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Sample records for bisphosphonate treatment increases

  1. Bisphosphonate Treatment and Pregnancy

    Science.gov (United States)

    Bisphosphonate treatment and Pregnancy In every pregnancy, a woman starts out with a 3-5% chance of ... risk. This sheet talks about whether exposure to bisphosphonates may increase the risk for birth defects over ...

  2. PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats.

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    Murphy, Ciara M; Schindeler, Aaron; Cantrill, Laurence C; Mikulec, Kathy; Peacock, Lauren; Little, David G

    2015-06-01

    Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide (PTH(1-34) ) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH(1-34) acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647-labelled pamidronate (Pam) and radiolabeled (14) C-ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25 μg/kg/d PTH(1-34) , and the effects on BP liberation and bone healing were examined by X-ray, micro-CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH(1-34) , there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for (14) C-ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus-bound BP with PTH(1-34) , these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH(1-34) increases bone turnover as well as BP turnover. © 2015 American Society for Bone and Mineral Research.

  3. SAPHO: Treatment options including bisphosphonates.

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    Zwaenepoel, Tom; Vlam, Kurt de

    2016-10-01

    Both the diagnosis and treatment of the syndrome of synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) remain difficult. We describe a case series of 21 patients with SAPHO and their response to several pharmacological treatments. Clinical and biochemical data, along with medical imaging, were collected from the medical records of 21 patients, diagnosed as SAPHO during follow-up between 2005 and 2013. Symptoms and inflammatory markers were recorded twice, once at first patient presentation, and once at the end of follow-up. Synovitis, acne, pustulosis, hyperostosis, and osteitis were labeled as defining features. All treatment options were categorized according to their respective responses (full remission, partial remission, and no disease control). There was a female predominance and a median age of 32 years (range: 12-54 years). Median follow-up duration was 45 months (range: 0-188 months). Total prevalence of defining features in this cohort increased for each defining feature during follow-up, except for acne. All patients reached full or partial remission at the end of follow-up. A total of 14 patients were treated with bisphosphonates. Of which 8 of them went into full or partial remission. In our case series, none of the patients had the full presentation of SAPHO at the first consultation. Some presented with symptoms suggestive for psoriatic arthritis. This explains why diagnosis of SAPHO can be challenging. Full remission was induced in the majority of individuals. Bisphosphonates seem to be a noteworthy treatment option. We suggest a prospective placebo-controlled clinical trial with bisphosphonates to confirm this observation. Copyright © 2016. Published by Elsevier Inc.

  4. [The impact of bisphosphonates on orthodontic treatment].

    NARCIS (Netherlands)

    Poelmans, S.; Carels, C.E.L.

    2012-01-01

    Bisphosphonates are used in the treatment of various diseases which are associated with a disturbance of the balance between bone apposition and degradation. The most important complication of bisphosphonate use is osteonecrosis of the jaw. Certain components of an orthodontic treatment plan, such

  5. Bisphosphonates for treatment of osteoporosis

    Science.gov (United States)

    Brown, Jacques P.; Morin, Suzanne; Leslie, William; Papaioannou, Alexandra; Cheung, Angela M.; Davison, Kenneth S.; Goltzman, David; Hanley, David Arthur; Hodsman, Anthony; Josse, Robert; Jovaisas, Algis; Juby, Angela; Kaiser, Stephanie; Karaplis, Andrew; Kendler, David; Khan, Aliya; Ngui, Daniel; Olszynski, Wojciech; Ste-Marie, Louis-Georges; Adachi, Jonathan

    2014-01-01

    Abstract Objective To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate “drug holiday.” Quality of evidence MEDLINE (PubMed, through December 31, 2012) was used to identify relevant publications for inclusion. Most of the evidence cited is level II evidence (non-randomized, cohort, and other comparisons trials). Main message The antifracture efficacy of approved first-line bisphosphonates has been proven in randomized controlled clinical trials. However, with more extensive and prolonged clinical use of bisphosphonates, associations have been reported between their administration and the occurrence of rare, but serious, adverse events. Osteonecrosis of the jaw and atypical subtrochanteric and diaphyseal femur fractures might be related to the use of bisphosphonates in osteoporosis, but they are exceedingly rare and they often occur with other comorbidities or concomitant medication use. Drug holidays should only be considered in low-risk patients and in select patients at moderate risk of fracture after 3 to 5 years of therapy. Conclusion When bisphosphonates are prescribed to patients at high risk of fracture, their antifracture benefits considerably outweigh their potential for harm. For patients taking bisphosphonates for 3 to 5 years, reassess the need for ongoing therapy. PMID:24733321

  6. Atypical femoral fracture combined with osteonecrosis of jaw during osteoporosis treatment with bisphosphonate.

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    Won, Yougun; Lim, Joon-Ryul; Kim, Young-Hwan; Song, Hyung-Keun; Yang, Kyu Hyun

    2014-05-01

    Bisphosphonate, a potent anti-resorptive agent, is generally accepted as a safe, effective, well tolerated treatment for postmenopausal osteoporosis. Atypical femoral fracture (AFF) and bisphosphonate related osteonecrosis of jaw (BRONJ) are the increasing morbidities in patients treated with long term bisphosphonate. Pathogenic mechanisms of AFF and BRONJ are not fully identified and not identical. We report a case of BRONJ followed by AFF and its nonunion in a 67-year-old woman patient receiving an oral bisphosphonate during 7 years for the treatment of osteoporosis.

  7. Treatment of post-menopausal osteoporosis: beyond bisphosphonates.

    Science.gov (United States)

    Ishtiaq, S; Fogelman, I; Hampson, G

    2015-01-01

    Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1-34) and anti-sclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention.

  8. [Treatment of bone metastases with bisphosphonates].

    Science.gov (United States)

    Gremaud, M; Delouche, D; Monnerat, C

    2006-08-09

    Bone metastasis are very common in many cancers; metastatic bone disease is the most common cause of cancer pain and also of serious complications, which reduce the quality of life of these patients. Management of skeletal cancer involves a multimodality approach who include bisphosphonates, which in association with anti-tumour treatments reduce the apparition of new skeletal-related events (SRE) and prolong the delay to first SRE. They although reduce the pain of bone metastasis. All this facts do the quality of life better.

  9. Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002-2012.

    Science.gov (United States)

    Wysowski, Diane K; Greene, Patty

    2013-12-01

    Bisphosphonates have been widely prescribed to postmenopausal women for treatment and prevention of osteoporosis. Given a background of reports of recent safety problems, questions about optimal duration of use, and the patent expiration of Fosamax in February 2008, we accessed data from pharmaceutical marketing research databases to describe trends in dispensed prescriptions and sales of oral bisphosphonates, characteristics of patients and prescribers, and sales of intravenous bisphosphonates for osteoporosis treatment. An estimated 21.3million prescriptions for oral bisphosphonates were dispensed in U.S. retail pharmacies in 2002 that increased 46% to a peak of 31.0million in 2007 and 2008, and declined by 53% in a four year-period to 14.7million in 2012. Sales data (number of packages sold in all settings of care) showed parallel trends (66% increase from 2002 through 2007 and 51% decrease from 2007 through 2012). Similarly, intravenous bisphosphonate sales for osteoporosis treatment grew 3.8-fold from 149.5 thousand packages in 2007 to 561.6 thousand in 2010, followed by a 22% decrease in 2012. Data from an ongoing monthly office-based survey indicated physicians mentioned oral bisphosphonates primarily in visits of older aged Caucasian women with lower body mass for osteoporosis. Frequencies of oral bisphosphonate mentions increased between 2002 and 2012 in visits of Asians and for osteopenia diagnoses. These data indicate a substantial decline in prescriptions and sales of oral (since 2007-2008) and intravenous (since 2010) bisphosphonates for osteoporosis treatment in the United States. Reasons for, and implications of, the decline should be considered for future research. © 2013.

  10. [Treatment with bisphosphonates and atypical fractures].

    Science.gov (United States)

    Spivacow, Francisco R; Sarli, Marcelo; Buttazzoni, Mirena

    2009-01-01

    In the last twenty five years aminobisphosphonates have became the drugs of choice for the treatment of osteoporosis. They strongly inhibit osteoclastic bone resorption and reduce the incidence of new fractures in patients with established osteoporosis, but their long half-life and their chronic effects on bone physiology are a matter of concern. Theoretically a harmful consequence of a prolonged inhibition of bone 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.

  11. Dental implications of osteogenesis imperfecta: treatment with IV bisphosphonate: report of a case.

    Science.gov (United States)

    Milano, Michael; Wright, Timothy; Loechner, Karen J

    2011-01-01

    Osteogenesis imperfect (OI) is a group of genetically diverse connective tissue disorders. Bisphosphonates therapy to manage bone fragility, a now common medical therapy for OI, can increase the risk of bisphosphonate-associated osteonecrosis of the jaws. In this report, a 6 ½ year child, who was receiving bisphosphonate therapy for OI, underwent full mouth dental rehabilitation in the operating room while under general anesthesia. The child had numerous teeth restored and multiple primary molar extractions. The patient, who received prophylactic antibiotics intraoperatively, demonstrated no clinical signs of bisphosphonate-associated osteonecrosis when seen at follow-up. Although bisphosphonate osteonecrosis is a possible sequel in children who receive multiple extractions, no clinical signs were manifested in our patient, who required multiple primary tooth extractions along with restorative treatment under general anesthesia. While no dental guidelines have been developed to manage OI children having been treated with bisphosphonates, consent for extractions should include the risk of bone necrosis and careful post-operative observation to monitor wound healing.

  12. Gastrointestinal tolerability with ibandronate after previous weekly bisphosphonate treatment

    Directory of Open Access Journals (Sweden)

    Richard Derman

    2009-09-01

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

  13. Bisphosphonate Treatment: Risk Management in Long Duration Spaceflight

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    Fogarty, Jennifer A.; Aunon, Serena M.

    2007-01-01

    Bisphosphonates are a class of pharmaceuticals used to treat diverse bone disorders such as osteoporosis, Paget's disease, and multiple myeloma. They constitute a class of drugs which adhere to bony surfaces and interfere with the resorptive activity of osteoclasts. They also represent a potential countermeasure towards the loss of bone mass experienced by astronauts during spaceflight. Recently, the medical literature has revealed cases of osteonecrosis of the jaw in individuals receiving intravenous bisphosphonate therapy with a smaller number of cases occurring in individuals receiving the oral form of the medication. Risk management for long duration missions requires consideration of mission success and lifetime health care of astronauts. We performed MEDLINE and PubMed searches (1966 December 2006) using the following keywords: osteonecrosis, jaw, bisphosphonates. Additional references were obtained from the citations of the retrieved articles. Injectable bisphosphonates such as pamidronate and zoledronic acid have been highlighted recently in the literature due to a possible link with osteonecrosis of the jaw. The mechanism of action remains unclear but may be linked to physiologic microdamage in the jawbones resulting from suppression of bone metabolism. The most predisposing factors appear to be the type and dose of bisphosphonate used, a history of dental surgery, trauma, and/or dental infection. In addition, patients diagnosed with a malignancy such as breast cancer or multiple myeloma, who have been on intravenous bisphosphonate therapy for several months seem to be at increased risk. The use of oral bisphosphonates appears to place patients more at risk from acute events such as gastrointestinal tract injury or perforation. Although some studies report little to no increase in GI events compared to placebo, we must remember that in microgravity, astronauts may be unable to comply with medication instructions. They may have difficulty remaining upright

  14. Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review.

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    Eriksen, Erik F; Díez-Pérez, Adolfo; Boonen, Steven

    2014-01-01

    Osteoporosis is a progressive skeletal disorder that requires long-term treatment. However, there is little guidance regarding optimal treatment duration and what the treatment discontinuation and retreatment criteria should be. Given that bisphosphonates are the most commonly prescribed class of agent for the treatment of osteoporosis, we reviewed the long-term data relating to these therapies and discussed the considerations for using bisphosphonates in postmenopausal women with osteoporosis. A PubMed search, using the search terms 'bisphosphonate', 'postmenopausal osteoporosis' and 'long term' and/or 'extension' was conducted in January 2013. Results from nine controlled studies that prospectively assessed alendronate, risedronate, ibandronate or zoledronic acid in women with postmenopausal osteoporosis were reviewed. Clinical studies in postmenopausal women with osteoporosis showed that long-term use of bisphosphonates resulted in persistent antifracture and bone mineral density (BMD) increasing effects beyond 3 years of treatment. No unexpected adverse events were identified in these studies and the long-term tolerability profiles of bisphosphonates remain favorable. Data from the withdrawal extension studies of alendronate and zoledronic acid also showed that residual fracture benefits were seen in patients who discontinued treatment for 3 to 5 years after an initial 3- to 5-year treatment period. BMD monitoring and fracture risk assessments should be conducted regularly to determine whether treatment could be stopped or should be reinitiated. Patients exhibiting T-scores-2.5 could be considered for discontinuation of active treatment while undergoing continued monitoring of their bone health. The duration and potential discontinuation of treatment should be personalized for individual patients based on their response to treatment, fracture risk and comorbidities. © 2013. Published by Elsevier Inc. All rights reserved.

