective among those initially randomized to one of the 60-minute massage groups. "Booster" doses for those initially receiving 60 minutes of massage should be incorporated into future trials of massage for chronic neck pain

The Relevance of Osteoclastic and Osteoblastic Activity Markers Follow-Up in Patients on Antiresorptive Osteoporosis Treatment.

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Smilic, Tanja N; Novakovic, Tatjana R; Markovic-Jovanovic, Snezana R; Smilic, Ljiljana L J; Mitic, Javorka S; Radunovic, Miodrag L

2017-11-02

In general, markers of bone formation and markers of bone resorption are changing synergistically, so the monitoring of any osteoclastic and any osteoblastic marker should reflect the rate of bone transformation. The aim of the study is to monitor the bone metabolism markers in postmenopausal women with osteoporosis and osteopenia along with the variations caused by the effects of bisphosphonate therapy. The study involved 55 women of average age of 57.95 years, with osteopenia or osteoporosis. The patients with osteoporosis were treated with bisphosphonates (75 mg once a week); the laboratory tests were performed before the treatment and 6 months later. Patients with osteopenia were evaluated at the first assessment and 6 months later. The tests included bone densitometry, dual-energy X-ray absorptiometry, osteocalcin, alkaline phosphatase, collagen 1 N-terminal pro-peptide (P1NP), and beta C telopeptide of type I collagen (CTX). The mean T-score was -2.80 ± 0.63 before therapy and -2.64 ± 0.45 6 months later (p < 0.001). Women with osteoporosis had elevated levels of osteocalcin and P1NP at the first assessment, whereas the alkaline phosphatase level did not change with the treatment. After the introduction of antiresorptive therapy, the levels of osteocalcin and P1NP significantly decreased (p < 0.001). In the group with osteopenia, the biochemical markers activity were increased in both assessments. In patients with osteoporosis, Beta-CTX was increased in the first evaluation, and decreased after treatment (p = 0.001). The results indicate that the assessment of biochemical markers of bone metabolism show excellent results in the assessment of prognosis, monitoring the course and the response to various treatment regimens of osteoporosis and evince strong correlation with standard densitometry and dual-energy X-ray absorptiometry procedures. P1NP and CTX show better diagnostic applicability compared with osteocalcin and alkaline phosphatase

Country report: United Kingdom. Bifunctional bisphosphonate complexes with {sup 99m}Tc and {sup 188}Re for the diagnosis and therapy of bone metastases

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Torres Martin de Rosales, Rafael; Blower, P.J., E-mail: rafael.torres@kcl.ac.uk, E-mail: philip.blower@kcl.ac.uk [Division of Imaging Sciences, King' s College London, 4th Floor, Lambeth Wing, St. Thomas Hospital, London (United Kingdom)

2010-07-01

1,1-Bisphosphonates (BPs) are a family of compounds extensively used in the management of disorders of bone metabolism.{sup 1} They accumulate in areas of high bone metabolism, such as bone metastases, and consequently have been receiving increasing attention as molecular imaging probes and pain palliation treatments.{sup 2} Imaging bone metastases with BPs using single photon emission computed tomography (SPECT) or planar scintigraphy is one of the most often-performed clinical imaging procedures. Beta-emitting analogues capable of producing a therapeutic effect have also been developed.{sup 3} In particular, the rhenium compounds {sup 186/188}Re-hydroxyethylidene-1,1-diphosphonate ({sup 186/188}Re-HEDP) have shown promise as palliative agents for bone metastases in recent clinical trials.{sup 4} The radiochemicals consist of a complex of a BP (e.g. methylene diphosphonate, MDP) with gamma- ({sup 99m}Tc) or beta- ({sup 186/186}Re) emitters.

A review of minodronic acid hydrate for the treatment of osteoporosis

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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

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

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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

Resective surgical approach shows a high performance in the management of advanced cases of bisphosphonate-related osteonecrosis of the jaws: a retrospective survey of 347 cases.

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Graziani, Filippo; Vescovi, Paolo; Campisi, Giuseppina; Favia, Gianfranco; Gabriele, Mario; Gaeta, Giovanni Maria; Gennai, Stefano; Goia, Franco; Miccoli, Mario; Peluso, Franco; Scoletta, Matteo; Solazzo, Luigi; Colella, Giuseppe

2012-11-01

The aim of this study was to evaluate the results of the surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in a large cohort. A retrospective cohort multicenter study was designed. Patients were enrolled if they were diagnosed with BRONJ and received operative treatment. Data on demographic, health status, perioperative, and surgical factors were collected retrospectively. The primary outcome variable was a change in BRONJ staging (improvement, worsening, or no change). Interventions were grouped by local debridement and resective surgery. Data were collected for other variables as cofactors. Univariate analysis and logistic regressions were then performed. Of the 347 BRONJ-affected subjects, 59% showed improvement, 30% showed no change, and 11% showed worsening. Improvement was observed in 49% of cases treated with local debridement and 68% of cases treated with resective surgery. Multivariate analysis indicated that maxillary location, resective surgery, and no additional corticosteroid treatment were associated with a positive outcome. Surgical treatment of BRONJ appeared to be more effective when resective procedures were performed. Nonetheless, other factors, such as the absence of symptoms and the types of drug administration, should be taken into account before clinical decisions are made. Copyright © 2012 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Running title: Treatment of postmenopausal osteoporosis.

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Bülent Tiras

2005-12-01

Full Text Available Osteoporosis is characterized with low bone mass and deterioration of skeletal microarchitecture. It leads to a fragile bone and increased risk of fracture by minimal trauma. Today, osteoporotic fractures have become a major health concern. Therefore many different studies have been organized to enlighten basic pathology, and to investigate efficient therapeutic modalities. The change in the prescription attitudes in postmenopausal hormone replacement therapy (HRT increased the value of non-HRT therapies. The purpose of this review is to evaluate all therapeutic modalities which could be used in this setting by analyzing prospective randomized studies. By a general scope of view, the choice of treatment should be individualized with respect to age, risk factors,\tand concomitant disorders. In early menopause HRT can be used for women with severe vasomotor symptoms if there is no contraindication. Since no difference was noted between HRT and bisphosphonates, there is no need to combination regimens.\tAfter vasomotor symptoms are subsided, raloxifene can be used to the patients who have T score of below -2 without non-vertebral fracture. It is obvious that the most efficient therapies to prevent new osteoporotic fractures are bisphosphonates, strontium ranelate, and parathyroid hormone (PTH. PTH should not be used longer than 24 months. The first two large series showed that strontium ranelate prevents fractures very effectively. In addition the side effects of this unique medication is not higher than placebo which is one of the major advantage of it. Many series identified the important role of bisphosphonates in the prevention of osteoporosis related morbidities. Calcitonin has a role in patients having pain. Daily calcium and vitamin D supplement should be recommended to all patients, and diet and exercise programmes should be organized.

Clinical effect of etidronate on alveolar pyorrhoea associated with chronic marginal periodontitis: report of four cases.

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Takaishi, Y; Miki, T; Nishizawa, Y; Morii, H

2001-01-01

Etidronate 200 mg daily was administered to four female patients with periodontitis and resultant alveolar pyorrhoea for periods of 2 weeks, followed by off-periods of 10 weeks or more, for 2-3 years. The macroscopic appearance of gingival mobility of the teeth, depth of periodontal pockets, and X-ray findings of alveolar bones improved markedly during this time. The effects were first observed after 6-12 months of treatment. These findings indicate that bisphosphonates may be effective in the treatment of periodontitis and resultant alveolar pyorrhoea. The effect may be mediated by the inhibitory action on bone resorption and the anti-inflammatory action of etidronate. Concomitant conventional dental management is also required.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial

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Gimsing, Peter; Carlson, Kristina; Turesson, Ingemar

2010-01-01

Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effec...

Weekly Docetaxel, Cisplatin, and Cetuximab in Palliative Treatment of Patients with Squamous Cell Carcinoma of the Head and Neck.

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Trieu, Vanessa; Pinto, Harlan; Riess, Jonathan W; Lira, Ruth; Luciano, Richard; Coty, Jessie; Boothroyd, Derek; Colevas, A Dimitrios

2018-03-14

Chemotherapy for recurrent, metastatic squamous cell carcinoma of the head and neck need not be known for extreme toxicity.The weekly regimen studied here has been demonstrated to be tolerable and effective. The objective of this study was to establish the response rate, progression-free survival (PFS) and overall survival (OS), and safety profile of weekly docetaxel, platinum, and cetuximab (TPC) in patients with relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-nine patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group (ECOG) performance status <3 were enrolled in an institutional review board-approved phase II trial. This study permitted prior chemoradiation, radiation, and/or surgery, provided that 3 months had elapsed since the end of the potentially curative treatment. Patients received cisplatin 30 mg/m 2 or carboplatin area under the curve (AUC) 2, docetaxel 30 mg/m 2 , and cetuximab 250 mg/m 2 weekly for 3 weeks, followed by a break during the fourth week, for a 28-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Twenty-seven patients received TPC and were evaluable for response and toxicity. Rates of complete response (CR), partial response (PR), and confirmed PR were 3%, 52%, and 30%, respectively. The overall objective response rate was 56%. Estimated median PFS and OS were 4.8 and 14.7 months, respectively. The rates of grade 3 and 4 worst-grade adverse events (AEs) per patient were 85% and 7%, respectively. Dose density through cycle 4 was preserved for all patients; however, treatment beyond cycle 6 with the TPC regimen proved unfeasible. Weekly docetaxel, cisplatin, and cetuximab is an effective regimen for patients with metastatic or recurrent SCCHN. Response rates, PFS, and OS compare favorably with other combination chemotherapy treatments. Grade 4 toxicity rates observed in this study were substantially lower than those described with regimens

Role of the nurse in preserving patients' independence.

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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.

A reversible albumin-binding growth hormone derivative is well tolerated and possesses a potential once-weekly treatment profile.

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Rasmussen, Michael Højby; Olsen, Minna W Brændholt; Alifrangis, Lene; Klim, Søren; Suntum, Mette

2014-10-01

Human growth hormone (hGH) replacement therapy currently requires daily sc injections for years/lifetime, which may be both inconvenient and distressing for patients. NNC0195-0092 is a novel hGH derivative intended for once-weekly treatment of GH deficiency. A noncovalent albumin binding moiety is attached to the hGH backbone. Clearance is reduced as a consequence of a reversible binding to circulating serum albumin, which prolongs the pharmacodynamic (PD) effect. To evaluate safety, local tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose (SD) and multiple doses (MD) of NNC0195-0092. Randomized, single-center, placebo-controlled, double-blind, SD/MD, dose-escalation trial of 105 healthy male subjects. NNC0195-0092 sc administration: Five cohorts of eight subjects received one dose of NNC0195-0092 (0.01-0.32 mg/kg) (n = 6) or placebo (n = 2). Sixteen subjects (equal numbers of Japanese and non-Asian) received once-weekly doses of NNC0195-0092 (0.02-0.24 mg/kg; n=12) or placebo (n=4) for 4 weeks. Blood samples were drawn for assessment of safety, PK, IGF-1, and IGF binding protein 3 profiles and anti-drug antibodies. SD and MD of NNC0195-0092 were well tolerated at all dose levels. No safety concerns or local tolerability issues were identified. A dose-dependent IGF-1 response was observed. IGF-1 profiles suggest that NNC0195-0092 may be suitable for once-weekly dosing, with a clinically relevant dose ≤0.08 mg/kg/week. No differences in PK and PD were observed between Japanese and non-Asian subjects. SD and MD of NNC0195-0092 administered to healthy Japanese and non-Asian male subjects were well tolerated at all doses. The present trial suggests that NNC0195-0092 has the potential for an efficacious, well-tolerated, once-weekly GH treatment.

Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression.

Science.gov (United States)

Dean, Olivia M; Turner, Alyna; Malhi, Gin S; Ng, Chee; Cotton, Sue M; Dodd, Seetal; Sarris, Jerome; Samuni, Yuval; Tanious, Michelle; Dowling, Nathan; Waterdrinker, Astrid; Smith, Deidre; Berk, Michael

2015-01-01

Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder. This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC) alone or in combination (CT) with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase. The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment. This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression. Australian and New Zealand Clinical Trial Registry ACTRN12612000830897.

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.

A 6-week, multicenter, randomized, double-masked, parallel-group study comparing travoprost 0.004% to latanoprost 0.005% followed by 6-week, open-label treatment with travoprost 0.004%.

Science.gov (United States)

Maul, Eugenio; Carrasco, Félix Gil; Costa, Vital Paulino; Casiraghi, Javier F; Vargas, Enrique; Sarmina, Judith S; Mayol, Renato

2007-09-01

The aim of this study was to compare the tolerability and efficacy of once-daily travoprost 0.004% versus latanoprost 0.005% for 6 weeks followed by 6 weeks of once-daily travoprost 0.004% in decreasing intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension (OH). This multicenter, randomized, doublemasked, active-controlled, parallel-group trial was conducted at 32 centers across Latin America. Patients aged > or =18 years with OAG or OH were randomly assigned to receive topical travoprost 0.004% or latanoprost 0.005% 1 drop QD (9 PM) for 6 weeks (masked phase). At 6 weeks, all patients were assigned to receive open-label travoprost 0.004% 1 drop QD (9 PM) for 6 additional weeks (open-label phase). Study visits were scheduled at weeks 1, 2, 4, 6, 8, and 12. At each study visit, IOP was measured at 5 PM (+/-1 hour; approximately 20 hours after study drug administration). IOP changes from baseline were combined (pooled) from the 1-, 2-, 4-, and 6-week data to provide a comparison between the 2 treatment groups. Ocular adverse events (AEs) were monitored using slit-lamp examination. A total of 302 patients were enrolled (travoprost group, 155 patients; latanoprost group, 147 patients). The mean (SD) age of the travoprost group was 61.9 (10.6) years; 60.6% were female; and 47.1% were white. The mean (SD) age of the latanoprost group was 60.5 (12.4) years; 62.6% were female; and 49.0% were white. Mean IOP values were not significantly different between the travoprost and latanoprost groups at baseline (24.7 vs 24.2 mm Hg) or 6 weeks; however, the between-group difference in reductions from baseline in pooled IOP during the masked phase of the study was statistically significant (-8.3 vs -7.5 mm Hg; P = 0.009). At weeks 6 and 12, mean lOP levels were 16.1 and 16.2 mm Hg, respectively, in the travoprost group and 16.4 and 16.1 mm Hg in the group that was switched from latanoprost to travoprost (all, P = NS). The most common ocular AEs

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

Understanding Infidelity: An Interview with Gerald Weeks

Science.gov (United States)

Smith, Travis

2011-01-01

In this interview, Gerald Weeks shares his expertise on the topic of infidelity and couples counseling. Dr. Weeks defines infidelity, presents assessment strategies for treating the issue of infidelity, and discusses an intersystemic model for infidelity treatment when counseling couples. Dr. Weeks also provides insight into common mistakes made…

Pregnancy-associated spinal osteoporosis treated with bisphosphonates: long-term follow-up of maternal and infants outcome.