  15. 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.

  16. Responses to Treatment With Teriparatide in Patients With Atypical Femur Fractures Previously Treated With Bisphosphonates.

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    Watts, Nelson B; Aggers, Deborah; McCarthy, Edward F; Savage, Tina; Martinez, Stephanie; Patterson, Rachel; Carrithers, Erin; Miller, Paul D

    2017-05-01

    If oversuppression of bone turnover explained the association between bisphosphonate use and atypical subtrochanteric femur fractures (AFF), this could be reversed with anabolic treatment such as teriparatide. We conducted a prospective, open-label study in patients previously treated with bisphosphonates who sustained AFF, examining the response to 24-month treatment with teriparatide on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers (BTM), and fracture healing as well as quantitative histomorphometry. We studied 14 patients. Baseline BMD, BTM, and TBS varied widely. On initial bone biopsies, 12 of 14 patients showed tetracycline labels, but mineralizing surface/bone surface was below published normal values in all but 2. Lumbar spine BMD increased significantly at month 24 (6.1% ± 4.3%, p teriparatide after prior bisphosphonate treatment. At month 24, fractures were healed in 6 patients, showed partial healing in 3, were unchanged in 2, and showed nonunion in 1. In a patient with two fractures, the fracture that occurred before teriparatide treatment was reported as healed, but the fracture that occurred while on treatment showed only partial healing. Bisphosphonate-treated patients who sustain AFF show heterogeneity of bone turnover. Treatment with teriparatide resulted in increases in BTM and lumbar spine BMD, as has been reported for patients without AFF. There was no significant effect of teriparatide on hip BMD, mineralizing surface to bone surface (MS/BS), or TBS and no consistent effect on fracture healing. In the context of a patient who has experienced an AFF after receiving bisphosphonate treatment, therapy with teriparatide for 24 months would be expected to increase BMD and BTM (and probably reduce the risk of fractures resulting from osteoporosis) but should not be relied on to aid in healing of the AFF. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

  17. Physicians' perspectives on the treatment of osteoporosis patients with bisphosphonates.

    Science.gov (United States)

    Gu, Tao; Eisenberg Lawrence, Debra F; Stephenson, Judith J; Yu, Jingbo

    2016-01-01

    Noncompliance with bisphosphonate therapy among osteoporosis patients attenuates the reduction of fracture risk. The objective of this study was to assess physicians' prescribing considerations, preferences for osteoporosis treatments, and perceptions of patients' compliance with oral bisphosphonates. This was an online survey of US physicians identified in the HealthCore Integrated Research Database (HIRD(SM)) as prescribing oral bisphosphonates to women aged ≥55 years. The survey gauged physicians' prescribing considerations and preferences for various types of osteoporosis medications. The physicians were asked to predict patient persistence and compliance, and rate various reasons for noncompliance. Bone mineral density, long-term medication use (eg, corticosteroids), and a history of fracture were ranked as major considerations by 94.9%, 88.6%, and 86.7% of participating physicians (N=158), respectively, when deciding whether to treat an osteoporosis patient. Most physicians expressed a preference for prescribing weekly or monthly oral bisphosphonates, for both newly diagnosed patients (54.4% and 34.2%, respectively) and long-term users of oral bisphosphonates (40.5% and 36.1%, respectively). Most physicians (23.4% always, 58.9% sometimes) incorporated a drug holiday into their prescribing patterns. Although most physicians predicted that more than half of the patients would comply with the prescribed medication for at least a year, 17.7% predicted that less than half of the patients would be compliant in the 1st year, and 29.7% predicted the same result for compliance beyond 1 year. In the opinion of the majority of physicians, the major reasons for noncompliance with oral bisphosphonates were intolerance of a medication due to a gastrointestinal condition (71.5%) and medication side effects (69.6%). US physicians consider several relevant risk factors when deciding whether to prescribe pharmacotherapy and exhibit a preference for weekly or monthly regimens

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

    Directory of Open Access Journals (Sweden)

    Wat WZM

    2014-11-01

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

  19. Osteoporosis treatment: bisphosphonates reign to continue for a few more years, at least?

    Science.gov (United States)

    Pazianas, Michael; Abrahamsen, Bo

    2016-07-01

    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 complete with any accumulated structural or material faults, their bone selectivity and effectiveness in reducing the risk of fractures, together with their low cost, have left little room for improvement for new antiresorptives. The osteoanabolic teriparatide increases new bone formation, but it is administered for up to 2 years only and the cost remains a consideration. Similar restrictions are expected to apply to an anti-sclerostin antibody, which could be evaluated by the U.S. Food and Drug Administration in the near future. Cathepsin K-inhibiting antibody could be an alternative if approved; although an antiresorptive, it maintains bone formation, in contrast with bisphosphonates, and can be probably used for long-term treatment.  Rare adverse effects of bisphosphonates, namely osteonecrosis of the jaws and atypical femoral fractures, have been disproportionally emphasized relative 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. © 2016 New York Academy of Sciences.

  20. 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.)

  1. Atypical dental implant failure with long-term bisphosphonate treatment--akin to atypical fractures?

    Science.gov (United States)

    Subramanian, Gayathri; Fritton, J Christopher; Iyer, Shankar; Quek, Samuel Y P

    2012-12-01

    Concern that long-term bisphosphonate therapy may significantly undermine bone quality in osteoporotic patients has been heightened by rare instances of low-impact atypical femoral fractures that are often bilateral. Reduced fracture toughness is believed to result from reduced bone remodeling, leading to increased homogeneity in bone microarchitecture, narrowed bone mineral density distribution, and increased bone tissue microdamage burden. We postulate that these long-term alterations in bone quality may undermine the ongoing remodeling surrounding osteointegrated endosseous dental implants as well. To illustrate our hypothesis, we report the catastrophic failure of multiple, successfully osteointegrated dental implants in an osteopenic patient following long-term bisphosphonate treatment. This clinical presentation may reflect underlying adverse changes in bone quality, in a manner analogous to atypical fractures in a small percentage of patients on bisphosphonates. This report highlights the need for multidisciplinary care of patients who have dental implants and begin or are receiving long-term bisphosphonate therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2017-07-01

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

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

    DEFF Research Database (Denmark)

    Ding, Ming

    2004-01-01

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

  4. The use of bisphosphonates does not contraindicate orthodontic and other types of treatment!

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    Consolaro, Alberto

    2014-01-01

    Bisphosphonates have been increasingly used not only to treat bone diseases as well as conditions such as osteopenia and osteoporosis, but also in oncotherapy. The use of bisphosphonates induces clinicians to fear and care. These reactions are associated with controversy resulting from lack of in-depth knowledge on the mechanisms of action as well as lack of a more accurate assessment of side effects. Scientific and clinical knowledge disclosure greatly contributes to professionals' discernment and inner balance, especially orthodontists. Fear does not lead to awareness. For these reasons, we present an article that focuses on that matter. This article was adapted from different journals of different dental specialties, as mentioned on footnote. There is no scientific evidence demonstrating that bisphosphonates are directly involved with etiopathogenic mechanisms of osteonecrosis and jaw osteomyelitis. Their use is contraindicated and limited in cases of dental treatment involving bone tissue. Nevertheless, such fact is based on professional opinion, case reports, and personal experience or trials with flaws in experimental methods. Additional studies will always be necessary; however, in-depth knowledge on bone biology is of paramount importance to offer an opinion about the clinical use of bisphosphonates and their further implications. Based on bone biopathology, this article aims at contributing to lay people the groundwork for this matter.

  5. Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report.

    Science.gov (United States)

    Rizzoli, R; Akesson, K; Bouxsein, M; Kanis, J A; Napoli, N; Papapoulos, S; Reginster, J-Y; Cooper, C

    2011-02-01

    This paper reviews the evidence for an association between atypical subtrochanteric fractures and long-term bisphosphonate use. Clinical case reports/reviews and case-control studies report this association, but retrospective phase III trial analyses show no increased risk. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is yet unproven. A Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the International Osteoporosis Foundation has reviewed the evidence for a causal association between subtrochanteric fractures and long-term treatment with bisphosphonates, with the aim of identifying areas for further research and providing recommendations for physicians. A PubMed search of literature from 1994 to May 2010 was performed using key search terms, and articles pertinent to subtrochanteric fractures following bisphosphonate use were analysed. Several clinical case reports and case reviews report a possible association between atypical fractures at the subtrochanteric region of the femur in bisphosphonate-treated patients. Common features of these 'atypical' fractures include prodromal pain, occurrence with minimal/no trauma, a thickened diaphyseal cortex and transverse fracture pattern. Some small case-control studies report the same association, but a large register-based study and retrospective analyses of phase III trials of bisphosphonates do not show an increased risk of subtrochanteric fractures with bisphosphonate use. The number of atypical subtrochanteric fractures in association with bisphosphonates is an estimated one per 1,000 per year. It is recommended that physicians remain vigilant in assessing their patients treated with bisphosphonates for the treatment or prevention of osteoporosis and advise patients of the potential risks. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is unproven and requires further

  6. Bisphosphonate treatment of aggressive primary, recurrent and metastatic Giant Cell Tumour of Bone

    Directory of Open Access Journals (Sweden)

    Balke Maurice

    2010-08-01

    Full Text Available Abstract Background Giant cell tumour of bone (GCTB is an expansile osteolytic tumour which contains numerous osteoclast-like giant cells. GCTB frequently recurs and can produce metastatic lesions in the lungs. Bisphosphonates are anti-resorptive drugs which act mainly on osteoclasts. Method In this study, we have examined clinical and radiological outcomes of treatment with aminobisphosphonates on 25 cases of aggressive primary, recurrent and metastatic GCTB derived from four European centres. We also analysed in vitro the inhibitory effect of zoledronic acid on osteoclasts isolated from GCTBs. Results Treatment protocols differed with several different aminobisphosphonates being employed, but stabilisation of disease was achieved in most of these cases which were refractory to conventional treatment. Most inoperable sacral/pelvic tumours did not increase in size and no further recurrence was seen in GCTBs that had repeatedly recurred in bone and soft tissues. Lung metastases did not increase in size or number following treatment. Zoledronic acid markedly inhibited lacunar resorption by GCTB-derived osteoclasts in vitro. Conclusion Our findings suggest that bisphosphonates may be useful in controlling disease progression in GCTB and that these agents directly inhibit GCTB - derived osteoclast resorption. These studies highlight the need for the establishment of standardised protocols to assess the efficacy of bisphosphonate treatment of GCTB.

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

    LENUS (Irish Health Repository)

    Memon, Adeel R

    2013-05-17

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

  8. Managing Osteoporosis Patients after Long-Term Bisphosphonate Treatment

    Science.gov (United States)

    Adler, Robert A.; Fuleihan, Ghada El-Hajj; Bauer, Douglas C.; Camacho, Pauline M.; Clarke, Bart L.; Clines, Gregory A.; Compston, Juliet E.; Drake, Matthew T.; Edwards, Beatrice J.; Favus, Murray J.; Greenspan, Susan L.; McKinney, Ross; Pignolo, Robert J.; Sellmeyer, Deborah E.

    2016-01-01

    Bisphosphonates (BPs) are the most commonly used medications for osteoporosis, but optimal duration of therapy is unknown. This ASBMR report provides guidance on BP therapy duration with a risk benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score between −2 and −2.5 in FLEX and below −2.5 in HORIZON extension predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, women should be reassessed. Women with previous major osteoporotic fracture, those who fracture on therapy, or others at high risk should generally continue therapy for up to 10 years (oral) or 6 years (intravenous), with periodic risk-benefit evaluation. Older women, those with a low hip T-score or high fracture risk score are considered high risk. The risk of osteonecrosis of the jaw and atypical femoral fracture increases with BP therapy duration, but such rare events are far outweighed by fracture risk reduction with BPs in high risk patients. For women not at high fracture risk after 3–5 years of BP treatment, a drug holiday of 2–3 years can be considered, with periodic reassessment. The algorithm provided for long term BP use is based on limited evidence in mostly Caucasian postmenopausal women and only for vertebral fracture reduction. It is probably applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future osteoporosis trials will provide data for formulating definitive recommendations. PMID:26350171

  9. The use of bisphosphonates in pediatrics.

    Science.gov (United States)

    Baroncelli, Giampiero I; Bertelloni, Silvano

    2014-01-01

    Bisphosphonates are widely used for the prevention and treatment of osteoporosis in adulthood. In the last years, bisphosphonates have been increasingly used in pediatric patients for the treatment of a growing number of disorders associated with osteoporosis, resistant hypercalcemia or heterotopic calcifications. The use of bisphosphonates in pediatric patients has been proven safe; however, the risk of potential severe consequences into adulthood should be kept in mind. Well-defined criteria for bisphosphonates treatment in pediatric patients are not specified, therefore an accurate selection of patients who could benefit from bisphosphonates is mandatory. A strict follow-up of pediatric patients receiving long-term bisphosphonate therapy is strongly recommended. The purpose of this mini review is to provide a summary of current knowledge on some main general aspects of the structure, mechanisms of action, pharmacokinetics, and bioavailability of bisphosphonates, and to focus on the latest advances of bisphosphonate treatment in pediatric patients. Particular attention has been paid to the common and potential adverse effects of bisphosphonate treatment, and some suggestions concerning the clinical approach and general measures for bisphosphonate treatment in pediatric patients are reported. 2014 S. Karger AG, Basel

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

    Directory of Open Access Journals (Sweden)

    Yohei Shimada

    2017-01-01

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

  11. Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials.

    Science.gov (United States)

    Van Acker, Heleen H; Anguille, Sébastien; Willemen, Yannick; Smits, Evelien L; Van Tendeloo, Viggo F

    2016-02-01

    A growing body of evidence points toward an important anti-cancer effect of bisphosphonates, a group of inexpensive, safe, potent, and long-term stable pharmacologicals that are widely used as osteoporosis drugs. To date, they are already used in the prevention of complications of bone metastases. Because the bisphosphonates can also reduce mortality in among other multiple myeloma, breast, and prostate cancer patients, they are now thoroughly studied in oncology. In particular, the more potent nitrogen-containing bisphosphonates have the potential to improve prognosis. The first part of this review will elaborate on the direct and indirect anti-tumoral effects of bisphosphonates, including induction of tumor cell apoptosis, inhibition of tumor cell adhesion and invasion, anti-angiogenesis, synergism with anti-neoplastic drugs, and enhancement of immune surveillance (e.g., through activation of γδ T cells and targeting macrophages). In the second part, we shed light on the current clinical position of bisphosphonates in the treatment of hematological and solid malignancies, as well as on ongoing and completed clinical trials investigating the therapeutic effect of bisphosphonates in cancer. Based on these recent data, the role of bisphosphonates is expected to further expand in the near future outside the field of osteoporosis and to open up new avenues in the treatment of malignancies. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Oral Bisphosphonate Use Increases the Risk for Inflammatory Jaw Disease: A Cohort Study

    DEFF Research Database (Denmark)

    Vestergaard, Peter; Schwartz, Kristoffer; Rejnmark, Lars

    2011-01-01

    to compare the rate of inflammatory jaw-related events, ie, osteomyelitis, osteitis, periostitis, or sequestrum, between Danish patients who had been prescribed oral bisphosphonates (BP) and other drugs for the treatment of osteoporosis between 1996 and 2006 (the exposed group), and a random sample...

  13. Bisphosphonate-associated osteonecrosis of the jaw in breast cancer patients: recommendations for prevention and treatment.

    Science.gov (United States)

    Fehm, T; Felsenberg, D; Krimmel, M; Solomayer, E; Wallwiener, D; Hadjii, P

    2009-08-01

    Osteonecrosis of the jaw (ONJ) is a rare but severe disease which has been diagnosed in women with breast cancer on a bisphosphonate (BP) therapy. Thus, the German society of senology appointed a multidisciplinary task force to establish a consensus on the use of bisphosphonates in breast cancer patients with bone metastases, considering in particular the possible risk of ONJ. This report summarizes the results and recommendations for the prevention and treatment of ONJ in breast cancer patients receiving BP.

  14. 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

  15. Osteoclast abnormalities in fractured bone during bisphosphonate treatment for osteoporosis: a case report.

    Science.gov (United States)

    Vigorita, V J V; Silver, J S; Eisemon, E O E

    2012-07-01

    Bisphosphonates have been widely used in the treatment of an array of bone disorders. Recent complications have included unusual femoral fractures in patients who have received long term bisphosphonate treatment for osteoporosis. Although it has been shown that bisphosphonates are effective by blunting osteoclast resorption, there has been little morphologic description of the local tissue activity at the site of these unusual fractures. To evaluate for local changes to bone morphology at the fracture site in patients presenting with a bisphosphonate-related femur fracture, a sample of cortical bone was obtained at the site of a bisphosphonate fracture and was processed in a nondecalcified manner. The specimen was evaluated for potential cellular changes consistent with bisphosphonate treatment. Significant osteoclast abnormalities at the fracture site were found in a 69-year-old woman treated for 2 years with Fosamax substantiating that bone remodeling at this site is distinctly abnormal. Addressing the osteoclast dysfunction should be a focus of future therapeutic attention and intervention.

  16. Diaphyseal Femur Fractures in Osteogenesis Imperfecta: Characteristics and Relationship With Bisphosphonate Treatment.

    Science.gov (United States)

    Trejo, Pamela; Fassier, François; Glorieux, Francis H; Rauch, Frank

    2017-05-01

    Several recent case reports have suggested that bisphosphonate treatment in individuals with osteogenesis imperfecta (OI) is causally related to atypical femur fractures. However, it is not known whether atypical femur fractures are actually more frequent in patients who have received bisphosphonates. In the present study, we retrospectively analyzed 166 femur fractures in 119 children with a diagnosis of OI that had not undergone intramedullary rodding procedures. A total of 130 fractures in 90 patients occurred in femurs with preexisting deformities (age at fracture between 1 month and 19.9 years; 43 girls). Because deformities are a typical cause of fracture in OI, deformed femurs were excluded from the analysis of atypical fractures. However, it was noted that in deformed femurs a transverse fracture pattern (one of the criteria of atypical fractures) was associated with a moderate to severe OI phenotype and not related to bisphosphonate treatment. Of the 36 fractures that occurred in nondeformed femurs (30 individuals; age at fracture between 1 month and 17.4 years; 13 girls), 11 (in nine children) occurred during bisphosphonate treatment. Three of these fractures (27%) resembled atypical femur fractures. Among the 25 femur fractures (23 patients) that occurred in the absence of prior bisphosphonate treatment, 8 (22%) resembled atypical femur fractures. Logistic regression analysis showed that bisphosphonate treatment history was not associated with the occurrence of atypical fractures. In contrast, the presence of moderate to severe OI (defined as any OI type other than OI type I) was strongly associated with atypical femur fractures. Thus, we observed an atypical appearance in about a quarter of nondeformed femur fractures that occurred in children with OI. Such atypical femur fractures seemed to be related to the severity of OI rather than to bisphosphonate treatment history. © 2016 American Society for Bone and Mineral Research. © 2016 American Society

  17. Bisphosphonate adverse effects, lessons from large databases

    DEFF Research Database (Denmark)

    Abrahamsen, Bo

    2010-01-01

    conditions - a proxy for ONJ - with oral bisphosphonates, but the risk of jaw necrosis was increased almost eight times in those receiving i.v. bisphosphonates. The risk of atrial fibrillation with alendronate may be increased in the first weeks of treatment, but no excess risk was seen in long-term users...

  18. Effects of bisphosphonates on osteoclastogenesis in RAW264.7 cells.

    Science.gov (United States)

    Abe, Keigo; Yoshimura, Yoshitaka; Deyama, Yoshiaki; Kikuiri, Takashi; Hasegawa, Tomokazu; Tei, Kanchu; Shinoda, Hisashi; Suzuki, Kuniaki; Kitagawa, Yoshimasa

    2012-06-01

    Bisphosphonates are used as therapeutic agents for the management of osteoporosis and other bone diseases. However, the precise effects and mechanisms of bisphosphonates on osteoclastogenesis are unclear, as previous studies have reported contradictory findings and no studies have circumstantially assessed the effects of bisphosphonates on osteoclastogenesis. Therefore, the aim of this study was to determine the effects of bisphosphonates on osteoclastogenesis in RAW264.7 (RAW) cells. To examine the direct effects of bisphosphonates on osteoclast differentiation via receptor activator of nuclear factor-κB (RANK) ligand (RANKL), RAW cells were cultured with bisphosphonates. Addition of bisphosphonates to RAW cells led to a significant decrease in the number of osteoclasts and large osteoclasts (≥ 8 nuclei) in a bisphosphonate concentration-dependent and time-dependent manner. The cytotoxicity of non-nitrogen-containing bisphosphonates was specific to osteoclasts, while nitrogen-containing bisphosphonates were cytotoxic and induced cell death in both osteoclasts and RAW cells. Resorption activity was significantly diminished by treatment with bisphosphonates, thus confirming that bisphosphonates impair the absorptive activity of osteoclasts. We also investigated the effects of bisphosphonates on the mRNA expression of genes associated with osteoclastogenesis, osteoclast-specific markers and apoptosis-related genes using quantitative real-time PCR. The results suggest that bisphosphonates suppress osteoclast differentiation and infusion, and induce osteoclast apoptosis. With regard to osteoclast apoptosis induced by bisphosphonates, we further investigated the detection of DNA fragmentation and Caspase-Glo 3/7 assay. DNA fragmentation was confirmed after treatment with bisphosphonates, while caspase-3/7 activity increased significantly when compared with controls. In conclusion, bisphosphonates directly inhibited RANKL-stimulated osteoclast differentiation and

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

    Directory of Open Access Journals (Sweden)

    Pavel Stanimirov

    2017-03-01

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

  20. Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis

    Directory of Open Access Journals (Sweden)

    Michael Pazianas

    2010-07-01

    Full Text Available Michael Pazianas1, Cyrus Cooper1,2, F Hal Ebetino3, R Graham G Russell1,41The Botnar Research Centre and Oxford University Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Diseases, Nuffield Orthopaedic Centre, Headington, Oxford, UK; 2MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK; 3Warner Chilcott, New Jersey, USA; 4The Mellanby Centre for Bone Research, Department of Human Metabolism, Sheffield University Medical School, Sheffield, UKAbstract: Bisphosphonates are the leading drugs for the treatment of osteoporosis. In ­randomized controlled trials (RCTs, alendronate, risedronate, and zoledronate have shown to reduce the risk of vertebral, nonvertebral, and hip fractures, whereas RCTs with ibandronate show antifracture efficacy at vertebral sites. Bisphosphonates are generally well tolerated and safe. Nevertheless, adverse events have been noted, and it is important to consider the strength of the evidence for causal relationships. Effects on the gastrointestinal tract and kidney function are well recognized, as are transient acute-phase reactions. Atrial fibrillation was first identified as a potential adverse event in a zoledronate trial, but subsequent trials and analyses failed to substantiate an association with bisphosphonates. Case reports have suggested a relationship between oral bisphosphonates and esophageal cancer, but this has not been demonstrated in epidemiologic studies. A possible association between bisphosphonate use and osteonecrosis of the jaw (ONJ has also been suggested. However, the risk of ONJ in patients with osteoporosis appears to be very low, with no evidence from prospective RCTs of a causal association. There are reports of occasional occurrence of subtrochanteric or diaphyseal fractures in osteoporotic patients, but an association with bisphosphonate therapy is not substantiated by

  1. Treatment with intravenous pamidronate is a good alternative in case of gastrointestinal side effects or contraindications for oral bisphosphonates

    Directory of Open Access Journals (Sweden)

    Dijkmans Ben AC

    2009-07-01

    Full Text Available Abstract Background In case of contraindications or intolerance during treatment with oral bisphosphonates (OB, administration of pamidronate intravenously is a widely used alternative. In this study we compared the effect on change in bone mineral density (BMD of the spine and hip during long term treatment with pamidronate iv in comparison to OB. Methods We studied 61 patients receiving treatment for at least two years. In case of contraindications or intolerance (within 3 months of an OB, pamidronate iv was started. BMD was measured on a Hologic 4500 and a Lunar DPX-IQ at the spine (L1-L4 and total hip. Results Thirty-one patients were enrolled in the OB group and 30 in the intravenous pamidronate group. Mean follow-up duration (SD was 4.3 (1.3 years. We observed a significant increase (p Conclusion We conclude that intravenous pamidronate is a good alternative for oral bisphosphonates in the treatment of osteoporosis in patients with contraindications or intolerance during treatment with oral bisphosphonates.