Science.gov (United States)

Vujasinovic-Stupar, Nada; Pejnovic, Nada; Markovic, Ljiljana; Zlatanovic, Maja

2012-03-01

Pregnancy-associated spinal osteoporosis (PPSO) is a rare condition characterized by severe back pain occurring near the end of the first pregnancy or shortly afterward. The aim of this report is to present a 12-year follow-up of a patient with PPSO. Also, the outcomes of patient's two pregnancies and her infants after long-term treatment with bisphosphonates are assessed. A young woman was referred to our tertiary care hospital aged 30 years, due to intense pain in thoracic and lumbar region that started during the last month of her first pregnancy and got worse after delivery. Bone mineral density (BMD) measurement, clinical, and biochemical parameters were performed. Extremely low lumbar spine BMD, L2-L4: 0.627 g/cm(2), T-score -4.8, Z-score -4.3, 52% young adult indicated severe osteoporosis. Cyclical treatment with etidronate and then pamidronate was started, and a substantial increase in the BMD and the reduction in back pain intensity were observed. An increase in BMD of 44.8% over baseline was observed after 12 years of follow-up. Her two pregnancies were uneventful, and no neonatal adverse effects were observed. Control DXA scan in her girl child aged 6.8 years revealed low BMD at the lumbar spine. As PPSO seems to be an underdiagnosed severe disease, caution is recommended if back pain occurs in the last trimester or early post-partum period. Although pre-pregnancy use of bisphosponates does not pose a substantial fetal risk, their use in women of childbearing age might best be done only when strong clinical indications exist.

Neurodynamic treatment did not improve pain and disability at two weeks in patients with chronic nerve-related leg pain: a randomised trial

Directory of Open Access Journals (Sweden)

Giovanni Ferreira

2016-10-01

Full Text Available Question: In people with nerve-related leg pain, does adding neurodynamic treatment to advice to remain active improve leg pain, disability, low back pain, function, global perceived effect and location of symptoms? Design: Randomised trial with concealed allocation and intention-to-treat analysis. Participants: Sixty participants with nerve-related leg pain recruited from the community. Interventions: The experimental group received four sessions of neurodynamic treatment. Both groups received advice to remain active. Outcome measures: Leg pain and low back pain (0, none, to 10, worst, Oswestry Disability Index (0, none, to 100, worst, Patient-Specific Functional Scale (0, unable to perform, to 30, able to perform, global perceived effect (–5 to 5 and location of symptoms were measured at 2 and 4 weeks after randomisation. Continuous outcomes were analysed by linear mixed models. Location of symptoms was assessed by relative risk (95% CI. Results: At 2 weeks, the experimental group did not have significantly greater improvement than the control group in leg pain (MD –1.1, 95% CI –2.3 to 0.1 or disability (MD –3.3, 95% CI –9.6 to 2.9. At 4 weeks, the experimental group experienced a significantly greater reduction in leg pain (MD –2.4, 95% CI –3.6 to –1.2 and low back pain (MD –1.5, 95% CI –2.8 to –0.2. The experimental group also improved significantly more in function at 2 weeks (MD 5.2, 95% CI 2.2 to 8.2 and 4 weeks (MD 4.7, 95% CI 1.7 to 7.8, as well as global perceived effect at 2 weeks (MD 2.5, 95% CI 1.6 to 3.5 and 4 weeks (MD 2.9, 95% CI 1.9 to 3.9. No significant between-group differences occurred in disability at 4 weeks and location of symptoms. Conclusion: Adding neurodynamic treatment to advice to remain active did not improve leg pain and disability at 2 weeks. Trial registration: NCT01954199. [Ferreira G, Stieven F, Araujo F, Wiebusch M, Rosa C, Plentz R, et al. (2016 Neurodynamic treatment did not improve

Brain structural properties predict psychologically mediated hypoalgesia in an 8-week sham acupuncture treatment for migraine.

Science.gov (United States)

Liu, Jixin; Mu, Junya; Liu, Qianqian; Dun, Wanghuan; Zhang, Ming; Tian, Jie

2017-09-01

Neuroimaging studies described brain structural changes that comprise the mechanisms underlying individual differences in migraine development and maintenance. However, whether such interindividual variability in migraine was observed in a pretreatment scan is a predisposition for subsequent hypoalgesia to placebo treatment that remains largely unclear. Using T1-weighted imaging, we investigated this issue in 50 healthy controls (HC) and 196 patients with migraine without aura (MO). An 8-week double-blinded, randomized, placebo-controlled acupuncture was used, and we only focused on the data from the sham acupuncture group. Eighty patients participated in an 8-weeks sham acupuncture treatment, and were subdivided (50% change in migraine days from baseline) into recovering (MOr) and persisting (MOp) patients. Optimized voxel-based morphometry (VBM) and functional connectivity analysis were performed to evaluate brain structural and functional changes. At baseline, MOp and MOr had similar migraine activity, anxiety and depression; reduced migraine days were accompanied by decreased anxiety in MOr. In our findings, the MOr group showed a smaller volume in the left medial prefrontal cortex (mPFC), and decreased mPFC-related functional connectivity was found in the default mode network. Additionally, the reduction in migraine days after placebo treatment was significantly associated with the baseline gray matter volume of the mPFC which could also predict post-treatment groups with high accuracy. It indicated that individual differences for the brain structure in the pain modulatory system at baseline served as a substrate on how an individual facilitated or diminished hypoalgesia responses to placebo treatment in migraineurs. Hum Brain Mapp 38:4386-4397, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Stress hormones and verbal memory in young people over the first 12 weeks of treatment for psychosis.

Science.gov (United States)

Allott, Kelly A; Yuen, Hok Pan; Bartholomeusz, Cali F; Rapado-Castro, Marta; Phassouliotis, Christina; Butselaar, Felicity; Wood, Stephen J; Proffitt, Tina-Marie; Savage, Greg; Phillips, Lisa J; Bendall, Sarah; Markulev, Connie; Reniers, Renate L E P; Pantelis, Christos; Baldwin, Lara; McGorry, Patrick D; Garner, Belinda

2017-11-21

Memory impairment in psychosis may be mediated through detrimental effects of hypothalamic-pituitary-adrenal (HPA) axis function. This study prospectively investigated the relationship between cortisol, sulphate dehydroepiandrosterone (DHEA(S) and cortisol: DHEA(S) ratio and memory in 35 first-episode psychosis (FEP) patients during the first 12 weeks of treatment and 23 healthy controls (HC). Morning blood sampling and tests of attention, working memory and verbal memory occurred at baseline and 12-week follow-up. FEP and HC groups did not significantly differ in levels of cortisol, DHEA(S) or their ratio at baseline or over 12-weeks. The FEP group performed significantly below HC on all cognitive measures at baseline and over 12-weeks. Cortisol levels were unrelated to cognition in both groups. At baseline, DHEA(S) was positively associated with attention in HCs, but negatively associated with attention in FEP participants. Change in DHEA(S) was negatively associated with change in memory over 12-weeks in both groups. At 12-weeks, there was a negative correlation between the cortisol: DHEA(S) ratio and attention in both groups. These findings are mostly in contrast to findings in chronic schizophrenia. Investigation at different illness phases and over longer-follow-up periods is required to determine the complex relationship between HPA-axis and memory functioning in psychosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Randomized Clinical Trial of Weekly vs. Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Locally Advanced Cervical Cancer

Energy Technology Data Exchange (ETDEWEB)

Ryu, Sang-Young, E-mail: ryu@kcch.re.kr [Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Won-Moo; Kim, Kidong [Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Park, Sang-Il [Department of Gynecologic Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Kim, Beob-Jong; Kim, Moon-Hong; Choi, Seok-Cheol [Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Cho, Chul-Koo [Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Nam, Byung-Ho [Cancer Biostatistics Branch, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of); Lee, Eui-Don [Department of Gynecologic Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of)

2011-11-15

Purpose: To compare compliance, toxicity, and outcome of weekly and triweekly cisplatin administration concurrent with radiotherapy in locally advanced cervical cancer. Methods and Materials: In this open-label, randomized trial, 104 patients with histologically proven Stage IIB-IVA cervical cancer were randomly assigned by a computer-generated procedure to weekly (weekly cisplatin 40 mg/m{sup 2}, six cycles) and triweekly (cisplatin 75 mg/m{sup 2} every 3 weeks, three cycles) chemotherapy arms during concurrent radiotherapy. The difference of compliance and the toxicity profiles between the two arms were investigated, and the overall survival rate was analyzed after 5 years. Results: All patients tolerated both treatments very well, with a high completion rate of scheduled chemotherapy cycles. There was no statistically significant difference in compliance between the two arms (86.3% in the weekly arm, 92.5% in the triweekly arm, p > 0.05). Grade 3-4 neutropenia was more frequent in the weekly arm (39.2%) than in the triweekly arm (22.6%) (p = 0.03). The overall 5-year survival rate was significantly higher in the triweekly arm (88.7%) than in the weekly arm (66.5%) (hazard ratio 0.375; 95% confidence interval 0.154-0.914; p = 0.03). Conclusions: Triweekly cisplatin 75-mg/m{sup 2} chemotherapy concurrent with radiotherapy is more effective and feasible than the conventional weekly cisplatin 40-mg/m{sup 2} regimen and may be a strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer.

Comparing the Efficacy of 8 Weeks Treatment of Cipram® and its Generic Citalopram in Patients With Mixed Anxiety-Depressive Disorder.

Science.gov (United States)

Khoonsari, Hasan; Oghazian, Mohammad Bagher; Kargar, Mona; Moin, Mahdiyeh; Khalili, Hossein; Alimadadi, Abbas; Torkamandi, Hassan; Ghaeli, Padideh

2015-06-01

Patients with mixed anxiety-depressive disorder (MADD) suffer both anxiety and depression. Antidepressants, especially, selective serotonin reuptake inhibitors are among agents of choice for treating this condition. This study compared the efficacy of Cipram® with its generic, citalopram. Forty adult outpatients (between 18 to 55 years of age) with a diagnosis of MADD who met the trial criteria, entered this double-blind, randomized study. Subjects were assigned to receive either generic citalopram or Cipram® for 8 weeks. Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) were utilized to assess depression and anxiety at baseline, weeks 4 and 8 of the study. Statistical analysis was performed using SPSS 14.0. Twenty patients received citalopram (mean dosages of 22 mg/day during the first 4 weeks and 33 mg/day during weeks 4 to 8) and 20 received Cipram® (mean dosages of 22 mg/day during the first 4 weeks and 29 mg/day during weeks 4 to 8). Both treatments were noted to be effective in improving the symptoms of MADD at weeks 4 and 8. The mean differences of HAM-D and HAM-A between Citalopram and Cipram® groups were significantly different at the end of week 4 (HAM-D: P = 0.038, HAM-A: P = 0.025), but not at the end of week 8 (HAM-D: P = 0.239, HAM-A: P = 0.204). Both medications were tolerated well by the patients. This study suggests that the efficacy of citalopram is similar to that of Cipram® in the treatment of MADD after 8 weeks. Meanwhile, Cipram® may reduce depression and anxiety quicker than its generic, citalopram.

Osteonecrosis of jawbone associated with the use of zometa

International Nuclear Information System (INIS)

Portuguez Morales, Francisco; Vargas Martinez, Jairo; Gamboa M, Rodolfo; Castro, Sergio

2008-01-01

Intravenous bisphosphonates are widely used in conjunction with conventional antineoplastic therapy, to treat hypercalcaemia of malignancy, multiple myeloma, and metastasis of solid tumors of head and neck; in which radiation is used. The bisphosphonates are synthetic analogs of pyrophosphates, have had affinity for bone formation and have increased bone resorption. These are potent inhibitors of osteoclast that have induced bone resorption in diseases such as osteoporosis and hypercalcaemia of malignancy. The bisphosphonates have produced adverse effects on kidney, eyes and muscles, but have been linked to osteonecrosis of the jaws, mainly related to the recent extraction of a dental piece. The use of bisphosphonates is related to the development of osteonecrosis of the maxilla in a patient of 50 years that has used for a long time zolendronate to handle bone metastasis due to multiple myeloma. Clinical aspects and treatment are presented. However, patients that have taked bisphosphonates should receive prophylactic care to maintain their oral health, the panoramic radiographs are used to display these conditions. Preventive measures must be taken before, during and after treatment with bisphosphonates. (author) [es

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.

Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression

Directory of Open Access Journals (Sweden)

Olivia M. Dean

2015-03-01

Full Text Available Objective: Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder. Methods: This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC alone or in combination (CT with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase. Results: The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment. Conclusion: This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression. Trial registration: Australian and New Zealand Clinical Trial Registry ACTRN12612000830897.

Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice

DEFF Research Database (Denmark)

Kristensen, Jonas Møller; Larsen, Steen; Helge, Jørn Wulff

2013-01-01

signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead a(2) (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism...... and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued...... the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice.We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems...

Prevention and treatment of postmenopausal osteoporosis.

Science.gov (United States)

Tella, Sri Harsha; Gallagher, J Christopher

2014-07-01

In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone loss, however there was no fracture data, even though it was thought to be effective. This continued until the Women's Health Initiative (WHI) study in 2001 that published data on 6 years of treatment with hormone therapy that showed an increase in heart attacks and breast cancer. Even though the risks were small, 1 per 1500 users annually, patients were worried and there was a large drop off in estrogen use. In later analyses the WHI study showed that estrogen reduced fractures and actually prevented heart attacks in the 50-60 year age group. Estrogen alone appeared to be safer to use than estrogen+the progestin medroxyprogesterone acetate and actually reduced breast cancer. At the same time other drugs were being developed for bone that belong to the bisphosphonate group and the first generation of compounds showed moderate potency on bone resorption. The second and third generation compounds were much more potent and in a series of large trials were shown to reduce fractures. For the last 15 years the treatment of osteoporosis belonged to the bisphosphonate compounds, most of which reduce fracture rates by 50 percent. With the exception of gastrointestinal irritation the drugs are well tolerated and highly effective. The sophistication of the delivery systems now allow treatment that can be given daily, weekly, monthly and annually either orally or intravenously. Bone remodeling is a dynamic process that repairs microfractures and replaces old bone with new bone. In the last 10 years there has been a remarkable understanding of bone biology so that new therapies can be specifically designed on a biological basis. The realization that RANKL was the final cytokine involved in the resorption process and that marrow cells produced a natural antagonist called Osteoprotegerin (OPG) quickly led to two

Aripiprazole in the treatment of irritability in pediatric patients (aged 6-17 years) with autistic disorder: results from a 52-week, open-label study.