  2. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

    NARCIS (Netherlands)

    Coleman, R.; Powles, T.; Paterson, A.; Gnant, M.; Anderson, S.; Diel, I.; Gralow, J.; von Minckwitz, G.; Moebus, V.; Bergh, J.; Pritchard, K. I.; Bliss, J.; Cameron, D.; Evans, V.; Pan, H.; Peto, R.; Bradley, R.; Gray, R.; Pritchard, K.; Albain, K.; Arriagada, R.; Barlow, W.; Bergsten-Nordström, E.; Boccardo, F.; Buyse, M.; Clarke, M.; Coates, A.; Correa, C.; Costantino, J.; Cuzick, J.; Davidson, N.; Davies, C.; Di Leo, A.; Dowsett, M.; Ewertz, M.; Forbes, J.; Gelber, R.; Geyer, C.; Gianni, L.; Goldhirsch, A.; Hayes, D.; Hill, C.; Ingle, J.; Janni, W.; MacKinnon, E.; Martín, M.; McGale, P.; Norton, L.; Ohashi, Y.; Paik, S.; Perez, E.; Piccart, M.; Pierce, L.; Raina, V.; Ravdin, P.; Robertson, J.; Rutgers, E.; Sparano, J.; Swain, S.; Taylor, C.; Viale, G.; Wang, X.; Whelan, T.; Wilcken, N.; Winer, E.; Wolmark, N.; Wood, W.; Abe, O.; Abe, R.; Enomoto, K.; Kikuchi, K.; Koyama, H.; Masuda, H.; Nomura, Y.; Sakai, K.; Sugimachi, K.; Toi, M.; Tominaga, T.; Uchino, J.; Yoshida, M.; Haybittle, J. L.; Leonard, C. F.; Calais, G.; Garaud, P.; Collett, V.; Delmestri, A.; Sayer, J.; Harvey, V. J.; Holdaway, I. M.; Kay, R. G.; Mason, B. H.; Forbes, J. F.; Bartsch, R.; Dubsky, P.; Fesl, C.; Fohler, H.; Greil, R.; Jakesz, R.; Lang, A.; Luschin-Ebengreuth, G.; Marth, C.; Mlineritsch, B.; Samonigg, H.; Singer, C. F.; Steger, G. G.; Stöger, H.; Canney, P.; Yosef, H. M. A.; Focan, C.; Peek, U.; Oates, G. D.; Powell, J.; Durand, M.; Mauriac, L.; Dolci, S.; Larsimont, D.; Nogaret, J. M.; Philippson, C.; Piccart, M. J.; Masood, M. B.; Parker, D.; Price, J. J.; Lindsay, M. A.; Mackey, J.; Martin, M.; Hupperets, P. S. G. J.; Bates, T.; Blamey, R. W.; Chetty, U.; Ellis, I. O.; Mallon, E.; Morgan, D. A. L.; Patnick, J.; Pinder, S.; Olivotto, I.; Ragaz, J.; Berry, D.; Broadwater, G.; Cirrincione, C.; Muss, H.; Weiss, R. B.; Abu-Zahra, H. T.; Portnoj, S. M.; Bowden, S.; Brookes, C.; Dunn, J.; Fernando, I.; Lee, M.; Poole, C.; Rea, D.; Spooner, D.; Barrett-Lee, P. J.; Mansel, R. E.; Monypenny, I. J.; Gordon, N. H.; Davis, H. L.; Sestak, I.; Lehingue, Y.; Romestaing, P.; Dubois, J. B.; Delozier, T.; Griffon, B.; Mace Lesec'h, J.; Brain, E.; de La Lande, B.; Mouret-Fourme, E.; Mustacchi, G.; Petruzelka, L.; Pribylova, O.; Owen, J. R.; Harbeck, N.; Jänicke, F.; Meisner, C.; Schmitt, M.; Thomssen, C.; Meier, P.; Shan, Y.; Shao, Y. F.; Zhao, D. B.; Chen, Z. M.; Pan, H. C.; Howell, A.; Swindell, R.; Burrett, J. A.; Cutter, D.; Duane, F.; Gettins, L.; Godwin, J.; James, S.; Kerr, A.; Liu, H.; Mannu, G.; McHugh, T.; Morris, P.; Read, S.; Wang, Y.; Wang, Z.; Albano, J.; de Oliveira, C. F.; Gervásio, H.; Gordilho, J.; Ejlertsen, B.; Jensen, M.-B.; Johansen, H.; Mouridsen, H.; Palshof, T.; Gelman, R. S.; Harris, J. R.; Henderson, C.; Shapiro, C. L.; Christiansen, P.; Møller, S.; Mouridsen, H. T.; Trampisch, H. J.; Dalesio, O.; de Vries, E. G. E.; Rodenhuis, S.; van Tinteren, H.; Comis, R. L.; Davidson, N. E.; Robert, N.; Sledge, G.; Solin, L. J.; Sparano, J. A.; Tormey, D. C.; Dixon, J. M.; Forrest, P.; Jack, W.; Kunkler, I.; Rossbach, J.; Klijn, J. G. M.; Treurniet-Donker, A. D.; van Putten, W. L. J.; Rotmensz, N.; Veronesi, U.; Bartelink, H.; Bijker, N.; Bogaerts, J.; Cardoso, F.; Cufer, T.; Julien, J. P.; van de Velde, C. J. H.; Cunningham, M. P.; Huovinen, R.; Joensuu, H.; Costa, A.; Bonadonna, G.; Valagussa, P.; Goldstein, L. J.; Bonneterre, J.; Fargeot, P.; Fumoleau, P.; Kerbrat, P.; Luporsi, E.; Namer, M.; Eiermann, W.; Hilfrich, J.; Jonat, W.; Kaufmann, M.; Kreienberg, R.; Schumacher, M.; Bastert, G.; Rauschecker, H.; Sauer, R.; Sauerbrei, W.; Schauer, A.; Blohmer, J. U.; Costa, S. D.; Eidtmann, H.; Gerber, B.; Jackisch, C.; Loibl, S.; de Schryver, A.; Vakaet, L.; Belfiglio, M.; Nicolucci, A.; Pellegrini, F.; Pirozzoli, M. C.; Sacco, M.; Valentini, M.; McArdle, C. S.; Smith, D. C.; Stallard, S.; Dent, D. M.; Gudgeon, C. A.; Hacking, A.; Murray, E.; Panieri, E.; Werner, I. D.; Carrasco, E.; Segui, M. A.; Galligioni, E.; Leone, B.; Vallejo, C. T.; Zwenger, A.; Lopez, M.; Erazo, A.; Medina, J. Y.; Horiguchi, J.; Takei, H.; Fentiman, I. S.; Hayward, J. L.; Rubens, R. D.; Skilton, D.; Scheurlen, H.; Sohn, H. C.; Untch, M.; Dafni, U.; Markopoulos, C.; Fountzilas, G.; Mavroudis, D.; Klefstrom, P.; Blomqvist, C.; Saarto, T.; Gallen, M.; Tinterri, C.; Margreiter, R.; de Lafontan, B.; Mihura, J.; Roché, H.; Asselain, B.; Salmon, R. J.; Vilcoq, J. R.; André, F.; Delaloge, S.; Koscielny, S.; Michiels, S.; Rubino, C.; A'Hern, R.; Ellis, P.; Kilburn, L.; Yarnold, J. R.; Benraadt, J.; Kooi, M.; van de Velde, A. O.; van Dongen, J. A.; Vermorken, J. B.; Castiglione, M.; Colleoni, M.; Collins, J.; Gelber, R. D.; Lindtner, J.; Price, K. N.; Regan, M. M.; Rudenstam, C. M.; Senn, H. J.; Thuerlimann, B.; Bliss, J. M.; Chilvers, C. E. D.; Coombes, R. C.; Hall, E.; Marty, M.; Possinger, K.; Schmid, P.; Wallwiener, D.; Foster, L.; George, W. D.; Stewart, H. J.; Stroner, P.; Borovik, R.; Hayat, H.; Inbar, M. J.; Peretz, T.; Robinson, E.; Bruzzi, P.; del Mastro, L.; Pronzato, P.; Sertoli, M. R.; Venturini, M.; Camerini, T.; de Palo, G.; Di Mauro, M. G.; Formelli, F.; Perrone, F.; Amadori, D.; Martoni, A.; Pannuti, F.; Camisa, R.; Cocconi, G.; Colozza, A.; Passalacqua, R.; Aogi, K.; Takashima, S.; Ikeda, T.; Inokuchi, K.; Sawa, K.; Sonoo, H.; Sadoon, M.; Tulusan, A. H.; Kohno, N.; Miyashita, M.; Takao, S.; Ahn, J.-H.; Jung, K. H.; Korzeniowski, S.; Skolyszewski, J.; Ogawa, M.; Yamashita, J.; Bastiaannet, E.; van de Water, W.; van Nes, J. G. H.; Christiaens, R.; Neven, P.; Paridaens, R.; van den Bogaert, W.; Braun, S.; Martin, P.; Romain, S.; Janauer, M.; Seifert, M.; Sevelda, P.; Zielinski, C. C.; Hakes, T.; Hudis, C. A.; Wittes, R.; Giokas, G.; Kondylis, D.; Lissaios, B.; de la Huerta, R.; Sainz, M. G.; Ro, J.; Altemus, R.; Camphausen, K.; Cowan, K.; Danforth, D.; Lichter, A.; Lippman, M.; O'Shaughnessy, J.; Pierce, L. J.; Steinberg, S.; Venzon, D.; Zujewski, J. A.; D'Amico, C.; Lioce, M.; Paradiso, A.; Chapman, W.; Gelmon, K.; Goss, P. E.; Levine, M. N.; Meyer, R.; Parulekar, W.; Pater, J. L.; Shepherd, L. E.; Tu, D.; Ohno, S.; Bass, G.; Brown, A.; Bryant, J.; Dignam, J.; Fisher, B.; Mamounas, E. P.; Redmond, C.; Wickerham, L.; Aihara, T.; Hozumi, Y.; Baum, M.; Jackson, I. M.; Palmer, M. K.; Ingle, J. N.; Suman, V. J.; Bengtsson, N. O.; Emdin, S.; Jonsson, H.; Lythgoe, J. P.; Kissin, M.; Erikstein, B.; Hannisdal, E.; Jacobsen, A. B.; Varhaug, J. E.; Gundersen, S.; Hauer-Jensen, M.; Høst, H.; Nissen-Meyer, R.; Mitchell, A. K.; Robertson, J. F. R.; Ueo, H.; Di Palma, M.; Mathé, G.; Misset, J. L.; Levine, M.; Morimoto, K.; Takatsuka, Y.; Crossley, E.; Harris, A.; Talbot, D.; Taylor, M.; di Blasio, B.; Ivanov, V.; Paltuev, R.; Semiglazov, V.; Brockschmidt, J.; Cooper, M. R.; Falkson, C. I.; Hadji, P.; Makris, A.; Parton, M.; Pennert, K.; Powles, T. J.; Smith, I. E.; Gazet, J. C.; Browne, L.; Graham, P.; Corcoran, N.; Clack, G.; van Poznak, C.; Deshpande, N.; di Martino, L.; Douglas, P.; Lindtner, A.; Notter, G.; Bryant, A. J. S.; Ewing, G. H.; Firth, L. A.; Krushen-Kosloski, J. L.; Anderson, H.; Killander, F.; Malmström, P.; Rydén, L.; Arnesson, L.-G.; Carstensen, J.; Dufmats, M.; Fohlin, H.; Nordenskjöld, B.; Söderberg, M.; Carpenter, J. T.; Murray, N.; Royle, G. T.; Simmonds, P. D.; Crowley, J.; Hortobagyi, G.; Livingston, R.; Martino, S.; Osborne, C. K.; Ravdin, P. M.; Adolfsson, J.; Bondesson, T.; Celebioglu, F.; Dahlberg, K.; Fornander, T.; Fredriksson, I.; Frisell, J.; Göransson, E.; Iiristo, M.; Johansson, U.; Lenner, E.; Löfgren, L.; Nikolaidis, P.; Perbeck, L.; Rotstein, S.; Sandelin, K.; Skoog, L.; Svane, G.; af Trampe, E.; Wadström, C.; Maibach, R.; Thürlimann, B.; Hakama, M.; Holli, K.; Isola, J.; Rouhento, K.; Saaristo, R.; Safra, T.; Brenner, H.; Hercbergs, A.; Yoshimoto, M.; Paterson, A. H. G.; Fyles, A.; Meakin, J. W.; Panzarella, T.; Bahi, J.; Reid, M.; Spittle, M.; Bishop, H.; Bundred, N. J.; Forsyth, S.; Pinder, S. E.; Deutsch, G. P.; Kwong, D. L. W.; Pai, V. R.; Senanayake, F.; Martin, A. L.; Rubagotti, A.; Hackshaw, A.; Houghton, J.; Ledermann, J.; Monson, K.; Tobias, J. S.; Carlomagno, C.; de Laurentiis, M.; de Placido, S.; Williams, L.; Bell, R.; Coleman, R. E.; Dodwell, D.; Hinsley, S.; Marshall, H. C.; Solomayer, E.; Fehm, T.; Horsman, J. M.; Lester, J.; Winter, M. C.; Broglio, K.; Buzdar, A. U.; Hsu, L.; Love, R. R.; Ahlgren, J.; Garmo, H.; Holmberg, L.; Liljegren, G.; Lindman, H.; Wärnberg, F.; Asmar, L.; Jones, S. E.; Aft, R.; Gluz, O.; Liedtke, C.; Nitz, U.; Litton, A.; Wallgren, A.; Karlsson, P.; Linderholm, B. K.; Chlebowski, R. T.; Caffier, H.; Brufsky, A. M.; Llombart, H. A.

    2015-01-01

    Background Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. Methods We sought individual patient data from all

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

    Directory of Open Access Journals (Sweden)

    Natalia Daniela Escudero

    2012-01-01

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

  4. [Bisphosphonate-associated osteonecrosis of the jaw in patients with multiple myeloma].

    Science.gov (United States)

    Lund, Thomas; Gregersen, Henrik; Vangsted, Annette; Marker, Peter; Abildgaard, Niels

    2009-01-05

    Bisphosphonate-associated osteonecrosis of the jaw (BON) is mainly observed in patients with multiple myeloma, and to a lesser extent in breast and prostate cancer patients receiving intravenous treatment with potent bisphosphonates. The incidence of BON increases with the duration 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.

  5. Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a metanalysis

    OpenAIRE

    Mauri, Davide; Valachis, Antonis; Polyzos, Ilias P.; Polyzos, Nikolaos P.; Kamposioras, Konstantinos; Pesce, Lorenzo L.

    2009-01-01

    Abstract To estimate the cumulative randomized evidence for the overall incidence of bisphosphonates induced jaw osteonecrosis in adjuvant treatment of breast cancer. Systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meetings searches. We identified 15 studies reporting data on osteonecrosis of the jaw. A total of 10,694 randomized women were included, of whom 5,312 received bisp...

  6. Use of bisphosphonates in orthopedic surgery: pearls and pitfalls.

    Science.gov (United States)

    Lozano-Calderon, Santiago A; Colman, Matthew W; Raskin, Kevin A; Hornicek, Francis J; Gebhardt, Mark

    2014-07-01

    Bisphosphonates are medications known to decrease bone resorption by inhibiting osteoclastic activity. They are the first-line therapy for the treatment of osteoporosis because a significant body of literature has proved their efficacy in reducing the risk of fracture in the hip, spine and other nonvertebral osseous sites. In addition, the use of bisphosphonates has significantly decreased morbidity and increased survival, and they have also proved to be cost-effective. Unexpected adverse effects have been reported recently, but the benefit of bisphosphonates use outweighs the risks. This article reviews the current use of bisphosphonates in orthopedic surgery. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Efficacy and safety of teriparatide in bisphosphonate-pretreated and treatment-naive patients with osteoporosis at high risk of fracture: Post hoc analysis of a prospective observational study.

    Science.gov (United States)

    Yoshiki, Fumito; Nishikawa, Atsushi; Taketsuna, Masanori; Kajimoto, Kenta; Enomoto, Hiroyuki

    2017-03-01

    Teriparatide is the first anabolic agent shown to reduce the risk of fractures in patients with osteoporosis. In Japan, teriparatide is prescribed to treat patients at high risk of fracture. Given that bisphosphonates are commonly used prior to teriparatide as treatment for osteoporosis, information on the effectiveness and safety of teriparatide with or without previous bisphosphonate treatment is helpful for physicians in clinical practice. This study aims to report the effectiveness and safety of teriparatide in treatment-naive and bisphosphonate-pretreated patients in Japan as real-world evidence. A post hoc analysis of a postmarketing surveillance study was conducted in Japanese patients with osteoporosis at high risk of fracture who received 24-month treatment of daily teriparatide. Changes in bone turnover biomarkers and bone mineral density and incidence of new fractures were analyzed in treatment-naive as well as bisphosphonate-pretreated patients. The analysis included 1433 patients (treatment-naive, n = 659; bisphosphonate-pretreated, n = 774). Bone mineral density increased significantly from baseline at 24 months in both treatment-naive (lumbar spine, 13.45%; femoral neck, 5.16%; total hip, 4.46%) and bisphosphonate-pretreated (lumbar spine, 11.20%; femoral neck, 2.22%; total hip, 0.67%) patients. The incidence rates of new vertebral and nonvertebral fractures at 24 months were 1.69% and 3.37%, respectively, in treatment-naive patients and 3.60% and 5.56%, respectively, in bisphosphonate-pretreated patients. The incidence of adverse drug reactions was 6% in treatment-naive patients and 10% in bisphosphonate-pretreated patients. The most common adverse drug reaction in treatment-naive and bisphosphonate-pretreated patients was nausea (0.91%) and hyperuricaemia (1.81%), respectively. In this post hoc analysis, no new safety concerns and similar effectiveness of teriparatide were observed in Japanese patients with osteoporosis at high risk of fracture

  8. CAD/CAM-fabricated telescopic prostheses on periodontally compromised abutments of a patient undergoing intravenous bisphosphonate treatment for osteoporosis: a case report.

    Science.gov (United States)

    Lin, Wei-Shao; Harris, Bryan T; Zandinejad, Amirali; Morton, Dean

    2014-01-01

    Preserving periodontally compromised abutments in patients who are actively undergoing oral and intravenous bisphosphonate treatment for osteoporosis provides an alternative to tooth extraction and dental implants, both of which put patients at risk for bisphosphonate-related osteonecrosis of the jaw. This case report describes how a CAD/CAM-fabricated cobalt-chromium telescopic prosthesis was placed on periodontally compromised abutments of a 74-year-old woman actively undergoing oral and intravenous bisphosphonate treatment for osteoporosis.

  9. Local Administration of Bisphosphonate-soaked Hydroxyapatite for the Treatment of Osteonecrosis of the Femoral Head in Rabbit

    Science.gov (United States)

    Ma, Jin-Hui; Guo, Wan-Shou; Li, Zi-Rong; Wang, Bai-Liang

    2016-01-01

    Background: Systemic administration of bisphosphonates has shown promising results in the treatment of osteonecrosis of the femoral head (ONFH). However, few studies have evaluated the efficacy of local zoledronate (ZOL) administration in the treatment of ONFH. The purpose of this study was to investigate whether local administration of bisphosphonate-soaked hydroxyapatite (HA) could improve bone healing in an experimental rabbit model of ONFH. Methods: This experimental study was conducted between October 2014 and June 2015. Forty-five rabbits underwent simulated ONFH surgery. Immediately following surgery, they were divided into three groups: model (untreated, n = 15), HA (treated with HA alone, n = 15), and HA + ZOL (treated with HA soaked in a low-dose ZOL solution, n = 15). Histological, immunohistochemical, and quantitative analyses were performed to evaluate bone formation and resorption 2, 4, and 8 weeks after surgery. Results: Gross bone matrix and hematopoietic tissue formation were observed in the HA + ZOL group 4 weeks after surgery. The immunohistochemical staining intensities for 5-bromodeoxyuridine, runt-related transcription factor 2, osteocalcin, osteopontin, and osteoprotegerin were significantly higher in the HA + ZOL group than that in the model (P 0.05). Conclusions: Local administration of HA soaked in a low-dose ZOL solution increased new bone formation while inhibiting bone resorption in an animal model of ONFH, which might provide new evidence for joint-preserving surgery in the treatment of ONFH. PMID:27779162

  10. Change in arterial stiffness associated with monthly bisphosphonate treatment in women with postmenopausal osteoporosis.

    Science.gov (United States)

    Igase, Michiya; Kohara, Katsuhiko; Tabara, Yasuharu; Ohara, Maya; Takita, Rie; Ochi, Masayuki; Okada, Yoko; Miki, Tetsuro

    2014-09-01

    Osteoporosis and atherosclerosis are the two most common diseases in postmenopausal women. In most cases, they are simultaneously present in the same individual and commonly lead to bone fracture or cardiovascular disease (CVD). Bisphosphonates (BPs) are frequently used in the treatment of osteoporosis and have the ability to increase lumbar spine bone mineral density (L-BMD). BPs may also protect against CVD. A single monthly 50-mg dose of minodronate (monthly minodronate) is now common practice and is highly anticipated to reduce the incidence of both bone fracture and CVD. A useful approach to independently predicting CVD is brachial-ankle pulse wave velocity (baPWV). Here, we directly compared the effects of monthly minodronate with those of a standard single weekly 35-mg dose of alendronate (weekly alendronate) on L-BMD and baPWV in postmenopausal women with osteoporosis across a 12-month period. Thirty-eight postmenopausal women with osteoporosis were randomized into two treatment groups (group 1, weekly alendronate, n = 19; group 2, monthly minodronate, n = 19). L-BMD and baPWV were assessed at baseline and 12-month follow-up. At the end of the 12-month period, increases in L-BMD were similar between group 1 (7.6%) and group 2 (8.5%), but baPWV was significantly reduced in group 2 compared with group 1. The change in baPWV during the study period showed a significant negative correlation with the change in L-BMD. Changes in L-BMD in the monthly minodronate and weekly alendronate groups are generally comparable. Good control of changes in L-BMD in the postmenopausal phase might be associated with regression of CVD. Monthly minodronate is a promising new BP and potential first-line drug for the treatment of osteoporosis in postmenopausal women.

  11. Predictors of fracture while on treatment with oral bisphosphonates: a population-based cohort study.

    Science.gov (United States)

    Prieto-Alhambra, Daniel; Pagès-Castellà, Aina; Wallace, Gemma; Javaid, M Kassim; Judge, Andrew; Nogués, Xavier; Arden, Nigel K; Cooper, Cyrus; Diez-Perez, Adolfo

    2014-01-01

    Although oral bisphosphonates (BPs) are highly effective in preventing fractures, some patients will fracture while on treatment. We identified predictors of such fractures in a population-based cohort of incident users of oral BPs. We screened the Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària (SIDIAP) database to identify new users of oral BPs in 2006-2007. SIDIAP includes pharmacy invoice data and primary care electronic medical records for a representative 5 million people in Catalonia (Spain). Exclusion criteria were the following: Paget disease; 6 months of therapy. Incidence of fracture while on treatment was 3.4/100 person-years (95% confidence interval [CI], 3.1-3.7). Predictors of these among patients persisting and adhering to treatment included: older age (subhazard ratio [SHR] for 60 to <80 years, 2.18 [95% CI, 1.70-2.80]; for ≥80 years, 2.5 [95% CI, 1.82-3.43]); previous fracture (1.75 [95% CI, 1.39-2.20] and 2.49 [95% CI, 1.98-3.13], in the last 6 months and longer, respectively); underweight, 2.11 (95% CI, 1.14-3.92); inflammatory arthritis, 1.46 (95% CI, 1.02-2.10); use of proton pump inhibitors (PPIs), 1.22 (95% CI, 1.02-1.46); and vitamin D deficiency, 2.69 (95% CI, 1.27-5.72). Even among high compliers, 3.4% of oral BP users will fracture every year. Older age, underweight, vitamin D deficiency, PPI use, previous fracture, and inflammatory arthritides increase risk. Monitoring strategies and/or alternative therapies should be considered for these patients. © 2014 American Society for Bone and Mineral Research.

  12. Bisphosphonates are associated with increased risk for jaw surgery in medical claims data: is it osteonecrosis?

    Science.gov (United States)

    Zavras, Athanasios I; Zhu, Shao

    2006-06-01

    Bisphosphonates (BPs) have recently been associated with increased risk of osteonecrosis of the jaw. Using a large automated insurance database, we searched the medical claims for common procedure codes (CPT codes) denoting major surgery to the mandible or the maxilla. The primary aim of this pilot study was to alert readers to clinically relevant but preliminary information regarding the risk of jaw surgery among patients who received BPs, as compared with patients who did not. The study utilized 2001-2004 claims data from a large nationwide medical insurer. Medical claims from 255,757 cancer patients with breast, lung, or prostate malignancies, or multiple myeloma were analyzed for CPT codes 21015, 21025, 21026, 21034, 21040, 21045, 21046, and 21047. We identified 224 cases of jaw surgery; of those, 39 cases were found among 26,288 BP users and 185 cases were found among 229,469 never-users. The odds ratio of jaw surgery for intravenous BP users was 4.24 (PBreast cancer patients experienced a 6-fold increase in risk as compared with nonusers. A trend of increased risk was noted for those on orally administered BPs, but the association was not significant. A significant association was noted between the administration of IV BPs and oral surgery in cancer patients. More studies are needed to understand the role of BPs in bone biology and necrosis along with the associated biologic pathways.