Science.gov (United States)

Marcus, Ronald N; Owen, Randall; Manos, George; Mankoski, Raymond; Kamen, Lisa; McQuade, Robert D; Carson, William H; Corey-Lisle, Patricia K; Aman, Michael G

2011-06-01

To report the long-term efficacy of aripiprazole in the treatment of irritability in children and adolescents (ages 6-17 years) with autistic disorder. This was a 52-week, open-label, flexible-dose (2-15 mg/day) study of aripiprazole for the treatment of children and adolescents with irritability associated with autistic disorder. Eligible subjects were enrolled from two 8-week randomized trials or were enrolled as de novo subjects. "Prior aripiprazole" subjects had received treatment with aripiprazole for 8 weeks before entering this study. Evaluation of efficacy, a secondary objective after evaluation of safety and tolerability in this study, was conducted using the caregiver-rated Aberrant Behavior Checklist-Irritability subscale and the clinician-rated Clinical Global Impression-Improvement score. Three hundred thirty subjects received treatment (de novo, n = 86; prior aripiprazole, n = 174; prior placebo, n = 70) and 199 subjects (60.3%) completed 52 weeks of treatment. At their last study visit, 38.2% of subjects were receiving concomitant central nervous system medications (commonly antidepressants, 13.4%; psychostimulants, 11.5%; antiepileptics, 5.9%). At week 52 (observed cases data set), the mean change from baseline in Aberrant Behavior Checklist Irritability subscale scores was -8.0 in de novo subjects and -6.1 in prior placebo subjects; prior aripiprazole subjects maintained symptom improvement that was achieved with treatment in the prior study. At endpoint, the majority of subjects had a Clinical Global Impressions-Improvement score of 2 (much improved) or 1 (very much improved). Aripiprazole reduced symptoms of irritability associated with autistic disorder in pediatric subjects ages 6-17 years who were studied for up to 1 year.

Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment

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Hafeez, Shaista, E-mail: shaista.hafeez@icr.ac.uk [The Institute of Cancer Research, London (United Kingdom); The Royal Marsden NHS Foundation Trust, Sutton, Surrey (United Kingdom); McDonald, Fiona; Lalondrelle, Susan [The Royal Marsden NHS Foundation Trust, Sutton, Surrey (United Kingdom); McNair, Helen; Warren-Oseni, Karole; Jones, Kelly [The Institute of Cancer Research, London (United Kingdom); The Royal Marsden NHS Foundation Trust, Sutton, Surrey (United Kingdom); Harris, Victoria [The Royal Marsden NHS Foundation Trust, Sutton, Surrey (United Kingdom); Taylor, Helen; Khoo, Vincent [The Royal Marsden NHS Foundation Trust, London (United Kingdom); Thomas, Karen [The Royal Marsden NHS Foundation Trust, Sutton, Surrey (United Kingdom); Hansen, Vibeke; Dearnaley, David; Horwich, Alan; Huddart, Robert [The Institute of Cancer Research, London (United Kingdom); The Royal Marsden NHS Foundation Trust, Sutton, Surrey (United Kingdom)

2017-05-01

Purpose and Objectives: We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment. Methods and Materials: Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A “plan of the day” radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 months using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method. Results: Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade ≥3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%). Conclusion: Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment.

Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment

International Nuclear Information System (INIS)

Hafeez, Shaista; McDonald, Fiona; Lalondrelle, Susan; McNair, Helen; Warren-Oseni, Karole; Jones, Kelly; Harris, Victoria; Taylor, Helen; Khoo, Vincent; Thomas, Karen; Hansen, Vibeke; Dearnaley, David; Horwich, Alan; Huddart, Robert

2017-01-01

Purpose and Objectives: We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment. Methods and Materials: Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A “plan of the day” radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 months using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method. Results: Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade ≥3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%). Conclusion: Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment.

The economics of improving medication adherence in osteoporosis: validation and application of a simulation model.

Science.gov (United States)

Patrick, Amanda R; Schousboe, John T; Losina, Elena; Solomon, Daniel H

2011-09-01

Adherence to osteoporosis treatment is low. Although new therapies and behavioral interventions may improve medication adherence, questions are likely to arise regarding their cost-effectiveness. Our objectives were to develop and validate a model to simulate the clinical outcomes and costs arising from various osteoporosis medication adherence patterns among women initiating bisphosphonate treatment and to estimate the cost-effectiveness of a hypothetical intervention to improve medication adherence. We constructed a computer simulation using estimates of fracture rates, bisphosphonate treatment effects, costs, and utilities for health states drawn from the published literature. Probabilities of transitioning on and off treatment were estimated from administrative claims data. Patients were women initiating bisphosphonate therapy from the general community. We evaluated a hypothetical behavioral intervention to improve medication adherence. Changes in 10-yr fracture rates and incremental cost-effectiveness ratios were evaluated. A hypothetical intervention with a one-time cost of $250 and reducing bisphosphonate discontinuation by 30% had an incremental cost-effectiveness ratio (ICER) of $29,571 per quality-adjusted life year in 65-yr-old women initiating bisphosphonates. Although the ICER depended on patient age, intervention effectiveness, and intervention cost, the ICERs were less than $50,000 per quality-adjusted life year for the majority of intervention cost and effectiveness scenarios evaluated. Results were sensitive to bisphosphonate cost and effectiveness and assumptions about the rate at which intervention and treatment effects decline over time. Our results suggests that behavioral interventions to improve osteoporosis medication adherence will likely have favorable ICERs if their efficacy can be sustained.

Atomoxetine once daily for 24 weeks in adults with attention-deficit/hyperactivity disorder (ADHD): impact of treatment on family functioning.

Science.gov (United States)

Wietecha, Linda; Young, Joel; Ruff, Dustin; Dunn, David; Findling, Robert L; Saylor, Keith

2012-01-01

To assess the efficacy of atomoxetine (ATX) and impact of treatment on family functioning in adults with ADHD. Adults with attention-deficit/hyperactivity disorder (ADHD) having both a spouse/partner and child were randomized to placebo (n = 234) or ATX (n = 268) for 24 weeks. Attention-deficit/hyperactivity disorder measures included the Conners Adult ADHD Rating Scale total ADHD Symptoms score and Clinical Global Impression-ADHD-Severity. Marital measures included the Dyadic Adjustment Scale and the Family Assessment Measure Dyadic Relationship Scale (FAM III). Parenting measures included the Parenting Stress Index, Alabama Parenting Questionnaire, and Parenting Sense of Competence Scale (PSCS). Improvement was greater with ATX over placebo at 24 weeks on the Conners Adult ADHD Rating Scale (-16.43 vs -8.65; P ADHD yielded significant interaction and treatment differences for the FAM III Task Accomplishment and the FAM III and Dyadic Adjustment Scale affective expression items, PSCS total score, Alabama Parenting Questionnaire Corporal Punishment, and Parenting Stress Index attachment items. Atomoxetine demonstrated significant ADHD symptom reduction over 24 weeks. Although both groups demonstrated baseline-to-end point changes on many marital and parenting measure items, there were no treatment differences. Maladaptive behaviors of long-standing ADHD may benefit from both medication and behavioral-psychosocial intervention.

Utility of preoperative imaging diagnosis for a malignant tumor of the mandible. A malignant tumor of the mandible is difficult to discriminate from bisphosphonate-related osteonecrosis of the jaw

International Nuclear Information System (INIS)

Kamio, Takashi; Imaizumi, Akiko; Nishikawa, Keiichi; Shibui, Takeo; Inoue, Kenji; Matsuzaka, Kenichi; Sakamoto, Junichiro; Sano, Tsukasa

2014-01-01

We report our experience of a case with a malignant tumor of the mandible in which diagnostic imaging played an important role in the differential diagnosis and therapeutic strategy decisions. The patient was a 78-year-old woman who visited our hospital because of poor healing after tooth extraction. Multiple cytological diagnoses provided class II results, and a histopathological diagnosis of a biopsy also failed to show malignant findings. Therefore, a definitive diagnosis could not be made. Although the patient had a history of osteoporosis treatment, details of her medications were unclear. Therefore, bisphosphonate-related osteonecrosis of the jaw (BRONJ) could not be excluded, causing difficulty in management of the patient's condition. Eventually, we mainly focused on the diagnostic imaging and planned the therapeutic strategy in accordance with treatment for a malignant tumor. A postoperative histopathological examination of the surgical specimen revealed squamous cell carcinoma. It is sometimes difficult to differentiate among atypical diseases such as malignant tumors of the mandible and BRONJ, based solely on clinical or diagnostic imaging results. However, in the present patient, diagnostic imaging suggested a malignant tumor, and the appropriate treatment could be selected. (author)

Tissue level material composition and mechanical properties in Brtl/+ mouse model of Osteogenesis Imperfecta after sclerostin antibody treatment

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Lloyd, William R.; Sinder, Benjamin P.; Salemi, Joseph; Ominsky, Michael S.; Marini, Joan C.; Caird, Michelle S.; Morris, Michael D.; Kozloff, Kenneth M.

2015-02-01

Osteogenesis imperfecta (OI) is a genetic disorder resulting in defective collagen or collagen-associated proteins and fragile, brittle bones. To date, therapies to improve OI bone mass, such as bisphosphonates, have increased bone mass in the axial skeleton of OI patients, but have shown limited effects at reducing long bone fragility. Sclerostin antibody (Scl- Ab), currently in clinical trials for osteoporosis, stimulates bone formation and may have the potential to reduce long bone fracture rates in OI patients. Scl-Ab has been investigated as an anabolic therapy for OI in the Brtl/+ mouse model of moderately severe Type IV OI. While Scl-Ab increases long bone mass in the Brtl/+ mouse, it is not known whether material properties and composition changes also occur. Here, we report on the effects of Scl-Ab on wild type and Brtl/+ young (3 week) and adult (6 month) male mice. Scl-Ab was administered over 5 weeks (25mg/kg, 2x/week). Raman microspectroscopy and nanoindentation are used for bone composition and biomechanical bone property measurements in excised bone. Fluorescent labels (calcein and alizarin) at 4 time points over the entire treatment period are used to enable measurements at specific tissue age. Differences between wild type and Brtl/+ groups included variations in the mineral and matrix lattices, particularly the phosphate v1, carbonate v1, and the v(CC) proline and hydroxyproline stretch vibrations. Results of Raman spectroscopy corresponded to nanoindentation findings which indicated that old bone (near midcortex) is stiffer (higher elastic modulus) than new bone. We compare and contrast mineral to matrix and carbonate to phosphate ratios in young and adult mice with and without treatment.

Predictive Modeling of Response to Pregabalin for the Treatment of Neuropathic Pain Using 6-Week Observational Data: A Spectrum of Modern Analytics Applications.

Science.gov (United States)

Emir, Birol; Johnson, Kjell; Kuhn, Max; Parsons, Bruce

2017-01-01

This post hoc analysis used 11 predictive models of data from a large observational study in Germany to evaluate potential predictors of achieving at least 50% pain reduction by week 6 after treatment initiation (50% pain response) with pregabalin (150-600 mg/d) in patients with neuropathic pain (NeP). The potential predictors evaluated included baseline demographic and clinical characteristics, such as patient-reported pain severity (0 [no pain] to 10 [worst possible pain]) and pain-related sleep disturbance scores (0 [sleep not impaired] to 10 [severely impaired sleep]) that were collected during clinic visits (baseline and weeks 1, 3, and 6). Baseline characteristics were also evaluated combined with pain change at week 1 or weeks 1 and 3 as potential predictors of end-of-treatment 50% pain response. The 11 predictive models were linear, nonlinear, and tree based, and all predictors in the training dataset were ranked according to their variable importance and normalized to 100%. The training dataset comprised 9187 patients, and the testing dataset had 6114 patients. To adjust for the high imbalance in the responder distribution (75% of patients were 50% responders), which can skew the parameter tuning process, the training set was balanced into sets of 1000 responders and 1000 nonresponders. The predictive modeling approaches that were used produced consistent results. Baseline characteristics alone had fair predictive value (accuracy range, 0.61-0.72; κ range, 0.17-0.30). Baseline predictors combined with pain change at week 1 had moderate predictive value (accuracy, 0.73-0.81; κ range, 0.37-0.49). Baseline predictors with pain change at weeks 1 and 3 had substantial predictive value (accuracy, 0.83-0.89; κ range, 0.54-0.71). When variable importance across the models was estimated, the best predictor of 50% responder status was pain change at week 3 (average importance 100.0%), followed by pain change at week 1 (48.1%), baseline pain score (14

Very low calorie diet without aspartame in obese subjects: improved metabolic control after 4 weeks treatment.

Science.gov (United States)

Norén, Erik; Forssell, Henrik

2014-07-28

Very low calorie diet (VLCD) is routinely used in programs for treatment of obesity and before bariatric surgery in order to reduce risk of postoperative complications. Aspartame, an artificial sweetener, is commonly used in VLCD and is well approved as a food additive without any adverse effects. The development of a new fructose containing VLCD formula without aspartame raises questions as to effects on glucose and lipid control. As part of an ongoing study of a novel bariatric surgery procedure, twenty-five obese subjects with mean body mass index (BMI) 39.8 kg/m2 and mean age of 48.8 years enrolled in a single center observational study. Seven subjects presented with type 2 diabetes mellitus. The subjects underwent four weeks dietary treatment with VLCD Slanka (Slanka). Blood samples including fasting plasma glucose, HbA1c, cholesterol and triglycerides were performed at start and after four weeks of diet. Blood pressure and weight were noted. All subjects completed the diet without any adverse events. Mean weight reduction was 8.2 kg with 95% confidence interval 7.1-9.2 kg (p = 0.001). Excess weight (i.e. proportion of weight exceeding BMI 25) loss decreased by median 19.5% (inter quartile range (IQR) 16,8-24,2). Median fasting plasma glucose was at inclusion 5,6 mmol/l (IQR 5,3-6,8) and after diet 4.8 mmol/l (IQR 4,6-5,2) (p = 0.001). Median HbA1c changed from 39 mmol/mol (IQR 37-44) to 37 mmol/mol (IQR 35-43) (p = 0.001). There was also significant reduction in cholesterol and triglyceride levels as well as in systolic blood pressure. Changes in other monitored blood chemistry values were without clinical importance. Four weeks treatment with fructose containing VLCD of obese subjects preparing for bariatric surgery gave a substantial weight reduction without any significant negative metabolic effects.