  13. Eleven years of experience with bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I

    Directory of Open Access Journals (Sweden)

    Iwamoto J

    2012-12-01

    Full Text Available Jun Iwamoto,1 Yoshihiro Sato,2 Mitsuyoshi Uzawa,3 Hideo Matsumoto11Institute for Integrated Sports Medicine, Keio University School of Medicine, Tokyo, 2Department of Neurology, Mitate Hospital, Fukuoka, 3Department of Orthopaedic Surgery, Keiyu Orthopaedic Hospital, Gunma, JapanAbstract: We report the 11-year follow-up of a man with osteogenesis imperfecta type I who was treated with bisphosphonates and alfacalcidol. A 36-year-old Japanese man with osteogenesis imperfecta type I who had frequently experienced painful fragility fractures consulted our clinic because of chronic back pain. The patient had multiple morphometric vertebral fractures and a low bone mineral density (BMD at the lumbar spine. The patient was treated with cyclical etidronate 200 mg, for 2 weeks every 3 months, plus alfacalcidol 1 µg daily, for 2 years; and alendronate 5 mg daily or 35 mg weekly, plus alfacalcidol 1 µg daily for 9 years. After 11 years of treatment, BMD at the lumbar spine increased by 6.4%, following a 20.3% reduction in serum alkaline phosphatase. Serum calcium, phosphorus, and intact parathyroid hormone levels remained within the normal ranges. Three clinical fractures occurred at two ribs and the metacarpus, and two morphometric vertebral fractures occurred at the thoracic spine during the 11-year treatment period, but the patient experienced no adverse effects. Thus, the present case report shows the long-term outcome and safety of bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I.Keywords: etidronate, alendronate, fragility fracture, bone mineral density, osteogenesis imperfecta

  14. Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis.

    Science.gov (United States)

    Mauri, Davide; Valachis, Antonis; Polyzos, Ilias P; Polyzos, Nikolaos P; Kamposioras, Konstantinos; Pesce, Lorenzo L

    2009-08-01

    To estimate the cumulative randomized evidence for the overall incidence of bisphosphonates induced jaw osteonecrosis in adjuvant treatment of breast cancer. Systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meetings searches. We identified 15 studies reporting data on osteonecrosis of the jaw. A total of 10,694 randomized women were included, of whom 5,312 received bisphosphonates and 5,382 received either placebo or no treatment. Osteonecrosis of the jaw was a rare event, occurring in 13 (0.24%) of the 5,312 patients receiving bisphosphonates, and in one of the 5,382 patients in the control group. All the 13 events of osteonecrosis of the jaw reported among bisphosphonates arms occur in patients undergoing treatment with zoledronic acid (13/3,987, 0.33%). No events of osteonecrosis of the jaw were reported among patients randomized to receive clodronate (n = 669), pamidronate (n = 460), risedronate (n = 171), and ibandronate (n = 25); however, these samples were too small to be able to rule out the condition. Treatment with zoledronic acid was significantly associated to the occurrence of osteonecrosis of the jaw (OR = 3.23, 95% CI = 1.7-8) compared with no use. No significant between-study heterogeneity was observed. Despite use of zoledronic acid is associated to a higher number of events compared with no use, the osteonecrosis of the jaw during the adjuvant treatment of breast cancer is a rare event. At current dosage, adjuvant use of bisphosphonates in breast cancer treatment is safe.

  15. The benefits of photodynamic therapy on vertebral bone are maintained and enhanced by combination treatment with bisphosphonates and radiation therapy.

    Science.gov (United States)

    Lo, Victor C K; Akens, Margarete K; Wise-Milestone, Lisa; Yee, Albert J M; Wilson, Brian C; Whyne, Cari M

    2013-09-01

    Photodynamic therapy (PDT) has been shown to ablate tumors within vertebral bone and yield short-term improvements in vertebral architecture and biomechanical strength, in particular when combined with bisphosphonate (BP) treatment. Longer-term outcomes of PDT combined with current treatments for skeletal metastases are essential to understand its therapeutic potential. The objective of this study is to evaluate the response of vertebrae to PDT after a longer (6-week) time period, alone and combined with previous BP or radiation treatment (RT). Sixty-three female rnu/rnu rats were randomized to six treatment groups: untreated control, BP-only, RT-only, PDT-only, combined BP + PDT and combined RT + PDT. L2 vertebrae were structurally analyzed through µCT-based analysis, axial compressive load-to-failure testing and histological analysis of morphology, osteoid formation and osteoclast activity. Combined BP + PDT treatment yielded the largest improvements in bone architecture with combined RT + PDT treatment yielding similar findings, but of a lesser magnitude. Mechanically, ultimate force and stress were correlated to stereological parameters that demonstrated a positive structural effect from combinatory treatment. Increased osteoid formation was observed in both combination therapies without any significant differences in osteoclast activity. Overall, multimodality treatment demonstrated a sustained positive effect on vertebral structural integrity, motivating PDT as a minimally-invasive adjuvant treatment for spinal metastases. Copyright © 2013 Orthopaedic Research Society.

  16. Further significant effects of eldecalcitol on bone resorption markers and bone mineral density in postmenopausal osteoporosis patients having undergone long-term bisphosphonate treatment.

    Science.gov (United States)

    Iba, Kousuke; Sonoda, Tomoko; Takada, Junichi; Dohke, Takayuki; Yamashita, Toshihiko

    2017-03-01

    We investigated whether eldecalcitol has further significant effects on bone metabolic markers and bone mineral density (BMD) in osteoporosis patients having undergone long-term bisphosphonate treatment. Eldecalcitol treatment was initiated in 48 postmenopausal osteoporosis patients who had undergone bisphosphonate treatment with or without alfacalcidol treatment for more than 2 years (average period 6.3 years). Age, height, weight, total muscle volume, total fat volume, estimated glomerular filtration rate, and BMD at the lumbar spine, total hip, and distal third of the radius were measured as background data for each patient. Serum alkaline phosphatase, tartrate-resistant acid phosphatase 5b, calcium, and phosphate levels were measured at the baseline and 3 and 12 months after the initiation of eldecalcitol treatment, and BMD was measured at the baseline and 12 months after the initiation of eldecalcitol treatment. Tartrate-resistant acid phosphatase 5b level was significantly decreased at 3 and 12 months after the initiation of eldecalcitol treatment in comparison with the baseline level. There were no significant changes in alkaline phosphatase, calcium, or phosphate levels in comparison with the baseline levels. In addition, the lumbar spine BMD at 12 months after the initiation of treatment was significantly increased in comparison with the baseline level, although no significant changes in BMD at the total hip and distal third of the radius were observed. Eldecalcitol demonstrated significant effects in additionally decreasing the level of the bone resorption marker tartrate-resistant acid phosphatase 5b and increasing BMD at the lumbar spine, even in osteoporosis patients having undergone long-term bisphosphonate treatment.

  17. Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw.

    Science.gov (United States)

    Polidoro, Silvia; Broccoletti, Roberto; Campanella, Gianluca; Di Gaetano, Cornelia; Menegatti, Elisa; Scoletta, Matteo; Lerda, Ennio; Matullo, Giuseppe; Vineis, Paolo; Berardi, Daniela; Scully, Crispian; Arduino, Paolo G

    2013-10-09

    Bisphosphonates are used in the treatment of hypocalcaemia, mainly in cancer and osteoporosis. Some patients experience adverse events, such as BP-related osteonecrosis of the jaw (BRONJ). DNA methylation plays a key role in gene regulation in many tissues, but its involvement in bone homeostasis is not well characterized, and no information is available regarding altered methylation in BRONJ. Using the Illumina Infinium HumanMethylation27 BeadChip assay, we performed an epigenome-wide association study in peripheral blood samples from 68 patients treated with nitrogenous BP, including 35 with BRONJ. Analysis of the estimated cumulative BP exposure distribution indicated that the exposure of the case group to BP was slightly higher than that of the control group; more severely affected cases (i.e., with BRONJ in both mandible and maxilla) were significantly more exposed to BP than were those with BRONJ only in the mandible or maxilla (one-sided Wilcoxon rank sum test, p=0.002). Logistic regression analysis confirmed the positive association between cumulative bisphosphonates exposure and risk of BRONJ (OR 1.015 per mg of cumulative exposure, 95% CI 1.004-1.032, p=0.036). Although no statistically significant differences were observed between case and control groups, methylation levels of probes mapping on three genes, ERCC8, LEPREL1 and SDC2, were strongly associated with cumulative BP exposure levels (p<1.31E-007). Enrichment analysis, combining differentially methylated genes with genes involved in the mevalonate pathway, showed that BP treatment can affect the methylation pattern of genes involved in extracellular matrix organization and inflammatory responses, leading to more frequent adverse effects such as BRONJ. Differences in DNA methylation induced by BP treatment could be involved in the pathogenesis of the bone lesion. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Bisphosphonates for osteoporosis in primary biliary cirrhosis

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  19. Bisphosphonate-associated osteonecrosis of the jaw 2 years after teeth extractions: a case report solved with non-invasive treatment.

    Science.gov (United States)

    Gómez-Moreno, G; Arribas-Fernández, M C; Fernández-Guerrero, M; Boquete-Castro, A; Aguilar-Salvatierra, A; Guardia, J; Botticelli, D; Calvo-Guirado, J L

    2014-01-01

    Bisphosphonates are a type of drugs known to inhibit bone resorption through complex interventions. Their primary mechanism of action is aimed at the cellular level, inhibiting osteoclast activity and, thus, bone resorption. Bisphosphonates are, therefore, very widely used, with many patients receiving continuous treatment for years. But it is well known that these drugs can produce osteonecrosis of the jaw and this is their principal risk. A 75-year-old woman received dental treatment before starting intravenous BP therapy for a breast cancer. She started intravenous bisphosphonate treatment with monthly protocol and after two years the patient presented a wound compatible with osteonecrosis of the jaw.

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

    Science.gov (United States)

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

    2016-05-01

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

  1. Osseointegration of dental implants in patients undergoing bisphosphonate treatment: a literature review.

    Science.gov (United States)

    Javed, Fawad; Almas, Khalid

    2010-04-01

    Bisphosphonates (BPs) are an important group of drugs used for the treatment of metabolic and oncologic pathologies involving the skeletal system. Osteonecrosis of the jaw (ONJ) is a complication observed in patients using oral or intravenous (IV) BPs. It was suggested that all patients undergoing BP therapy who are expected to receive dental implants should be informed of the possible risks of development of ONJ. The aim of this literature review is to assess the osseointegration of dental implants in patients undergoing BP therapy. The MEDLINE-PubMed databases of The National Library of Medicine, National Institutes of Health, Bethesda, Maryland, were searched for articles addressing the focused question: Can dental implants osseointegrate and remain functionally stable in patients undergoing oral and IV BP therapy? Databases were searched from 1995 up to and including February 2010 using the following terms in different combinations: bisphosphonate, dental implant, immediate-loading, implant survival rate, intravenous, oral, osseointegration, and osteonecrosis. The initial search yielded 89 articles. Scrutiny of the titles and abstracts reduced the number of articles to 12 (seven case reports and five retrospective studies). In 10 studies, the patients were using oral BPs, and in two studies, patients were using IV BPs. Six case reports showed that the placement of implants in patients using BPs could yield a successful osseointegration and function. Four retrospective studies demonstrated that BPs did not have a negative influence on implant success. Two studies showed a negative impact of BPs on implant success. Dental implants can osseointegrate and remain functionally stable in patients using BPs.

  2. External auditory canal and middle ear cholesteatoma and osteonecrosis in bisphosphonate-treated osteoporosis patients

    DEFF Research Database (Denmark)

    Thorsteinsson, A-L; Vestergaard, P; Eiken, P

    2014-01-01

    UNLABELLED: Long-term treatment with bisphosphonates against osteoporosis may cause atypical femur fractures and osteonecrosis of the jaw. Eight cases of bisphosphonate-associated osteonecrosis of the external auditory canal area are published. Based on Danish national registers, we report a time......- and dose-dependent increased risk of cholesteatoma in osteoporosis patients treated with bisphosphonates. INTRODUCTION: In the recent years, there has been a focus on possible rare side effects of bisphosphonates (BPs). Eight cases of BP-associated osteonecrosis of the external auditory canal have been...

  3. The fracture toughness of small animal cortical bone measured using arc-shaped tension specimens: Effects of bisphosphonate and deproteinization treatments.

    Science.gov (United States)

    Hunckler, Michael D; Chu, Ethan D; Baumann, Andrew P; Curtis, Tyler E; Ravosa, Matthew J; Allen, Matthew R; Roeder, Ryan K

    2017-12-01

    Small animal models, and especially transgenic models, have become widespread in the study of bone mechanobiology and metabolic bone disease, but test methods for measuring fracture toughness on multiple replicates or at multiple locations within a single small animal bone are lacking. Therefore, the objective of this study was to develop a method to measure cortical bone fracture toughness in multiple specimens and locations along the diaphysis of small animal bones. Arc-shaped tension specimens were prepared from the mid-diaphysis of rabbit ulnae and loaded to failure to measure the radial fracture toughness in multiple replicates per bone. The test specimen dimensions, crack length, and maximum load met requirements for measuring the plane strain fracture toughness. Experimental groups included a control group, bisphosphonate treatment group, and an ex vivo deproteinization treatment following bisphosphonate treatment (5 rabbits/group and 15 specimens/group). The fracture toughness of ulnar cortical bone from rabbits treated with zoledronic acid for six months exhibited no difference compared with the control group. Partially deproteinized specimens exhibited significantly lower fracture toughness compared with both the control and bisphosphonate treatment groups. The deproteinization treatment increased tissue mineral density (TMD) and resulted in a negative linear correlation between the measured fracture toughness and TMD. Fracture toughness measurements were repeatable with a coefficient of variation of 12-16% within experimental groups. Retrospective power analysis of the control and deproteinization treatment groups indicated a minimum detectable difference of 0.1MPa·m 1/2 . Therefore, the overall results of this study suggest that arc-shaped tension specimens offer an advantageous new method for measuring the fracture toughness in small animal bones. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Trajectories of Bone Remodeling Markers and Bone Mineral Density during Treatment with Strontium Ranelate in Postmenopausal Women Previously Treated with Bisphosphonates

    Directory of Open Access Journals (Sweden)

    Helisane Lima

    2014-01-01

    Full Text Available Objective To evaluate the responses of C-terminal telopeptide (CTX and serum osteocalcin after the first 4 months of treatment with strontium ranelate (SR and demonstrate their association with long-term bone density changes. Subjects and Methods A sample of 13 postmenopausal women with osteoporosis was analyzed (mean age 65 ± 7.7 years, who were treated with SR for an average of 2.56 ± 0.86 years. All patients had undergone previous treatment with bisphosphonates for an average period of 4.88 ± 2.27 years. Serum CTX and osteocalcin levels were determined before and after four months of treatment with SR. Bone mineral density in the lumbar spine and femoral neck were obtained before and after treatment with SR. Results We observed an average increase of 53.7% in the CTX levels, and 30.7% in the osteocalcin levels. The increase in bone markers was associated with a mean 4.8% increase in lumbar spine bone mineral density (BMD from 0.820 to 0.860 g/cm 2 ( T -score from –2.67 to –1.92; P= 0.001, after 2.5 years of treatment with SR. Conclusion These data suggest an anabolic effect of SR on postmenopausal women who were previously treated with long-term bisphosphonates.

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

    International Nuclear Information System (INIS)

    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

  6. Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung Cancer Patients with Bone Metastasis

    DEFF Research Database (Denmark)

    Fabian, Katalin; Puskás, Rita; Kakuk, Tímea

    2017-01-01

    Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for chan......Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed...

  7. [Innovation of bisphosphonates for improvement of adherence.

    Science.gov (United States)

    Takeuchi, Yasuhiro

    Bisphosphonates are standard medicine for treatment of osteoporosis, and have been inovated to overcome complicated rules for their appropriate administration or their poor intestinal absorption. Not only weekly but also monthly oral bisphosphonates have been available. Furthermore, we are now allowed to choose intravenous administration of bisphosphonates for osteorporosis. Good persistance and adherence is another critical and essential issue to be solved to achive the aim of osteoprosis treatment with bisphosphonates. Variable formulations of bisphosphonate are now able to bring patients closer to a goal of reduction in fragile fracture due to osteoporosis.

  8. Patterns of bisphosphonate treatment among patients with multiple myeloma treated at oncology clinics across the USA: observations from real-world data.

    Science.gov (United States)

    Kim, Christopher; Hernandez, Rohini K; Cyprien, Lori; Liede, Alexander; Cheng, Paul C

    2018-03-07

    Current guidelines recommend that intravenous bisphosphonates be initiated in all patients with multiple myeloma for management of bone disease. The objective of this study was to describe real-world bisphosphonate treatment patterns. This was a retrospective observational study using oncology electronic health record (EHR) data contained in Amgen's Oncology Services Comprehensive Electronic Records (OSCER) database, generated by Flatiron Health (New York, NY), representing over 1.5 million US oncology patients. Patients were newly diagnosed with multiple myeloma between January 1, 2009 and April 30, 2016. Timing of bisphosphonate administration, frequency, schedule, changes in dosing schedule, and discontinuations were calculated. Bisphosphonate treatment relative to renal function and anti-multiple myeloma therapy regimens were also assessed. A total of 11,112 patients were enrolled in the study with a median follow-up of 687 days. Sixty-three percent received ≥ 1 bisphosphonate administration, primarily every 4 weeks (67.7%). Mean time from diagnosis to bisphosphonate administration was 106 days (median, 29). Most patients (58.2%) initiated treatment in first year after diagnosis and about half (51.9%) either discontinued or changed dosing. Patients with poorer renal function by estimated glomerular filtration rate (eGFR) stage at baseline were less likely to receive bisphosphonates (eGFR stage 5 vs 1: 24 vs 72%) and more likely to have delayed initiation of bisphosphonate treatment from diagnosis (eGFR stage 5 vs 1: median 70 vs 25 days). Real-world data from US oncology practices indicate that many patients with multiple myeloma may not receive optimal therapy for bone disease, particularly those with renal impairment.

  9. Comparison of treatment effects of teriparatide and the bisphosphonate risedronate in an aged, osteopenic, ovariectomized rat model under various clinical conditions.

    Science.gov (United States)

    Sugie-Oya, Ayano; Takakura, Aya; Takao-Kawabata, Ryoko; Sano, Hiroko; Shimazu, Yukari; Isogai, Yukihiro; Yamaguchi, Akira; Ishizuya, Toshinori

    2016-05-01

    Teriparatide and bisphosphonates are osteoporosis medications that increase bone mineral density (BMD) and prevent fracture, but each has a different mechanism of action. Teriparatide promotes bone formation, while bisphosphonates suppress bone resorption. In the clinical setting, however, drug selection is not always tailored to the particular clinical condition of the patient or mechanism of action of the drug. We compared the effects of teriparatide and the bisphosphonate risedronate on bone metabolism using two ovariectomized rat models to elucidate the optimal use of these two drugs in the clinical setting. We first performed dose-finding experiments to determine the equivalent effective doses of each drug (5.6 and 3.0 µg/kg for teriparatide and risedronate, respectively). We then compared the effects of these doses on bone metabolism after subcutaneous administration three times weekly for 4 months starting either the day after ovariectomy (preventive study) or 12 months after ovariectomy (therapeutic study). The increase in proximal tibial BMD under the physical conditions that increased bone turnover at 1 to 2 months after ovariectomy was greater in the risedronate group than in the teriparatide group. In contrast, the increases in lumbar vertebral BMD and bone strength under the physical conditions that significantly decreased BMD and bone strength at 12 months after ovariectomy were greater in the teriparatide group than in the risedronate group. The present study provides important information on the selection of antiosteoporotic drugs, including teriparatide and risedronate, in treatment protocols tailored to the clinical conditions of patients and drug mechanisms.

  10. Detecting the effect of bisphosphonates during osteoporosis treatment on jawbones using multidetector computed tomography: The OSTEOSYR project.

    Science.gov (United States)

    Barngkgei, Imad; Khattab, Razan

    2018-03-25

    The aim of the present cross-sectional study was to investigate the effects of bisphosphonates (BP), prescribed for osteoporosis, on jawbones using multidetector computed tomography (MDCT). Fifty-three women who had dual-energy X-ray absorptiometry examination were scanned by MDCT. Both the cortical and the trabecular parts of the alveolar and the cortical bones were compared between BP users and non-BP users using a number of radiological measurements. Linear regression was used for the statistical analysis. The cortical part of the basal bone of the mandible revealed a significant increase in the BP group (.001 > P-value ≤ .026) after using BP for 5 years. No alternations were observed in the trabecular part of the basal bone or in the cortical or trabecular parts of the alveolar bone over the same duration. The use of BP as a treatment for osteoporosis for 5 years increased the thickness of the cortex of the basal bone of the mandible, as detected by MDCT. The other parts of the jawbones showed no influence by BP for such a purpose, as detected on MDCT images. Accordingly, models (equations) for predicting the alternations in the inferior cortex of the mandible induced by BP therapy during osteoporosis have been suggested. © 2018 John Wiley & Sons Australia, Ltd.

  11. Oroantral fistula from bisphosphonate induced osteonecrosis of the jaw

    Directory of Open Access Journals (Sweden)

    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.

  12. Tratamiento de osteogénesis imperfecta con bisfosfonatos Treatment of osteogenesis imperfecta with bisphosphonates

    Directory of Open Access Journals (Sweden)

    Cristina Tau

    2007-08-01

    Full Text Available El tratamiento con bisfosfonatos (BP, ha mejorado la calidad de vida de los pacientes con osteogénesis imperfecta (OI. Los efectos benéficos son el alivio del dolor, la reducción de la incidencia de fracturas, la mejor movilidad corporal y la recuperación en las formas vertebrales. El tratamiento es más efectivo durante el período de crecimiento. Se presenta una actualización del tema. De la lectura de los anales se destacan los siguientes interrogantes: ¿Por cuánto tiempo deberá instituirse el tratamiento? ¿Es la vía oral tan efectiva como la endovenosa? ¿Cuál es la mejor dosis? ¿Cuándo suspender el tratamiento? ¿Se conservará la integridad del tejido óseo después de un tratamiento prolongado? ¿Qué fenómenos ocurren en el tejido óseo después de la interrupción de la terapia?.Treatment with bisphosphonates (BP improves the quality of life of patients with osteogenesis imperfecta (OI. Beneficial effects are the relief of bone pain, a reduction of fracture incidence, improvement of corporal mobility and recovery of normal vertebral form. Treatment is less effective after completion of growth is here. An update of the literature is here presented. A number of important unsolved questions have been pointed out: for how long should treatment be instituted? Is the oral route as effective as the intravenous one? Which is the best dose? When treatment should be stopped? How well preserved is the longterm integrity of the bones? Which are the phenomena occurring in bone tissue after interruption of therapy?.

  13. Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model

    NARCIS (Netherlands)

    Ersan, N.; van Ruijven, L.J.; Bronckers, A.L.J.J.; Olgaç, V.; Ìlgüy, D.; Everts, V.

    2014-01-01

    Objectives: The objectives of this study were to establish a bisphosphonate-related osteonecrosis of the jaw (BRONJ) rat model and to analyse the effects of teriparatide (TP) on this model. Methods: Sprague-Dawley rats were divided into three groups: I—zoledronic acid (ZA, n = 10); II—ZA and

  14. Bisphosphonates in the Treatment of Patients With Metastatic Breast, Lung, and Prostate Cancer

    Science.gov (United States)

    Liu, Jing; Huang, Wenhui; Zhou, Ruoyu; Jia, Shuting; Tang, Wenru; Luo, Ying; Zhang, Jihong

    2015-01-01

    Abstract The purpose of this meta-analysis was to investigate whether bisphosphonates are a key therapy for bone metastases in lung cancer, breast cancer, and prostate cancer by comparing all randomized controlled trials that appraised the effects of bisphosphonates on risk of skeletal-related events (SREs). PubMed, Embase, and Medline databases (up to December 2014) were used to search all related articles. Using the data from 19 available publications, the authors examined the efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer by meta-analysis. Bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.69–0.95, P = 0.008], breast cancer (OR = 0.62, 95% CI = 0.54–0.71, P = 0.000), and prostate cancer (OR = 0.62, 95% CI = 0.45–0.86, P = 0.004). This meta-analysis suggests that bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer. PMID:26579808

  15. Bisphosphonates for steroid-induced osteoporosis.

    Science.gov (United States)

    Allen, Claire S; Yeung, James Hs; Vandermeer, Ben; Homik, Joanne

    2016-10-05

    This is an update of a Cochrane Review first published in 1999. Corticosteroids are widely used in inflammatory conditions as an immunosuppressive agent. Bone loss is a serious side effect of this therapy. Several studies have examined the use of bisphosphonates in the prevention and treatment of glucocorticosteroid-induced osteoporosis (GIOP) and have reported varying magnitudes of effect. To assess the benefits and harms of bisphosphonates for the prevention and treatment of GIOP in adults. We searched CENTRAL, MEDLINE and Embase up to April 2016 and International Pharmaceutical Abstracts (IPA) via OVID up to January 2012 for relevant articles and conference proceedings with no language restrictions. We searched two clinical trial registries for ongoing and recently completed studies (ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal). We also reviewed reference lists of relevant review articles. We included randomised controlled trials (RCTs) satisfying the following criteria: 1) prevention or treatment of GIOP; 2) adults taking a mean steroid dose of 5.0 mg/day or more; 3) active treatment including bisphosphonates of any type alone or in combination with calcium or vitamin D; 4) comparator treatment including a control of calcium or vitamin D, or both, alone or with placebo; and 4) reporting relevant outcomes. We excluded trials that included people with transplant-associated steroid use. At least two review authors independently selected trials for inclusion, extracted data, performed 'risk of bias' assessment and evaluated the certainty of evidence using the GRADE approach. Major outcomes of interest were the incidence of vertebral and nonvertebral fractures after 12 to 24 months; the change in bone mineral density (BMD) at the lumbar spine and femoral neck after 12 months; serious adverse events; withdrawals due to adverse events; and quality of life. We used standard Cochrane

  16. 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.