A comparative study of olanzapine versus asenapine in acute treatment of manic episode: A 3-week prospective study

Directory of Open Access Journals (Sweden)

Ajeet Sidana

2014-01-01

Full Text Available Introduction: Treatment of bipolar disorders has evolved over the years from conventional mood stabilizers to second-generation antipsychotics. Among the atypical antipsychotics, few have been approved by Food and Drug Administration as treatment of bipolar disorders. Aim: To study the efficacy and tolerability of olanzapine and asenapine in the acute treatment of bipolar disorder-manic episode in a 3-week randomized prospective study. Materials and Methods: A 3-week randomized, prospective, comparative, flexible doses of olanzapine (5-30 mg/day and asenapine (10-20 mg/day for acute treatment of bipolar disorder-current manic episode with or without psychotic symptoms in hospitalized patients. Results: The end-point reduction in mean score of Young Mania rating scale in the olanzapine group was 15.82 in comparison to 6.88 in the asenapine group. Mean score on clinical global impression for bipolar disorder and positive and negative syndrome scale was significantly less in the olanzapine group at the end of the study. 81.81% patients in olanzapine group and 17.60% patients in asenapine group had clinical response. There was significant average weight gain in the olanzapine group - 1.9 kg in comparison to 0.87 kg in asenapine group. Conclusion: The clinical response with olanzapine is significantly higher than the asenapine in the treatment of bipolar disorder-manic episode with or without psychotic symptoms. However, there is significant weight gain in olanzapine-treated patients.

Potential benefits of slow titration of paroxetine treatment in an elderly population: eight-week results from a naturalistic setting.

Science.gov (United States)

Gibiino, Sara; Mori, Elisa; De Ronchi, Diana; Serretti, Alessandro

2013-08-01

Late-life depression, often in association with anxiety, affects approximately 15% of individuals older than 65 years. Selective serotonin reuptake inhibitors are the first-line treatment but could be responsible of an early exacerbation of anxiety, possibly reduced by a very gradual titration of drugs. The main aim of this study is to compare gradual and rapid (standard) titration of paroxetine in an elderly population. In a naturalistic setting, 50 elderly (≥60 years old) outpatients with unipolar mood disorder or anxiety disorder were naturalistically assigned to abrupt initiation of 10 mg of paroxetine or to a gradual increase with 2.5 mg on alternate days up to 10 mg in 7 days. Then dosage could be maintained at 10 mg or increased according to clinical response. Primary outcome was efficacy as assessed by the Hamilton Depression Rating Scale (HAM-D) 21, HAM-D symptom subscales (core, psychic anxiety, somatic anxiety cluster), and Hamilton Anxiety Rating Scale changes. Secondary outcome was evaluation of overall dropouts at eighth week and evaluation of most common adverse effects through the global judgment of the Dosage Record and Treatment Emergent Symptom Scale. All data were recorded weekly for the first 8 weeks of treatment (with 1 more evaluation after 3 days from the baseline). Samples were comparable at baseline, with patients in gradual titration showing a higher level of psychic anxiety. During the first 3 days of treatment, a significant worsening in psychic anxiety was observed in patients treated abruptly with 10 mg of paroxetine (difference in HAM-D psychic anxiety subscale from baseline: 110.61% vs 89.38% with rapid and slow titration, respectively; t test P = 0.03). Overall, a significantly greater improvement in depressive and anxious symptoms favored gradual titration (HAM-D core cluster and HAM-D psychic anxiety cluster, respectively, P = 0.014 and P titration). Our results suggest that a gradual titration of paroxetine could avoid the

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.

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.

Anabolic Therapy for the Treatment of Osteoporosis in Childhood.

Science.gov (United States)

Ward, Leanne M; Rauch, Frank

2018-06-01

Numerous forms of osteoporosis in childhood are characterized by low bone turnover (for example, osteoporosis due to neuromuscular disorders and glucocorticoid exposure). Anti-resorptive therapy, traditionally used to treat osteoporosis in the young, is associated with further reductions in bone turnover, raising concerns about the long-term safety and efficacy of such therapy. These observations have led to increasing interest in the role of anabolic therapy to treat pediatric osteoporosis. While growth hormone and androgens appears to be relatively weak anabolic modulators of bone mass, emerging therapies targeting bone formation pathways (anti-transforming growth factor beta antibody and anti-sclerostin antibody) hold considerable promise. Teriparatide remains an attractive option that merits formal study for patients post-epiphyseal fusion, although it must be considered that adult studies have shown its effect is blunted when administered following bisphosphonate therapy. Mechanical stimulation of bone through whole body vibration therapy appears to be much less effective than bisphosphonate therapy for treating osteoporosis in children. New anabolic therapies which target important pathways in skeletal metabolism merit further study in children, including their effects on fracture risk reduction and after treatment discontinuation.

75 FR 10993 - Save Your Vision Week, 2010

Science.gov (United States)

2010-03-10

... proclaim the first week in March of each year as ``Save Your Vision Week.'' NOW, THEREFORE, I, BARACK OBAMA... Your Vision Week, 2010 By the President of the United States of America A Proclamation While many... identified risk factors, early detection methods, and new treatments for many eye conditions, but individuals...

Treatment of visceral leishmaniasis in a patient with AIDS with antimony and gamma-interferon: remission and prevention of relapse by maintenance therapy with weekly pentamidine

NARCIS (Netherlands)

Lustig, V.; Kager, P. A.; Meenhorst, P. L.

1995-01-01

A 41-year-old AIDS patient with fever, nightly perspiration, diarrhoea, anaemia and leukopenia was diagnosed as having visceral leishmaniasis (VL). After 8 weeks of antimony treatment combined with gamma-interferon, given in 2 courses of 3 and 5 weeks, 12 weeks apart, the bone marrow revealed no

Encounter Decision Aid vs. Clinical Decision Support or Usual Care to Support Patient-Centered Treatment Decisions in Osteoporosis: The Osteoporosis Choice Randomized Trial II.

Directory of Open Access Journals (Sweden)

Annie LeBlanc

Full Text Available Osteoporosis Choice, an encounter decision aid, can engage patients and clinicians in shared decision making about osteoporosis treatment. Its effectiveness compared to the routine provision to clinicians of the patient's estimated risk of fracture using the FRAX calculator is unknown.Patient-level, randomized, three-arm trial enrolling women over 50 with osteopenia or osteoporosis eligible for treatment with bisphosphonates, where the use of Osteoporosis Choice was compared to FRAX only and to usual care to determine impact on patient knowledge, decisional conflict, involvement in the decision-making process, decision to start and adherence to bisphosphonates.We enrolled 79 women in the three arms. Because FRAX estimation alone and usual care produced similar results, we grouped them for analysis. Compared to these, use of Osteoporosis Choice increased patient knowledge (median score 6 vs. 4, p = .01, improved understanding of fracture risk and risk reduction with bisphosphonates (p = .01 and p<.0001, respectively, had no effect on decision conflict, and increased patient engagement in the decision making process (OPTION scores 57% vs. 43%, p = .001. Encounters with the decision aid were 0.8 minutes longer (range: 33 minutes shorter to 3.0 minutes longer. There were twice as many patients receiving and filling prescriptions in the decision aid arm (83% vs. 40%, p = .07; medication adherence at 6 months was no different across arms.Supporting both patients and clinicians during the clinical encounter with the Osteoporosis Choice decision aid efficiently improves treatment decision making when compared to usual care with or without clinical decision support with FRAX results.clinical trials.gov NCT00949611.

Root canal therapy for the prevention of osteonecrosis of the jaws: an evidence-based clinical update.

Science.gov (United States)

Kyrgidis, Athanassios; Arora, Amit; Lyroudia, Kleoniki; Antoniades, Konstantinos

2010-12-01

Osteonecrosis of the jaws is an adverse effect of bone preservation treatment. There is a sufficient body of evidence to associate osteonecrosis of the jaws development with dental extractions and trauma caused from ill-fitting dentures. In this review, we critically appraise available evidence about the clinical efficacy of root canal therapy in patients receiving bisphosphonates.We review a series of theories to explain why endodontic treatment is a safe clinical intervention to prevent osteonecrosis of the jaws in patients receiving bisphosphonates. Root canal therapy could postpone or even eradicate the need for dental extractions of carious teeth in patients on bisphosphonates who may develop osteonecrosis of the jaws. Patients receiving bisphosphonates should be offered the full range of preventive care to reduce their risk to both dental caries and periodontal disease, so that the need for both endodontic therapy and dental extractions will be reduced. Implementing such a strategy would require both practitioner and patient education through the combined efforts of medical and dental societies. Such an approach is justified, as the risk of compromising the oral health of patients on bisphosphonates undertaking endodontic treatment is negligible compared with the benefit from avoiding dental extractions.

One week treatment with the IL-1 receptor antagonist anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus.

Science.gov (United States)

van Asseldonk, Edwin J P; van Poppel, Pleun C M; Ballak, Dov B; Stienstra, Rinke; Netea, Mihai G; Tack, Cees J

2015-10-01

Inflammation associated with obesity is involved in the development of insulin resistance. We hypothesized that anti-inflammatory treatment with the Interleukin-1 receptor antagonist anakinra would improve insulin sensitivity. In an open label proof-of-concept study, we included overweight patients diagnosed with type 1 diabetes with an HbA1c level over 7.5%. Selecting insulin resistant patients with longstanding type 1 diabetes allowed us to study the effects of anakinra on insulin sensitivity. Patients were treated with 100mg anakinra daily for one week. Insulin sensitivity, insulin need and blood glucose profiles were measured before, after one week and after four weeks of follow-up. Fourteen patients completed the study. One week of anakinra treatment led to an improvement of insulin sensitivity, an effect that was sustained for four weeks. Similarly, glucose profiles, HbA1c levels and insulin needs improved. In conclusion, one week of treatment with anakinra improves insulin sensitivity in patients with type 1 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

SU-D-BRD-02: Auto Weekly - An Automated Online Weekly Chart Check System for Medical Physics

Energy Technology Data Exchange (ETDEWEB)

Tan, J; Yan, Y; Hager, F; Gu, X; Jia, X; Pompos, A; Foster, R; Stojadinovic, S; Yang, M; Hrycushko, B; Folkerts, M; Zhao, B; Medin, P; Ding, C; Jiang, S [UT Southwestern Medical Center, Dallas, TX (United States)

2015-06-15

Purpose: Radiation therapy has evolved to become not only more precise and potent, but also more complicated to monitor and deliver. More rigorous and comprehensive quality assurance is needed to safeguard ever advancing radiation therapy. ICRU standards dictate that an ever growing set of treatment parameters are manually checked weekly by medical physicists. This “weekly chart check” procedure is laborious and subject to human errors or other factors. A computer-assisted chart checking process will enable more complete and accurate human review of critical parameters, reduce the risk of medical errors, and improve the efficiency. Methods: We developed a web-based software system that enables a thorough weekly quality assurance checks. In the backend, the software retrieves all machine parameters from a Treatment Management System (TMS) and compares them against the corresponding ones from the treatment planning system. They are also checked for validity against preset rules. The results are displayed as a web page in the front-end for physicists to review. Then a summary report is generated and uploaded automatically to the TMS as a record for weekly chart checking. Results: The software system has been deployed on a web server in our department’s intranet, and has been tested thoroughly by our clinical physicists. A plan parameter would be highlighted when it is off the preset limit. The developed system has changed the way of checking charts with significantly improved accuracy, efficiency, and completeness. It has been shown to be robust, fast, and easy to use. Conclusion: A computer-assisted system has been developed for efficient, accurate, and comprehensive weekly chart checking. The system has been extensively validated and is being implemented for routine clinical use.

SU-D-BRD-02: Auto Weekly - An Automated Online Weekly Chart Check System for Medical Physics

International Nuclear Information System (INIS)

Tan, J; Yan, Y; Hager, F; Gu, X; Jia, X; Pompos, A; Foster, R; Stojadinovic, S; Yang, M; Hrycushko, B; Folkerts, M; Zhao, B; Medin, P; Ding, C; Jiang, S

2015-01-01

Purpose: Radiation therapy has evolved to become not only more precise and potent, but also more complicated to monitor and deliver. More rigorous and comprehensive quality assurance is needed to safeguard ever advancing radiation therapy. ICRU standards dictate that an ever growing set of treatment parameters are manually checked weekly by medical physicists. This “weekly chart check” procedure is laborious and subject to human errors or other factors. A computer-assisted chart checking process will enable more complete and accurate human review of critical parameters, reduce the risk of medical errors, and improve the efficiency. Methods: We developed a web-based software system that enables a thorough weekly quality assurance checks. In the backend, the software retrieves all machine parameters from a Treatment Management System (TMS) and compares them against the corresponding ones from the treatment planning system. They are also checked for validity against preset rules. The results are displayed as a web page in the front-end for physicists to review. Then a summary report is generated and uploaded automatically to the TMS as a record for weekly chart checking. Results: The software system has been deployed on a web server in our department’s intranet, and has been tested thoroughly by our clinical physicists. A plan parameter would be highlighted when it is off the preset limit. The developed system has changed the way of checking charts with significantly improved accuracy, efficiency, and completeness. It has been shown to be robust, fast, and easy to use. Conclusion: A computer-assisted system has been developed for efficient, accurate, and comprehensive weekly chart checking. The system has been extensively validated and is being implemented for routine clinical use

Subclinical Cardiac Dysfunction Detected by Strain Imaging During Breast Irradiation With Persistent Changes 6 Weeks After Treatment

Energy Technology Data Exchange (ETDEWEB)

Lo, Queenie [University of New South Wales, Sydney, NSW (Australia); Liverpool Hospital, Sydney, NSW (Australia); Hee, Leia; Batumalai, Vikneswary [University of New South Wales, Sydney, NSW (Australia); Liverpool Hospital, Sydney, NSW (Australia); Ingham Institute of Applied Medical Research, Liverpool, NSW (Australia); Allman, Christine [Liverpool Hospital, Sydney, NSW (Australia); MacDonald, Peter [University of New South Wales, Sydney, NSW (Australia); St. Vincent' s Hospital, Sydney, NSW (Australia); Delaney, Geoff P. [University of New South Wales, Sydney, NSW (Australia); Liverpool Hospital, Sydney, NSW (Australia); Ingham Institute of Applied Medical Research, Liverpool, NSW (Australia); Lonergan, Denise [Liverpool Hospital, Sydney, NSW (Australia); Ingham Institute of Applied Medical Research, Liverpool, NSW (Australia); Thomas, Liza, E-mail: l.thomas@unsw.edu.au [University of New South Wales, Sydney, NSW (Australia); Liverpool Hospital, Sydney, NSW (Australia)

2015-06-01

Purpose: To evaluate 2-dimensional strain imaging (SI) for the detection of subclinical myocardial dysfunction during and after radiation therapy (RT). Methods and Materials: Forty women with left-sided breast cancer, undergoing only adjuvant RT to the left chest, were prospectively recruited. Standard echocardiography and SI were performed at baseline, during RT, and 6 weeks after RT. Strain (S) and strain rate (Sr) parameters were measured in the longitudinal, circumferential, and radial planes. Correlation of change in global longitudinal strain (GLS % and Δ change) and the volume of heart receiving 30 Gy (V30) and mean heart dose (MHD) were examined. Results: Left ventricular ejection fraction was unchanged; however, longitudinal systolic S and Sr and radial S were significantly reduced during RT and remained reduced at 6 weeks after treatment [longitudinal S (%) −20.44 ± 2.66 baseline vs −18.60 ± 2.70* during RT vs −18.34 ± 2.86* at 6 weeks after RT; longitudinal Sr (s{sup −1}) −1.19 ± 0.21 vs −1.06 ± 0.18* vs −1.06 ± 0.16*; radial S (%) 56.66 ± 18.57 vs 46.93 ± 14.56* vs 49.22 ± 15.81*; *P<.05 vs baseline]. Diastolic Sr were only reduced 6 weeks after RT [longitudinal E Sr (s{sup −1}) 1.47 ± 0.32 vs 1.29 ± 0.27*; longitudinal A Sr (s{sup −1}) 1.19 ± 0.31 vs 1.03 ± 0.24*; *P<.05 vs baseline], whereas circumferential strain was preserved throughout. A modest correlation between S and Sr and V30 and MHD was observed (GLS Δ change and V30 ρ = 0.314, P=.05; GLS % change and V30 ρ = 0.288, P=.076; GLS Δ change and MHD ρ = 0.348, P=.03; GLS % change and MHD ρ = 0.346, P=.031). Conclusions: Subclinical myocardial dysfunction was detected by 2-dimensional SI during RT, with changes persisting 6 weeks after treatment, though long-term effects remain unknown. Additionally, a modest correlation between strain reduction and radiation dose was observed.

Multidisciplinary Treatment of Severe Osteogenesis Imperfecta: Functional Outcomes at Skeletal Maturity.

Science.gov (United States)

Montpetit, Kathleen; Palomo, Telma; Glorieux, Francis H; Fassier, François; Rauch, Frank

2015-10-01

To determine the functional outcomes associated with long-term multidisciplinary treatment, intravenous bisphosphonate treatment, orthopedic surgery, and rehabilitation in children with severe osteogenesis imperfecta (OI) (diagnosed clinically as OI types III or IV). Retrospective study where outcomes were measured prospectively. Pediatric orthopedic hospital. Adolescents (N=41; age range, 15-21y) with severe OI (OI type III: n=17; OI type IV: n=24) who had started therapy before the age of 6 years, had received treatment for at least 10 years, and had achieved final height. Intravenous bisphosphonate treatment, orthopedic surgery, and rehabilitation. Pediatric Evaluation of Disability Inventory. At the time of the last available follow-up examination, none of the individuals diagnosed with OI type III (most severely affected group) was able to ambulate without ambulation aids, whereas 20 (83%) patients with OI type IV were able to ambulate without ambulation aids. Regarding self-care, we specifically assessed 8 skills that we deemed essential for living independently (grooming; dressing; toileting; bed, chair, toilet, tub, and car transfers). Only 6 (35%) of the youths with OI type III were able to complete all 8 items, whereas 23 (96%) individuals with OI type IV managed to perform all tasks. Teens with OI type III often needed assistance for the transfer to toilet, tub, and car and for personal hygiene and clothing management associated with toileting, usually because of limitations in upper-extremity function. These observations suggest that further improvements in the functional status of the most severely affected children with OI are contingent on advances in the clinical management of upper-extremity issues. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Evaluation of third treatment week as temporal window for assessing responsiveness on repeated FDG-PET-CT scans in Non-Small Cell Lung Cancer patients.

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Lazzeroni, M; Uhrdin, J; Carvalho, S; van Elmpt, W; Lambin, P; Dasu, A; Wersäll, P; Toma-Dasu, I

2018-02-01

Early assessment of tumour response to treatment with repeated FDG-PET-CT imaging has potential for treatment adaptation but it is unclear what the optimal time window for this evaluation is. Previous studies indicate that changes in SUV mean and the effective radiosensitivity (α eff , accounting for uptake variations and accumulated dose until the second FDG-PET-CT scan) are predictive of 2-year overall survival (OS) when imaging is performed before radiotherapy and during the second week. This study aims to investigate if multiple FDG-PET-derived quantities determined during the third treatment week have stronger predictive power. Twenty-eight lung cancer patients were imaged with FDG-PET-CT before radiotherapy (PET1) and during the third week (PET2). SUV mean , SUV max , SUV peak , MTV41%-50% (Metabolic Tumour Volume), TLG41%-50% (Total Lesion Glycolysis) in PET1 and PET2 and their change (), as well as average α eff (α¯ eff ) and the negative fraction of α eff values [Formula: see text] ) were determined. Correlations were sought between FDG-PET-derived quantities and OS with ROC analysis. Neither SUV mean , SUV max , SUV peak in PET1 and PET2 (AUC = 0.5-0.6), nor their changes (AUC = 0.5-0.6) were significant for outcome prediction purposes. Lack of correlation with OS was also found for α¯ eff (AUC = 0.5) and [Formula: see text] (AUC = 0.5). Threshold-based quantities (MTV41%-50%, TLG41%-50%) and their changes had AUC = 0.5-0.7. P-values were in all cases ≫0.05. The poor OS predictive power of the quantities determined from repeated FDG-PET-CT images indicates that the third week of treatment might not be suitable for treatment response assessment. Comparatively, the second week during the treatment appears to be a better time window. Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Clinical and radiographic evaluation of effect of risedronate 5 mg as an adjunct to treatment of chronic periodontitis in postmenopausal women (12-month study).

Science.gov (United States)

Bhavsar, N V; Trivedi, S R; Dulani, K; Brahmbhatt, N; Shah, S; Chaudhri, D

2016-08-01

Bisphosphonates are beneficial to women, after menopause, in treatment of gum diseases. In this study, significant improvement in the disease condition was found and that no further progress was noted, and no side effects were reported. Bisphosphonates can be safely and successfully be used to support oral health procedures. The purpose of this study was to evaluate host modulating effect of bisphosphonate adjunct with the treatment of chronic periodontitis in osteopenic and osteoporotic postmenopausal women. Twenty-two osteopenic and osteoporotic postmenopausal women with moderate to severe chronic periodontitis were selected for the study. On intraoral examination, periodontal parameters like probing depth (PD), clinical attachment level (CAL), Plaque Index (PI) and Gingival Index (GI) were recorded. Scaling and root planing were done. Intraoral periapical X-rays were taken, and alveolar bone density (ABD) was measured with cone beam computed tomography (CBCT), and then, medications (risedronate 5 mg once daily (OD), calcium citrate 250 mg OD, vitamin D 400 IU OD) were given. Patients were recalled for follow-up at 3, 6 and 12 months. Intraoral periapical (IOPA) X-rays were taken at 6 and 12 months and ABD was measured at baseline and 12 months. There was a significant improvement in all the parameters. There was an increase of 0.02 ± 0.001 cm on CT scan and 0.38 ± 0.005 mm on IOPA in bone height over 12 months from baseline. Bone density increased by 118.56 ± 3.251 Hounsfield units (HU). There was no progress in the disease, and further bone loss was not noticed. This is in correlation with clinical parameters which showed highly significant gain in CAL (3.57 ± 0.234 mm) and reduction in PD (2.20 ± 0.229 mm) Bisphosphonate therapy as an adjunct to scaling and root planing may have significant beneficial clinical effects on the periodontium of postmenopausal women with moderate to severe chronic periodontitis.

Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function

DEFF Research Database (Denmark)

Kielgast, Urd; Krarup, Thure; Holst, Jens Juul

2011-01-01

OBJECTIVE To investigate the effect of 4 weeks of treatment with liraglutide on insulin dose and glycemic control in type 1 diabetic patients with and without residual ß-cell function. RESEARCH DESIGN AND METHODS Ten type 1 diabetic patients with residual ß-cell function (C-peptide positive) and 19.......1]; P Treatment with liraglutide in type 1 diabetic patients reduces insulin dose with improved or unaltered glycemic control....... activity was performed before (week 0) and during (week 4) treatment. Differences in insulin dose; HbA(1c); time spent with blood glucose 10, and 3.9-9.9 mmol/L; and body weight were evaluated. RESULTS Insulin dose decreased from 0.50 ± 0.06 to 0.31 ± 0.08 units/kg per day (P

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)

Neonatal abstinence syndrome: Neurobehavior at 6 weeks of age in infants with or without pharmacological treatment for withdrawal.

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Heller, Nicole A; Logan, Beth A; Morrison, Deborah G; Paul, Jonathan A; Brown, Mark S; Hayes, Marie J

2017-07-01

Use and abuse of prescription opioids and concomitant increase in Neonatal Abstinence Syndrome (NAS), a condition that may lead to protracted pharmacological treatment in more than 60% of infants, has tripled since 2000. This study assessed neurobehavioral development using the NICU Network Neurobehavioral Scale in 6-week old infants with prenatal methadone exposure who did (NAS+; n = 23) or did not (NAS-; n = 16) require pharmacological treatment for NAS severity determined by Finnegan Scale. An unexposed, demographically similar group of infants matched for age served as comparison (COMP; n = 21). NAS+, but not NAS- group, had significantly lower scores on the regulation (p < .01) and quality of movement (p < .01) summary scales than the COMP group. The NAS+ and NAS- groups had higher scores on the stress-abstinence scale than the COMP group (p < .05). NAS diagnosis (NAS +) was associated with poorer regulation and quality of movement at 6 weeks of age compared to infants without prenatal methadone exposure from the same demographic. © 2017 Wiley Periodicals, Inc.

An Internet treatment with weekly e-mail contacts used in a tobacco unit: clinical utility and predictors of outcome

NARCIS (Netherlands)

Gallego, M.J.; Modesto, M.; Muñoz, M.A.; Almajano, M.J.; Modolell, E.; Peris, C.P.; Emmelkamp, P.M.G.

2014-01-01

This work presents preliminary data on the clinical utility and outcome predictors of The San Francisco Stop Smoking Internet Site (SFSSIS) (Lenert et al., 2003) used with weekly e-mail contacts and the usual pharmacological treatment. Fifty smokers participated in the current series of cases, 24

Two weeks of metformin treatment induces AMPK dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

DEFF Research Database (Denmark)

Kristensen, Jonas Møller; Treebak, Jonas Thue; Schjerling, Peter

2014-01-01

signaling. Methods: Oral doses of metformin or saline treatment were given muscle-specific kinase α2 dead AMPK mice (KD) and wild type (WT) littermates either once or chronically for 2 weeks. Soleus and Extensor Digitorum Longus (EDL) muscles were used for measurements of glucose transport and Western blot......Background: Metformin-induced activation of AMPK has been associated with enhanced glucose uptake in skeletal muscle but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent upon AMPK...... analyzes. Results: Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (45%, P...

Effects of short-term alendronate treatment on the three-dimensional microstructural, physical and mechanical properties of dog trabecular bone

DEFF Research Database (Denmark)

Hu, J; Ding, Ming; Søballe, K

2002-01-01

The bisphosphonate, alendronate, is well known for its potent inhibition of osteoclast-mediated bone resorption. It has been used clinically for the treatment of osteoporosis and has also recently been used to reduce osteolysis around prostheses in a canine revision model of implant loosening...... proximal humeri. These specimens were scanned using a high-resolution microcomputed tomography (micro-CT) system. From accurate data sets, three-dimensional microstructural properties were calculated and physical and mechanical properties were determined. Treatment with alendronate increased bone volume...

Denosumab – a new medication in the treatment of postmenopausal osteoporosis

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Radosław Słopień

2017-10-01

Full Text Available Osteoporosis is a chronic, systemic skeletal disorder characterised by decreased bone density. It leads to an increased risk of bone fractures – one of the major causes of disability in modern societies. Bisphosphonates are the most commonly used medications in the treatment of postmenopausal osteoporosis. Denosumab, a new approach to fracture prevention, is a fully human monoclonal antibody that targets nuclear factor-B ligand (RANKL, an important cytokine regulating formation and function of osteoclasts. Generally, denosumab is not used as initial therapy; however, in some cases it should be considered. It concerns patients at high risk of fracture, such as older patients who have difficulty with the dosing requirements of oral bisphosphonates or who have markedly impaired renal function. Denosumab can be also considered in patients who present intolerance or unresponsiveness to other therapies. Clinical studies have shown that denosumab is highly effective in increasing bone mineral density (BMD in postmenopausal women regardless of the site analysed, as well as reducing the risk of bone fractures. The risk of developing antiresorptive, agent-induced osteonecrosis of the jaw related to denosumab therapy is low.

MANAGEMENT OF ENDOCRINE DISEASE: Atypical femoral fractures: risks and benefits of long-term treatment of osteoporosis with anti-resorptive therapy.

Science.gov (United States)

Adler, Robert A

2018-03-01

Modern osteoporosis treatment began in the mid-1990s with the approval of amino-bisphosphonates, anti-resorptive agents that have been shown to decrease osteoporotic fracture risk by about half. In 2005, the first cases of atypical femoral fractures (AFF), occurring in the shaft of the femur, were reported. Since then, more cases have been found, leading to great concern among patients and a dramatic decrease in bisphosphonate prescribing. The pathogenesis and incidence of AFF are reviewed herein. Management and an approach to prevention or early detection of AFF are also provided. Denosumab, a more recently approved anti-resorptive medication has also been associated with AFF. Long-term management of osteoporosis and prevention of fracture are challenging in light of this serious but uncommon side effect, yet with an aging population osteoporotic fracture is destined to increase in frequency. © 2018 European Society of Endocrinology.

Six weeks of continuous joint distraction appears sufficient for clinical benefit and cartilaginous tissue repair in the treatment of knee osteoarthritis.

Science.gov (United States)

van der Woude, J A D; van Heerwaarden, R J; Spruijt, S; Eckstein, F; Maschek, S; van Roermund, P M; Custers, R J H; van Spil, W E; Mastbergen, S C; Lafeber, F P J G

2016-10-01

Knee joint distraction (KJD) is a surgical joint-preserving treatment in which the knee joint is temporarily distracted by an external frame. It is associated with joint tissue repair and clinical improvement. Initially, patients were submitted to an eight-week distraction period, and currently patients are submitted to a six-week distraction period. This study evaluates whether a shorter distraction period influences the outcome. Both groups consisted of 20 patients. Clinical outcome was assessed by WOMAC questionnaires and VAS-pain. Cartilaginous tissue repair was assessed by radiographic joint space width (JSW) and MRI-observed cartilage thickness. Baseline data between both groups were comparable. Both groups showed an increase in total WOMAC score; 24±4 in the six-week group and 32±5 in the eight-week group (both p<0.001). Mean JSW increased 0.9±0.3mm in the six-week group and 1.1±0.3mm in the eight-week group (p=0.729 between groups). The increase in mean cartilage thickness on MRI was 0.6±0.2mm in the eight-week group and 0.4±0.1mm in the six-week group (p=0.277). A shorter distraction period does not influence short-term clinical and structural outcomes statistically significantly, although effect sizes tend to be smaller in six week KJD as compared to eight week KJD. Copyright © 2016 Elsevier B.V. All rights reserved.

Pregnancy Calendar: A Week-by-Week Guide

Science.gov (United States)

... Fitness Diseases & Conditions Infections Drugs & Alcohol School & Jobs Sports Expert Answers (Q&A) Staying Safe Videos for Educators Search English Español A Week-by-Week Pregnancy Calendar KidsHealth / For Parents / A Week-by-Week ...

Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength.

Science.gov (United States)

Sinder, B P; White, L E; Salemi, J D; Ominsky, M S; Caird, M S; Marini, J C; Kozloff, K M

2014-08-01

Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect. Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1. Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2×/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed. Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength. Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI.

A randomized, 4-week double-blind placebo control study on the efficacy of donepezil augmentation of lithium for treatment of acute mania

Directory of Open Access Journals (Sweden)

Chen J

2013-06-01

Full Text Available Jing Chen,1 Zheng Lu,1,2 Mingyuan Zhang,1 Jie Zhang,1 Xiaodong Ni,1 Xuefeng Jiang,1 Heding Xu,1 Anisha Heeramun-Aubeeluck,2 Qiaoyan Hu,3 Hua Jin,4 John M Davis31Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Psychiatry, Tongji Hospital of Tongji University, Shanghai, People’s Republic of China; 3University of Illinois at Chicago, Chicago, IL, USA; 4University of California at San Diego, San Diego, CA, USAIntroduction: A significant number of mania patients fail to respond to current pharmacotherapy, thereby there is need for novel augmentation strategies. The results of some early studies showed the effectiveness of cholinomimetics in the treatment of mania. One open case series suggested the efficacy of donepezil in the treatment of bipolar disorder. Our aim was to explore whether an oral cholinesterase inhibitor, donepezil, administered during a 4-week treatment period,would benefit patients with acute mania.Methods: We conducted a 4-week double-blind, placebo-controlled trial of donepezil as an adjunctive treatment to lithium in patients with acute mania. Eligible subjects were randomly assigned to receive donepezil or placebo in addition to lithium. Donepezil was started at 5 mg/day, and increased to 10 mg/day in the first week. Patients were rated with the Young Mania Rating Scale (YMRS and Brief Psychiatric Rating Scale (BPRS at baseline, day 1, week 1, week 2, and week 4.Results: Out of the 30 patients who were enrolled, 15 were on donepezil and 15 were on placebo. All patients completed the 4-week trial. On the first day, there was a difference of 1.97 units on the psychomotor symptoms scale of the YMRS in the donepezil group as compared to the placebo group (t = 2.39, P = 0.02. There was a difference of 0.57 units (t = 2.09, P = 0.04 in the speech item and a difference of 0.29 units in the sexual interest item (t = 2.11, P = 0.04 in the donepezil

Atomoxetine treatment may decrease striatal dopaminergic transporter availability after 8 weeks: pilot SPECT report of three cases

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Akay AP

2015-11-01

Full Text Available Aynur Pekcanlar Akay,1 Gamze Capa Kaya,2,3 Burak Baykara,1 Yusuf Demir,2,3 Handan Özek,1 Sevay Alsen,1 Mine Sencan Eren,2,3 Neslihan Inal Emiroglu,1 Turkan Ertay,2,3 Yesim Ozturk,4 Suha Miral,1 Hatice Durak,2,3 Evren Tufan4 1Department of Child and Adolescent Psychiatry, 2Department of Nuclear Medicine, 3Department of Pediatrics, Dokuz Eylul University Medical Faculty, Izmir, 4Department of Child and Adolescent Psychiatry, Abant İzzet Baysal University, Bolu, Turkey Abstract: Attention deficit/hyperactivity disorder is one of the most common neurodevelopmental disorders. The pathophysiology is thought to involve noradrenaline and dopamine. The role of dopamine transporter (DAT was evaluated in imaging studies using mostly dopamine reuptake inhibitors. Atomoxetine is a selective noradrenaline reuptake inhibitor. Here we report the results of a pilot study conducted to evaluate changes in striatal DAT after 8 weeks of atomoxetine treatment. Our results suggest that 8 weeks of atomoxetine treatment may change striatal DAT bioavailability as measured via SPECT but that change was not correlated with genotype or clinical improvement. Keywords: neuroimaging, dopamine, noradrenaline, SLC6A3 protein, human, pragmatic clinical trial, pilot study

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.

Changes of Heart Rate Variability during Methylphenidate Treatment in Attention-Deficit Hyperactivity Disorder Children: A 12-Week Prospective Study.

Science.gov (United States)

Kim, Hayeon Jennifer; Yang, Jaewon; Lee, Moon Soo

2015-09-01

The aim of this study was to clarify the relationship between the autonomic nervous system and attention deficit hyperactivity disorder (ADHD) rating scales and to evaluate the usefulness of heart rate variability (HRV) as a psychophysiological biomarker for ADHD. Subjects were recruited from outpatients in the Department of Child and Adolescent Psychiatry at the Korea University Medical Center from August 2007 to December 2010. Subjects received methylphenidate. Time- and frequency-domain analyses of HRV, the Korean ADHD rating scale (K-ARS), and computerized ADHD diagnostic system were evaluated before treatment. After a 12-week period of medication administration, we repeated the HRV measurements and K-ARS rating. Eighty-six subjects were initially enrolled and 37 participants completed the 12-week treatment and HRV measurements subsequent to the treatment. Significant correlations were found between the K-ARS inattention score and some HRV parameters. All of the HRV parameters, except the standard deviations of the normal-to-normal interval, very low frequency, and low frequency to high frequency, showed a significant positive correlation between baseline and endpoint measures in completers. High frequency (HF) and the square root of the mean squared differences of successive normal-to-normal intervals (RMSSD), which are related to parasympathetic vagal tone, showed significant decreases from baseline to endpoint. The HRV test was shown to be reproducible. The decrease in HF and RMSSD suggests that parasympathetic dominance in ADHD can be altered by methylphenidate treatment. It also shows the possibility that HRV parameters can be used as psychophysiological markers in the treatment of ADHD.

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...

An update of the Malaysian Clinical Guidance on the management of glucocorticoid-induced osteoporosis, 2015

Directory of Open Access Journals (Sweden)

Swan Sim Yeap

2017-03-01

Conclusions: In post-menopausal women and men above 50 years, bisphosphonates remain the mainstay of treatment in GIO. In pre-menopausal women and men below 50 years, bisphosphonates are recommended for those with a prevalent fracture or at very high risk only.

Successful treatment of chronic recurrent multifocal osteomyelitis using low-dose radiotherapy. A case report

Energy Technology Data Exchange (ETDEWEB)

Dietzel, Christian T.; Vordermark, Dirk [Klinikum der Martin-Luther-Universitaet Halle-Wittenberg, Universitaetslinik und Poliklinik fuer Strahlentherapie, Halle (Saale) (Germany); Schaefer, Christoph [Klinikum der Martin-Luther-Universitaet Halle-Wittenberg, Universitaetsklinik und Poliklinik fuer Innere Medizin II, Halle (Saale) (Germany)

2017-03-15

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disease, which lacks an infectious genesis and predominantly involves the metaphysis of long bones. Common treatments range from nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids at first onset of disease, to immunosuppressive drugs and bisphosphonates in cases of insufficient remission. The therapeutic use of low-dose radiotherapy for CRMO constitutes a novelty. A 67-year-old female patient presented with radiologically proven CRMO affecting the right tibia/talus and no response to immunosuppressive therapy. Two treatment series of radiation therapy were applied with an interval of 6 weeks. Each series contained six fractions (three fractions per week) with single doses of 0.5 Gy, thus the total applied dose was 6 Gy. Ten months later, pain and symptoms of osteomyelitis had completely vanished. Radiotherapy seems to be an efficient and feasible complementary treatment option for conventional treatment refractory CRMO in adulthood. The application of low doses per fraction is justified by the inflammatory pathomechanism of disease. (orig.) [German] Die chronisch rekurrierende multifokale Osteomyelitis (CRMO) ist eine seltene autoimmunologische Erkrankung und befaellt vorzugsweise die Metaphysen der langen Roehrenknochen. Die Therapie umfasst nichtsteroidale Antirheumatika (NSAIDs) und Kortikosteroide bei Erstbefall und reicht bis hin zu Immunsuppressiva und Bisphosphonaten bei insuffizientem Ansprechen. Die Anwendung einer niedrigdosierten Radiatio stellt ein therapeutisches Novum dar. Eine 67-jaehrige Patientin stellte sich mit einem radiologisch gesicherten Befall im Sinne einer CRMO im Bereich des rechten Talus und der Tibia vor. Eine initiale Behandlung mit Immunsuppressiva verblieb erfolglos. Wir fuehrten zwei Bestrahlungsserien im Intervall von 6 Wochen durch. Jede Serie bestand aus 6 Fraktionen (3 Fraktionen/Woche), mit einer Einzeldosis von jeweils 0,5 Gy. Die

The comparison between effect of chemoradiation with weekly cisplatin with or without celecoxib in treatment of nasopharyngeal carcinoma: A phase III clinical trial

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Mohamad Mohammadianpanah

2009-07-01

Full Text Available Introduction: Concurrent cisplatin-based chemoradiation is currently considered the treatment of choice for locoregional nasopharyngeal carcinoma. Celecoxib is a selective cyclooxygenase-2 (COX-2 inhibitor which can potentially enhance the effect of radiotherapy. The aim of this study was to determine the efficacy and safety of celecoxib in nasopharyngeal carcinoma. Materials and Methods: Patients with newly diagnosed locoregional nasopharyngeal carcinoma were included in this clinical trial study. The patients were assigned to receive 7 weeks concurrent chemoradiation with weekly cisplatin and either celecoxib 100 mg twice daily or placebo. After completion of chemoradiation, all patients received combined chemotherapy with cisplatin plus 5-Fu every 3 weeks for 3 cycles. Clinical response rates and treatment-related toxicity were the primary and secondary end-point of the study. Results: Total of 50 eligible patients with the median age of 43 years were enrolled in the trial. Overall (complete and partial clinical response rate was 100% in both groups. Complete and partial clinical response rates were 64% and 36% in study group and 44% and 56% in control group respectively (P>0.25. There was no difference in terms of treatment-related toxicity rates between two groups. Conclusions: This clinical trial showed that addition of celecoxib 100 mg twice daily to concurrent chemoradiation does not increase the response rates and treatment-related toxicities in patients with locoregional nasopharyngeal carcinoma.

The effects of 2 weeks of statin treatment on mitochondrial respiratory capacity in middle-aged males: the LIFESTAT study.

Science.gov (United States)

Asping, Magnus; Stride, Nis; Søgaard, Ditte; Dohlmann, Tine Lovsø; Helge, Jørn W; Dela, Flemming; Larsen, Steen

2017-06-01

Statins are used to lower cholesterol in plasma and are one of the most used drugs in the world. Many statin users experience muscle pain, but the mechanisms are unknown at the moment. Many studies have hypothesized that mitochondrial function could be involved in these side effects. The aim of the study was to investigate mitochondrial function after 2 weeks of treatment with simvastatin (S; n = 10) or pravastatin (P; n = 10) in healthy middle-aged participants. Mitochondrial respiratory capacity and substrate sensitivity were measured in permeabilized muscle fibers by high-resolution respirometry. Mitochondrial content (citrate synthase (CS) activity), antioxidant content, as well as coenzyme Q 10 concentration (Q 10 ) were determined. Fasting plasma glucose and insulin concentrations were measured, and whole body maximal oxygen uptake (VO 2max ) was determined. No differences were seen in mitochondrial respiratory capacity although a tendency was observed for a reduction when complex IV respiration was analyzed in both S (229 (169; 289 (95% confidence interval)) vs. 179 (146; 211) pmol/s/mg, respectively; P = 0.062) and P (214 (143; 285) vs. 162 (104; 220) pmol/s/mg, respectively; P = 0.053) after treatment. A tendency (1.64 (1.28; 2.00) vs. 1.28 (0.99; 1.58) mM, respectively; P = 0.092) for an increased mitochondrial substrate sensitivity (complex I-linked substrate; glutamate) was seen only in S after treatment. No differences were seen in Q 10 , CS activity, or antioxidant content after treatment. Fasting glucose and insulin as well as VO 2max were not changed after treatment. Two weeks of statin (S or P) treatment have no major effect on mitochondrial function. The tendency for an increased mitochondrial substrate sensitivity after simvastatin treatment could be an early indication of the negative effects linked to statin treatment.

A 2-Week Course of Enteral Treatment with a Very Low-Calorie Protein-Based Formula for the Management of Severe Obesity

Directory of Open Access Journals (Sweden)

Giuseppe Castaldo

2015-01-01

Full Text Available Background. Multiple weight loss failures among obese patients suggest the design of new therapeutic strategies. We investigated the role of 2-week course of enteral treatment with a very low-calorie protein-based formula in the management of severe obesity. Methods. We evaluated the feasibility, safety, and efficacy of 2-week continuous administration of a protein-based formula (1.2 g/kg of ideal body weight/day by nasogastric tube in severely obese adults (body mass index (BMI ≥ 40 kg/m2. Results. In total, 364 patients (59% women; BMI = 46.6±7.2 kg/m2 were recruited. The intervention was discontinued within 48 hours in 26 patients, due to nasogastric tube intolerance. No serious adverse events occurred. During the first and the second week, 65% and 80% patients, respectively, reported no side effects. All biochemical safety parameters were affected by the intervention, particularly uric acid (+45% and aminotransferases (+48%. In the other cases the change was negligible. We observed significant weight loss (5.7±2.3% and improvement in blood pressure and glucose and lipid metabolism parameters (P<0.001. Conclusions. A 2-week course of enteral treatment with a very low-calorie protein-based formula appeared a feasible, likely safe, and efficacious therapeutic option to be considered for inclusion into a composite weight loss program for the management of severe obesity. This trial is registered with ClinicalTrials.gov Identifier: NCT01965990.

Impact of bone turnover markers and/or educational information on persistence to oral bisphosphonate therapy: a community setting-based trial.

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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.

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

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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...

Meta-analysis of oral Chinese herbal medicine as an adjuvant treatment in relieving pain secondary to bone metastases.

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Wang, Shi-Jun; Xu, Juan; Gong, Dan-Dan; Man, Chang-Feng; Fan, Yu

2013-10-14

To assess the effectiveness of oral Chinese herbal medicine (CHM) in relieving pain secondary to bone metastases in patients. The searched electronic literature databases included both English and Chinese articles published in the MEDLINE, EMBASE, Wanfang database and China National Knowledge Infrastructure (up to December 2012). The studies included randomized controlled trials (RCTs) comparing CHM plus conventional treatment with conventional treatment alone for patients with pain secondary to bone metastases. The outcomes were the odds ratio (OR) with 95% confidence intervals (CI) for the pain-relief rate and adverse events. A total of 16 RCTs involving 1,008 patients were identified and analyzed. All of the included RCTs were associated with a moderate to high risk of bias. In the metaanalysis, CHM plus conventional treatment increased the pain-relief rate compared with the conventional treatment alone (OR, 2.59; 95% CI 1.95 to 3.45). In subgroup analysis, the pooled OR of the pain-relief rate of CHM plus conventional treatment compared with conventional treatment was 3.11 (95% CI 2.01 to 4.79) for CHM plus bisphosphonates, 2.24 (95% CI 1.33 to 3.78) for CHM plus analgesics, 2.28 (95% CI 1.09 to 4.79) for CHM plus radiotherapy, and 2.22 (95% CI 0.95 to 5.15) for CHM plus analgesics and bisphosphonates. The adverse events included nausea, vomiting, dizziness, fever, and constipation. No serious adverse events were reported in any of the included studies. CHM interventions appear to have beneficial effects on pain secondary to bone metastases in patients. However, published efficacy trials are small in size to draw any firm conclusions.

Treatment of osteoporosis after alendronate or risedronate

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Eiken, P; Vestergaard, P

2016-01-01

Alendronate (ALN) and risedronate (RIS) are ideal as first-choice therapy options in the treatment of postmenopausal osteoporosis. What to do for patients who do not respond adequately to bisphosphonates has not been conclusively determined, but transitioning to other therapies should be considered....... The aim of this article is to describe potential alternatives for patients switching from ALN or RIS to other therapies for osteoporosis. A systematic search of PubMed was conducted to find papers that evaluate the effects of switching therapies on fractures, bone mineral density (BMD), or bone turnover...... markers. Results from 11 studies that prospectively assessed treatment after ALN or RIS in women with postmenopausal osteoporosis were reviewed. All studies are of short duration (all 24 months or less) and assess the topic of transitioning therapy from ALN or RIS. None of the studies had the statistical...

Weekly intra-amniotic IGF-1 treatment increases growth of growth-restricted ovine fetuses and up-regulates placental amino acid transporters.

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Jibran A Wali

Full Text Available Frequent treatment of the growth-restricted (IUGR ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization treated with weekly intra-amniotic injections of either saline (IUGR or 360 µg IGF-1 (IGF1. IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2 mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3 and SLC2A4 (GLUT4 levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3 mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y(+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway.

Four-week rapamycin treatment improves muscular dystrophy in a fukutin-deficient mouse model of dystroglycanopathy.

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Foltz, Steven J; Luan, Junna; Call, Jarrod A; Patel, Ankit; Peissig, Kristen B; Fortunato, Marisa J; Beedle, Aaron M

2016-01-01

Secondary dystroglycanopathies are a subset of muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (αDG). Loss of αDG functional glycosylation prevents it from binding to laminin and other extracellular matrix receptors, causing muscular dystrophy. Mutations in a number of genes, including FKTN (fukutin), disrupt αDG glycosylation. We analyzed conditional Fktn knockout (Fktn KO) muscle for levels of mTOR signaling pathway proteins by Western blot. Two cohorts of Myf5-cre/Fktn KO mice were treated with the mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) for 4 weeks and evaluated for changes in functional and histopathological features. Muscle from 17- to 25-week-old fukutin-deficient mice has activated mTOR signaling. However, in tamoxifen-inducible Fktn KO mice, factors related to Akt/mTOR signaling were unchanged before the onset of dystrophic pathology, suggesting that Akt/mTOR signaling pathway abnormalities occur after the onset of disease pathology and are not causative in early dystroglycanopathy development. To determine any pharmacological benefit of targeting mTOR signaling, we administered RAPA daily for 4 weeks to Myf5/Fktn KO mice to inhibit mTORC1. RAPA treatment reduced fibrosis, inflammation, activity-induced damage, and central nucleation, and increased muscle fiber size in Myf5/Fktn KO mice compared to controls. RAPA-treated KO mice also produced significantly higher torque at the conclusion of dosing. These findings validate a misregulation of mTOR signaling in dystrophic dystroglycanopathy skeletal muscle and suggest that such signaling molecules may be relevant targets to delay and/or reduce disease burden in dystrophic patients.

Trazodone plus pregabalin combination in the treatment of fibromyalgia: a two-phase, 24-week, open-label uncontrolled study

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Rodriguez-Lopez Carmen M

2011-05-01

Full Text Available Abstract Background Although trazodone is frequently used by fibromyalgia patients, its efficacy on this disease has not been adequately studied. If effective, pregabalin, whose beneficial effects on pain and sleep quality in fibromyalgia have been demonstrated, could complement the antidepressant and anxiolytic effects of trazodone. The aim of the present study was to assess the effectiveness of trazodone alone and in combination with pregabalin in the treatment of fibromyalgia. Methods This was an open-label uncontrolled study. Trazodone, flexibly dosed (50-300 mg/day, was administered to 66 fibromyalgia patients during 12 weeks; 41 patients who completed the treatment accepted to receive pregabalin, also flexibly dosed (75-450 mg/day, added to trazodone treatment for an additional 12-week period. Outcome measures included the Fibromyalgia Impact Questionnaire (FIQ, the Pittsburgh Sleep Quality Index (PSQI, the Beck Depression Inventory (BDI, the Hospital Anxiety and Depression Scale (HADS, the Brief Pain Inventory (BPI, the Short-Form Health Survey (SF-36, and the Patients' Global Improvement scale (PGI. Emergent adverse reactions were recorded. Data were analyzed with repeated measures one-way ANOVA and paired Student's t test. Results Treatment with trazodone significantly improved global fibromyalgia severity, sleep quality, and depression, as well as pain interference with daily activities although without showing a direct effect on bodily pain. After pregabalin combination additional and significant improvements were seen on fibromyalgia severity, depression and pain interference with daily activities, and a decrease in bodily pain was also apparent. During the second phase of the study, only two patients dropped out due to side effects. Conclusions Trazodone significantly improved fibromyalgia severity and associated symptomatology. Its combination with pregabalin potentiated this improvement and the tolerability of the drugs in

PAGET'S DISEASE: CURRENT TREATMENT MODALITIES

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Yulia Leonidovna Korsakova

2010-01-01

Full Text Available Paget's disease is a chronic local bone disease included into a group of metabolic osteopathies in which rearrangement foci emerge in one or several bones. The disease is characterized by the appearance of ostealgia, skeletal deformity, or, for example, hearing loss occurring with skull lesion or hip or knee arthrosis and, less frequently, sarcoma or giant cell tumor. There is evidence that bisphosphonates may control the activity of Paget's disease as they inhibit the function of osteoclasts. The use of these drugs reduces the intensity of osteoalgia and the level of biochemical markers for bone resorption and osteogenesis and can decelerate or reverse the early osteolytic phase of the disease. It is promising to use of zolendronic acid (Aclasta, 5 mg, a new heterocyclic amino-containing bisphosphonate that has a significantly higher efficacy than previously used antiresorptive agents.

Correlation of Bone Mineral Density on Quality of Life in Patients with Osteogenesis Imperfecta during Treatment with Denosumab.

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Hoyer-Kuhn, Heike; Stark, Christina; Franklin, Jeremy; Schoenau, Eckhard; Semler, Oliver

2017-11-01

Osteogenesis imperfecta (OI) is a rare hereditary skeletal disease leading to recurrent fractures, short stature and impaired mobility. The phenotype varies from mildly affected patients to perinatal lethal forms. In most cases an impaired collagen production due to mutations in COL1A1 or COL1A2 cause this hereditary bone fragility syndrome with an autosomal dominant inheritance. Currently an interdisciplinary therapeutic approach with antiresorptive drugs, physiotherapy and surgical procedures is the state of the art therapy. The effect of such a therapy is evaluated by measuring different surrogate parameters like areal bone mineral density or by using different mobility tests or questionnaires. Up till now the impact of these parameters on quality of life of the patients is not evaluated. Currently pharmacological strategies are based on antiresorptive treatment with bisphosphonates. In this trial we investigated the effect of an antiresorptive therapy with the monoclonal antibody denosumab decreasing the activity of osteoclasts. Denosumab was administered subcutaneously in a dose of 1mg/kg body weight in 10 children with OI (5-10 years of age) every 12 weeks for 48 weeks. Areal bone mineral density, mobility, pain scores and quality of life were measured. The results showed a good effect of the treatment on bone mineral density but this improvement showed no correlation to pain and quality of life. In conclusion further trials have to define parameters to assess interventions which influence activities of daily life of the patients. An interdisciplinary approach including physicians, basic researchers and patient organisation is needed to focus research on topics improving quality of life of patients with severe skeletal diseases. Copyright© of YS Medical Media ltd.

The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases

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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.

Effects of long-term alendronate treatment on bone mineralisation, resorption parameters and biomechanics of single human vertebral trabeculae

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M Krause

2014-09-01

Full Text Available Due to their well-established fracture risk reduction, bisphosphonates are the most frequently used therapeutic agent to treat osteoporosis. Bisphosphonates reduce fracture risk by suppressing bone resorption, but the lower bone turnover could have a negative impact on bone quality at the tissue level. Here, we directly assess the structural and mechanical characteristics of cancellous bone from the lumbar vertebrae (L5 in non-treated osteoporotic controls (n = 21, mid-term alendronate-treated osteoporotic patients (n = 6, and long-term alendronate-treated osteoporotic patients (n = 7. The strength and toughness of single trabeculae were evaluated, while the structure was characterised through measurements of microdamage accumulation, mineralisation distribution, and histological indices. The alendronate-treated cases had a reduced eroded surface (ES/BS, p < 0.001 and a higher bone mineralisation in comparison to non-treated controls (p = 0.037, which is indicative of low turnover associated with treatment. However, the amount of microdamage and the mechanical properties were similar among the control and treatment groups. As the tissue mineral density (TMD increased significantly with alendronate treatment compared to non-treated osteoporotic controls, the reduction in resorption cavities could counterbalance the higher TMD allowing the alendronate-treated bone to maintain its mechanical properties and resist microdamage accumulation. A multivariate analysis of the possible predictors supports the theory that multiple factors (e.g., body mass index, TMD, and ES/BS can impact the mechanical properties. Our results suggest that long-term alendronate treatment shows no adverse impact on mechanical cancellous bone characteristics.

Multimodality treatment including postoperative radiation and concurrent chemotherapy with weekly docetaxel is feasible and effective in patients with oral and oropharyngeal cancer

International Nuclear Information System (INIS)

Kovacs, A.F.; Bitter, K.; Mose, S.; Boettcher, H.D.

2005-01-01

Background: to examine the feasibility and efficacy of weekly docetaxel with concurrent radiation as postoperative treatment in a multimodality approach to oral and oropharyngeal cancer. Patients and methods: 94 patients (Table 1) with primary resectable squamous cell carcinoma of the oral cavity and oropharynx (UICC stage I 14%, II 15%, III 18%, IV 53%; Table 2) were treated with a multimodality therapy program consisting of neoadjuvant intra-arterial high-dose chemotherapy (cisplatin 150 mg/m 2 with parallel systemic sodium thiosulfate 9 g/m 2 for neutralization), followed by surgery of the primary and neck, and postoperative concurrent radiation and chemotherapy with weekly docetaxel (20-30 mg/m 2 ; Table 3). Chronic toxicities were followed over a period of 5 years. Results: at a median follow-up of 4 years, the 5-year survival rate for all 94 patients was 80%, and disease-free survival was 73% (Figures 1 and 2). Among patients with advanced disease (stage III and IV), survival was 83 and 59%, respectively (Figure 4). Grade 3 and 4 mucositis was the main acute toxicity necessitating supportive care. Long-term toxicity appears to be moderate (Table 4). The maximum tolerated dose of weekly docetaxel was 25 mg/m 2 . Conclusions: concurrent radiation and chemotherapy with weekly docetaxel is a feasible postoperative treatment in a multimodality approach to oral and oropharyngeal cancer, resulting in high overall and disease-free survival. This approach warrants further evaluation in prospective randomized trials. (orig.)

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

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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

Bisphophonates in CKD Patients with Low Bone Mineral Density

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Wen-Chih Liu

2013-01-01

Full Text Available Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD have a high risk of bone fracture because of low bone mineral density and poor bone quality. Osteoporosis also features low bone mass, disarranged microarchitecture, and skeletal fragility, and differentiating between osteoporosis and CKD-MBD in low bone mineral density is a challenge and usually achieved by bone biopsy. Bisphosphonates can be safe and beneficial for patients with a glomerular filtration rate of 30 mL/min or higher, but prescribing bisphosphonates in advanced CKD requires caution because of the increased possibility of low bone turnover disorders such as osteomalacia, mixed uremic osteodystrophy, and adynamic bone, even aggravating hyperparathyroidism. Therefore, bone biopsy in advanced CKD is an important consideration before prescribing bisphosphonates. Treatment also may induce hypocalcemia in CKD patients with secondary hyperparathyroidism, but vitamin D supplementation may ameliorate this effect. Bisphosphonate treatment can improve both bone mineral density and vascular calcification, but the latter becomes more unlikely in patients with stage 3-4 CKD with vascular calcification but no decreased bone mineral density. Using bisphosphonates requires considerable caution in advanced CKD, and the lack of adequate clinical investigation necessitates more studies regarding its effects on these patients.

Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model.

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Perosky, Joseph E; Khoury, Basma M; Jenks, Terese N; Ward, Ferrous S; Cortright, Kai; Meyer, Bethany; Barton, David K; Sinder, Benjamin P; Marini, Joan C; Caird, Michelle S; Kozloff, Kenneth M

2016-12-01

Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in OI, or in any animal model. To determine whether cessation of sclerostin antibody therapy in a growing OI skeleton requires sequential anti-resorptive treatment to preserve anabolic gains in bone mass, we treated 3week old Brtl/+ and wild type mice for 5weeks with SclAb, and then withdrew treatment for an additional 6weeks. Trabecular bone loss was evident following cessation, but was preserved in a dose-dependent manner with single administration of pamidronate at the time of cessation. In vivo longitudinal near-infrared optical imaging of cathepsin K activation in the proximal tibia suggests an anti-resorptive effect of both SclAb and pamidronate which is reversed after three weeks of cessation. Cortical bone was considerably less susceptible to cessation effects, and showed no structural or functional deficits in the absence of pamidronate during this cessation period. In conclusion, while SclAb induces a considerable anabolic gain in the rapidly growing Brtl/+ murine model of OI, a single sequential dose of antiresorptive drug is required to maintain bone mass at trabecular sites for 6weeks following cessation. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Effect of Intravenous Pamidronate Treatment in Children with Osteogenesis Imperfecta

International Nuclear Information System (INIS)

Atta, I.; Iqbal, F.; Lone, S. W.; Ibrahim, M.; Khan, Y. N.; Raza, J.

2014-01-01

Objective: To assess the beneficial effect of intravenous pamidronate treatment in children with osteogenesis imperfecta (OI). Study Design: Experimental study. Place and Duration of Study: Endocrine Unit at the National Institute of Child Health, Karachi, Pakistan, from January 2007 to December 2011. Methodology: All children diagnosed with osteogenesis imperfecta on the basis of repeated spontaneous fractures and typical radiological findings registered during the study period, were included in this study. Pamidronate therapy were offered to those with more than 3 fractures per year or had platyspondyly. Pamidronate disodium was diluted in isotonic saline and administered by slow ravenous infusion over 3 hours in a dosage 1 mg/kg/day for 3 consecutive days 3 monthly for 2 years. Fracture rate, bone mineral density (BMD), mobility score, wellbeing and pain episodes were evaluated at baseline and 2 years after the treatment. Good response was defined as less than 2 fractures per year or mobility score improvement and poor response as more than 2 fracture per year with mobility score less than 2. Results: Seventy two patients were included in this study. There were 40 boys and 32 girls with mean age of 3.64 +- 3.2 years. The annual fracture rate decreased overall from 5.8 +- 1.61 to 0.6 +- 0.93 (p < 0.001). BMD Z-score improved from -5.3 +- 1.74 to -1.7 +- 0.72 (p < 0.001). Mobility score was 0.94 +- 1.30 at baseline and 2.5 +- 1.02 at the end of the treatment (p < 0.001). Wellbeing gained from 3.63 +- 1.44 to 7.8 +- 1.18 (p < 0.001) and pain episode improved from 24.1 +- 8.15 to 2.7 +- 8.31 (p < 0.001). Good response was noted in 92% of patients and poor response in 8% patients. Conclusion: Bisphosphonate seems to be an effective symptomatic treatment for children with osteogenesis imperfecta irrespective of severity of mutation or clinical phenotype. Cyclical bisphosphonate therapy has a positive effect on fracture rate, BMD, mobility score, wellbeing and pain

Weekly low-dose docetaxel is an effective treatment with fewer adverse events for metastatic castration-resistant prostate cancer in Taiwanese patients

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Cheng-Li Kao

2015-12-01

Conclusion: For Taiwanese mCRPC patients, weekly DTX 30 mg/m2 is an efficient regimen for disease control with relatively low Grade 3 or 4 hematological adverse effects. The proper treatment duration of DTX therapy for mCRPC in Taiwanese patients is still uncertain, so further research is needed.

Study protocol: non-displaced distal radial fractures in adult patients: three weeks vs. five weeks of cast immobilization: a randomized trial.

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Bentohami, Abdelali; de Korte, Niels; Sosef, Nico; Goslings, Johan Carel; Bijlsma, Taco; Schep, Niels

2014-01-20

Up to 30% of patients suffer from long-term functional restrictions following conservative treatment of distal radius fractures. Whether duration of cast immobilisation influences functional outcome remains unclear. The aim of the study is to evaluate whether the duration of immobilization of non or minimally displaced distal radial fractures can be safely reduced. We will compare three weeks of plaster cast immobilization with five weeks of plaster cast immobilization in adult patient with non or minimally displaced distal radial fractures. a prospective randomized clinical trial. adult (>18 years) (independent in activities of daily living) patients with a non/minimal displaced distal radius fracture (dorsal angulation 15°, ulnar positive variance immobilization versus five weeks of plaster cast immobilization.Main study parameters: primary outcome parameters: Patient related wrist evaluation (PRWE) Quick Disability of Arm, Shoulder and Hand (QUICKDASH) score after a one year follow-up, and secondary parameters: range of motion, pain level (VAS) and complications. The expectation of this study is that shorter duration of plaster cast immobilisation is beneficial for the patient with a distal radius fracture. This risk of specific complications is low and generally similar in both treatment options. Moreover, the burden of the study is not much higher compared to standard treatment. Follow-up is standardized according to current trauma guidelines. Literature indicates that both treatment options from the study are accepted for displaced distal radius fractures. No clear advantage for one treatment options is found at present in the literature, although there is no level I evidence present. This trial will provide level-1 evidence for the comparison of consolidation and functional outcome between two treatment options for non-displaced distal radial fractures. The gathered data may support the development of a clinical guideline for conservative treatment of

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.

Hemophagocytic syndrome secondary to tuberculosis at 24-week gestation.

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Fernández, Alexandra Arteaga; de Velasco Pérez, David Fernández; Fournier, M C Jiménez; Moreno Del Prado, J C; Torras, B Paraíso; Cañete Palomo, M L

2017-01-01

Hemophagocytic syndrome is a life-threatening disease characterized by the uncontrolled activation of macrophages, resulting in hemophagocytosis of blood cells in the bone marrow. A 20-year-old gravida at 23-week and 5-day gestation was admitted to hospital to evaluate fever up to 104°F of unknown origin, moderate cytopenia, and elevated levels of liver enzymes. Bone marrow biopsy confirmed hemophagocytic syndrome, and polymerase chain reaction came back positive for Mycobacterium tuberculosis. Supportive care and tuberculosis treatment resulted in clinical improvement. At 27 weeks and 5 days, premature rupture of the membranes occurred, and because of the high probability of reactivating the hemophagocytic syndrome, a cesarean section was performed at 29-week and 2-day gestation. Hemophagocytic syndrome is an uncommon disease which rarely appears during pregnancy. Early diagnosis and treatment can save both maternal and fetal lives.

Local application of zoledronate for maximum anchorage during space closure.

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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.

EFFICACY AND SAFETY OF ALENDRONIC ACID IN PATIENTS WITH JUVENILE RHEUMATOID ARTHRITIS AND OSTEOPOROSIS

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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

Weekly Versus Fortnightly Cryotherapy For Warts On Extremities - A Pilot Study

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Eapen Annamma

1997-01-01

Full Text Available Forty two patients with verruca vulgaris on the extremities who attended the Government Wenlock Hospital and KMC, Attavar, were subjected to weekly and fortnightly cryotherapy. At the end of 8 weeks, it was found that of the 37 patients who were followed up, 94% in weekly group and 84% in fortnightly group responded to treatment.

Five-Week Outcomes From a Dosing Trial of Therapeutic Massage for Chronic Neck Pain

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Sherman, Karen J.; Cook, Andrea J.; Wellman, Robert D.; Hawkes, Rene J.; Kahn, Janet R.; Deyo, Richard A.; Cherkin, Daniel C.

2014-01-01

PURPOSE This trial was designed to evaluate the optimal dose of massage for individuals with chronic neck pain. METHODS We recruited 228 individuals with chronic nonspecific neck pain from an integrated health care system and the general population, and randomized them to 5 groups receiving various doses of massage (a 4-week course consisting of 30-minute visits 2 or 3 times weekly or 60-minute visits 1, 2, or 3 times weekly) or to a single control group (a 4-week period on a wait list). We assessed neck-related dysfunction with the Neck Disability Index (range, 0–50 points) and pain intensity with a numerical rating scale (range, 0–10 points) at baseline and 5 weeks. We used log-linear regression to assess the likelihood of clinically meaningful improvement in neck-related dysfunction (≥5 points on Neck Disability Index) or pain intensity (≥30% improvement) by treatment group. RESULTS After adjustment for baseline age, outcome measures, and imbalanced covariates, 30-minute treatments were not significantly better than the wait list control condition in terms of achieving a clinically meaningful improvement in neck dysfunction or pain, regardless of the frequency of treatments. In contrast, 60-minute treatments 2 and 3 times weekly significantly increased the likelihood of such improvement compared with the control condition in terms of both neck dysfunction (relative risk = 3.41 and 4.98, P = .04 and .005, respectively) and pain intensity (relative risk = 2.30 and 2.73; P = .007 and .001, respectively). CONCLUSIONS After 4 weeks of treatment, we found multiple 60-minute massages per week more effective than fewer or shorter sessions for individuals with chronic neck pain. Clinicians recommending massage and researchers studying this therapy should ensure that patients receive a likely effective dose of treatment. PMID:24615306

Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial

DEFF Research Database (Denmark)

Madruga, José Valdez; Berger, Daniel; McMurchie, Marilyn

2007-01-01

BACKGROUND: The protease inhibitor darunavir has been shown to be efficacious in highly treatment-experienced patients with HIV infection, but needs to be assessed in patients with a broader range of treatment experience. We did a randomised, controlled, phase III trial (TITAN) to compare 48-week....... The primary endpoint was non-inferiority (95% CI lower limit for the difference in treatment response -12% or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis). TITAN (TMC114-C214) is registered with ClinicalTrials.gov, number NCT00110877. FINDINGS: Of 595...

Benfotiamine in treatment of alcoholic polyneuropathy: an 8-week randomized controlled study (BAP I Study).

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Woelk, H; Lehrl, S; Bitsch, R; Köpcke, W

1998-01-01

A three-armed, randomized, multicentre, placebo-controlled double-blind study was used to examine the efficacy of benfotiamine vs a combination containing benfotiamine and vitamins B6 and B12 in out-patients with severe symptoms of alcoholic polyneuropathy (Benfotiamine in treatment of Alcoholic Polyneuropathy, BAP I). The study period was 8 weeks and 84 patients fulfilled all the prerequisite criteria and completed the study as planned. Benfotiamine led to significant improvement of alcoholic polyneuropathy. Vibration perception (measured at the tip of the great toe) significantly improved in the course of the study, as did motor function. and the overall score reflecting the entire range of symptoms of alcoholic polyneuropathy. A tendency toward improvement was evident for pain and co-ordination; no therapy-specific adverse effects were seen.

Hemophagocytic syndrome secondary to tuberculosis at 24-week gestation

Directory of Open Access Journals (Sweden)

Alexandra Arteaga Fernández

2017-01-01

Full Text Available Hemophagocytic syndrome is a life-threatening disease characterized by the uncontrolled activation of macrophages, resulting in hemophagocytosis of blood cells in the bone marrow. A 20-year-old gravida at 23-week and 5-day gestation was admitted to hospital to evaluate fever up to 104°F of unknown origin, moderate cytopenia, and elevated levels of liver enzymes. Bone marrow biopsy confirmed hemophagocytic syndrome, and polymerase chain reaction came back positive for Mycobacterium tuberculosis. Supportive care and tuberculosis treatment resulted in clinical improvement. At 27 weeks and 5 days, premature rupture of the membranes occurred, and because of the high probability of reactivating the hemophagocytic syndrome, a cesarean section was performed at 29-week and 2-day gestation. Hemophagocytic syndrome is an uncommon disease which rarely appears during pregnancy. Early diagnosis and treatment can save both maternal and fetal lives.

Cancer treatment-induced bone loss in premenopausal women: a need for therapeutic intervention?

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Hadji, P; Gnant, M; Body, J J; Bundred, N J; Brufsky, A; Coleman, R E; Guise, T A; Lipton, A; Aapro, M S

2012-10-01

Current clinical treatment guidelines recommend cytotoxic chemotherapy, endocrine therapy, or both (with targeted therapy if indicated) for premenopausal women with early-stage breast cancer, depending on the biologic characteristics of the primary tumor. Some of these therapies can induce premature menopause or are specifically designed to suppress ovarian function and reduce circulating estrogen levels. In addition to bone loss associated with low estrogen levels, cytotoxic chemotherapy may have a direct negative effect on bone metabolism. As a result, cancer treatment-induced bone loss poses a significant threat to bone health in premenopausal women with breast cancer. Clinical trials of antiresorptive therapies, such as bisphosphonates, have demonstrated the ability to slow or prevent bone loss in this setting. Current fracture risk assessment tools are based on data from healthy postmenopausal women and do not adequately address the risks associated with breast cancer therapy, especially in younger premenopausal women. We therefore recommend that all premenopausal women with breast cancer be informed about the potential risk of bone loss prior to beginning anticancer therapy. Women who experience amenorrhea should have bone mineral density assessed by dual-energy X-ray absorptiometry and receive regular follow-up to monitor bone health. Regular exercise and daily calcium and vitamin D supplementation are recommended. Women with a Z-score <-2.0 or Z-score ≤-1.0 and/or a 5-10% annual decrease in bone mineral density should be considered for bisphosphonate therapy in addition to calcium and vitamin D supplements. Copyright © 2012 Elsevier Ltd. All rights reserved.

Bisphosphonate-coated BSA nanoparticles lack bone targeting after systemic administration.

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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.

Emerging therapies for the treatment of osteoporosis

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Garima Bhutani

2013-01-01

Full Text Available Osteoporosis is a chronic disease of the osseous system characterized by decreased bone strength and increased fracture risk. It is due to an imbalance in the dynamic ongoing processes of bone formation and bone resorption. Currently available osteoporosis therapies like bisphosphonates, selective estrogen receptor modulators (SERMs, and denosumab are anti-resorptive agents. Parathyroid hormone analogs like teriparatide are the only anabolic agents currently approved for osteoporosis treatment. The side-effects and limited efficacy of the presently available therapies has encouraged extensive research into the pathophysiology of the disease and newer drug targets for its treatment. The novel anti-resorptive agents being developed are newer SERMs, osteoprotegerin, c-src (cellular-sarcoma kinase inhibitors, αVβ3 integrin antagonists, cathepsin K inhibitors, chloride channel inhibitors, and nitrates. Upcoming anabolic agents include calcilytics, antibodies against sclerostin and Dickkopf-1, statins, matrix extracellular phosphoglycoprotein fragments activin inhibitiors, and endo-cannabinoid agonists. Many of these new drugs are still in development. This article provides an insight into the emerging drugs for the treatment of osteoporosis.

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

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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.

Agomelatine for the treatment of patients with fibromyalgia and depressive symptomatology: an uncontrolled, 12-week, pilot study.

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