  17. Intravenous bisphosphonate-related osteonecrosis of the jaws: Influence of coadjuvant antineoplastic treatment and study of buccodental condition

    Science.gov (United States)

    Bagán, José; Poveda-Roda, Rafael

    2013-01-01

    Objectives: To determine whether coadjuvant antineoplastic treatment can influence the number and size of bone exposures among patients with intravenous bisphosphonate-related osteonecrosis of the jaws (iBRONJ), and to analyze the buccodental condition of these patients. Material and methods: The study sample comprised 67 patients with iBRONJ, 53 patients without iBRONJ receiving treatment with intravenous bisphosphonates, and 36 healthy subjects. In all three groups, measurements were made of the CAO index and of resting whole saliva and stimulated whole saliva. In the patients with iBRONJ, the size (cm) and number of bone exposures were recorded. The data obtained were subjected to analysis of variance (ANOVA), the Mann-Whitney U-test, and multivariate logistic regression analysis. Results: A total of 57.6% of the patients presented single bone exposure, 25.4% presented two, and 17% more than two exposures. The mean exposure size was 2.3±1.9 cm. Neither the bivariate analysis nor the multivariate multiple regression analysis found coadjuvant antineoplastic treatment to exert a statistically significant effect upon the number and size of bone exposures. On the other hand, there were statistically significant differences among the three study groups in relation to the CAO index (p=0.02) and the number of missing teeth (p=0.00). The resting whole saliva and stimulated whole saliva levels were similar in the three groups, though the patients with osteonecrosis of the jaws showed comparatively lower SWS levels. Conclusions: Coadjuvant antineoplastic treatment alone appears to exert no influence upon the size and number of bone exposures in iBRONJ. The patients with this disease show a higher CAO index and a larger number of missing teeth. Key words:Osteonecrosis of the jaws, bisphosphonates, bone exposure, CAO index, resting whole saliva, stimulated whole saliva. PMID:23229272

  18. The role of bisphosphonates in breast cancer: Direct effects of bisphosphonates on breast cancer cells

    Science.gov (United States)

    Senaratne, Siddhika G; Colston, Kay W

    2002-01-01

    In addition to inhibiting bone resorption, bisphosphonates have also been shown to exhibit antitumour effects. In vitro, bisphosphonates inhibit proliferation and induce apoptosis in cultured human breast cancer cells. In addition, bisphosphonate treatment interferes with breast cancer cell adhesion to bone matrix, and inhibits cell migration and invasion. The combination of bisphosphonates with other anticancer drugs such as the taxoids markedly enhances these effects. These newly recognized direct actions of bisphosphonates on breast cancer cells indicate that these agents may have a greater role to play in treatment of patients suffering from cancers with a propensity to metastasize to bone. PMID:11879555

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

    Science.gov (United States)

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

    2018-04-11

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

  20. Effect of low-power gallium-aluminum-arsenium laser therapy (830 nm) in combination with bisphosphonate treatment on osteopenic bone structure: an experimental animal study.

    Science.gov (United States)

    Diniz, Júlia S; Nicolau, Renata Amadei; de Melo Ocarino, Natália; do Carmo Magalhães, Fernanda; de Oliveira Pereira, Renato Dornas; Serakides, Rogéria

    2009-05-01

    Laser therapy is able to modulate cell metabolism and accelerate the repair of fracture. Little attention has been given to the effect of laser on bone with osteopenia or osteoporosis. The purpose of our study was to verify the effect of laser therapy in combination with bisphosphonate on osteopenic bone structure. The 35 Wistar female rats used were divided into five groups: (1) sham-operation rats (control), (2) ovariectomized (OVX'd) rats with osteopenia, (3) OVX'd rats with osteopenia treated with laser, (4) OVX'd rats with osteopenia treated with bisphosphonate and (5) OVX'd rats with osteopenia treated with bisphosphonate and laser. Groups 3 and 5 were given daily 6 mg doses of bisphosphonate orally. Groups 4 and 5 underwent low level laser therapy [gallium-aluminum-arsenium (GaAlAs) laser, 830 nm, 50 mW and 4 J/cm(2)] on the femoral neck and vertebral segments (T13-L2). Both treatments were performed over an 8-week period. Rats from the osteopenic control and osteopenic + laser groups presented marked osteopenia. In the osteopenic + bisphosphonate group, the trabecular bone volume in vertebra L2 was significantly greater than in the osteopenic control group. Notably, in the association between laser and bisphosphonate, the trabecular bone volume was significantly greater in vertebrae L2 and T13 and was similar to that in the sham-operation control group. It was concluded that the laser therapy associated with bisphosphonate treatment was the best method for reversing vertebral osteopenia caused by the ovariectomy.

  1. Osteoinductivity of Demineralized Bone Matrix Is Independent of Donor Bisphosphonate Use

    Science.gov (United States)

    Schwartz, Zvi; Hyzy, Sharon L.; Moore, Mark A.; Hunter, Shawn A.; Ronholdt, Chad J.; Sunwoo, MoonHae; Boyan, Barbara D.

    2011-01-01

    Background: Demineralized bone matrix is commonly used as a bone graft substitute, either alone or to supplement an osteoconductive material, because of its osteoinductive properties. The aging of the population has led to an increase in the number of prospective donors of demineralized bone matrix who have taken bisphosphonates to prevent osteoclast-mediated bone resorption. The aim of this study was to determine whether oral bisphosphonate usage affects the osteoinductivity of demineralized bone matrix from donors. Methods: Sex-matched and age-matched pairs of samples were provided by four tissue banks (three or four pairs per bank). Demineralized bone matrix donors without bisphosphonate treatment had a mean age (and standard deviation) of 69.1 ± 2.5 years, and donors with bisphosphonate treatment had a mean age of 68.9 ± 2.0 years. Each pair included one donor known to have taken bisphosphonates and one who had not taken bisphosphonates. Demineralized bone matrix previously confirmed as osteoinductive was the positive control, and heat-inactivated demineralized bone matrix was the negative control. Demineralized bone matrix incubated with 1 mL of phosphate-buffered saline solution containing 0, 0.002, 2.0, or 2000 ng/mL of alendronate was also tested. Gelatin capsules containing 15 mg of demineralized bone matrix were implanted bilaterally in the gastrocnemius muscle of male nude mice (eight implants per group). The mice were killed thirty-five days after implantation, and hind limbs were recovered and processed for histological analysis. Osteoinductivity was measured with use of a qualitative score and by histomorphometry. Results: Nine of fifteen samples from donors who had had bisphosphonate treatment and ten of fifteen samples from patients who had not had bisphosphonate treatment were osteoinductive. Qualitative mean scores were comparable (1.7 ± 0.4 for those without bisphosphonates and 1.9 ± 0.7 for those with bisphosphonates). Osteoinductive

  2. Strontium ranelate treatment in a postmenopausal woman with osteonecrosis of the jaw after long-term oral bisphosphonate administration: a case report

    Directory of Open Access Journals (Sweden)

    Pan WL

    2017-07-01

    Full Text Available Whei-Lin Pan,1,2 Pi-Lun Chen,2 Cho-Ying Lin,1,2 Yi-Chun Pan,2 Yuh-Ren Ju,1,2 Chiu-Po Chan,1,2 Robert WW Hsu2,3 1Department of Periodontics, Chang Gung Memorial Hospital, Taipei, Taiwan; 2Graduate Institute of Dental and Craniofacial Science, Chang Gung University, Taoyuan, Taiwan; 3Department of Orthopedics, Chang Gung Memorial Hospital, Taipei, Taiwan Abstract: Bisphosphonates (BPs suppress bone resorption and increase bone strength, thus reducing the risk of fracture. Oral BPs are widely used for the prevention and treatment of osteoporosis and osteopenia. Here, we describe the case of a postmenopausal woman who took oral alendronate for >3 years for osteoporosis. The patient presented at the clinic with sharp jaw pain and swelling on the left mandible 4 months after extraction of the third molar. Clinical examinations identified an inflamed mucosal opening with pus over an area of necrotic bone. Initial images of cone beam computed tomography revealed a sequestrum at the extracted socket. The condition did not improve after 1 week of antibiotic treatment; therefore, the alendronate treatment was terminated and the patient was prescribed strontium ranelate instead. The patient gradually recovered and, at the 2-year follow-up, the site of BP-related osteonecrosis of the jaw healed completely as determined by both clinical and cone beam computed tomography measures. The bone mineral densities in the femoral neck and lumbar spine improved after 1 year, and were maintained at the 3-year follow-up. The serum C-terminal cross-linking telopeptide values also gradually increased from the initial 130 pg/mL to 320 pg/mL at the 3-year follow-up. Taken together, this case supports the use of strontium ranelate as an alternative treatment for postmenopausal women who receive long-term oral BP treatments and are at risk for serious complications of BP-related osteonecrosis of the jaw. Keywords: bisphosphonate-related osteonecrosis of the jaw, BRONJ

  3. Toll-like receptor 9 expression is associated with breast cancer sensitivity to the growth inhibitory effects of bisphosphonates in vitro and in vivo.

    Science.gov (United States)

    Sandholm, Jouko; Lehtimäki, Jaakko; Ishizu, Tamiko; Velu, Sadanandan E; Clark, Jeremy; Härkönen, Pirkko; Jukkola-Vuorinen, Arja; Schrey, Aleksi; Harris, Kevin W; Tuomela, Johanna M; Selander, Katri S

    2016-12-27

    Bisphosphonates are standard treatments for bone metastases. When given in the adjuvant setting, they reduce breast cancer mortality and recurrence in bone but only among post-menopausal patients. Optimal drug use would require biomarker-based patient selection. Such biomarkers are not yet in clinical use. Based on the similarities in inflammatory responses to bisphosphonates and Toll-like receptor (TLR) agonists, we hypothesized that TLR9 expression may affect bisphosphonate responses in cells. We compared bisphosphonate effects in breast cancer cell lines with low or high TLR9 expression. We discovered that cells with decreased TLR9 expression are significantly more sensitive to the growth-inhibitory effects of bisphosphonates in vitro and in vivo. Furthermore, cancer growth-promoting effects seen with some bisphosphonates in some control shRNA cells were not detected in TLR9 shRNA cells. These differences were not associated with inhibition of Rap1A prenylation or p38 phosphorylation, which are known markers for bisphosphonate activity. However, TLR9 shRNA cells exhibited increased sensitivity to ApppI, a metabolite that accumulates in cells after bisphosphonate treatment. We conclude that decreased TLR9-expression sensitizes breast cancer cells to the growth inhibitory effects of bisphosphonates. Our results suggest that TLR9 should be studied as a potential biomarker for adjuvant bisphosphonate sensitivity among breast cancer patients.

  4. Bisphosphonate therapy for spinal aneurysmal bone cysts.

    Science.gov (United States)

    Kieser, David C; Mazas, Simon; Cawley, Derek T; Fujishiro, Takashi; Tavolaro, Celeste; Boissiere, Louis; Obeid, Ibrahim; Pointillart, Vincent; Vital, Jean-Marc; Gille, Olivier

    2018-04-01

    To assess the efficacy of bisphosphonate therapy in the management of spinal aneurysmal bone cysts (ABCs). A prospective study of six consecutive patients aged between 7 and 22 years with spinal ABCs treated with pamidronate (1 mg/kg) or zoledronate (4 mg). A visual analogue scale (VAS) for pain and radiological (contrast-enhanced MRI and CT scan at 3 and 6 months, then yearly X-rays) follow-up was continued for a minimum of 6 years. One patient with an unstable C2/3 failed to respond to a single dose of bisphosphonate and required surgical resection and stabilisation with autologous bone grafting. Another, with a thoraco-lumbar ABC, experienced progression of neurological dysfunction after one cycle of bisphosphonate and, therefore, required surgical resection and stabilisation. In all other patients pain progressively improved and was resolved after two to four cycles (VAS 7.3-0). These patients all showed reduction in peri-lesional oedema and increased ossification by 3 months. No patients have had a recurrence within the timeframe of this study. Bisphosphonate therapy can be used as the definitive treatment of spinal ABCs, except in patients with instability or progressive neurology, where surgical intervention is required. Clinicians should expect a patients symptoms to rapidly improve, their bone oedema to resolve by 3 months and their lesion to partially or completely ossify by 6-12 months.

  5. Bisphosphonates in multiple myeloma: an updated network meta-analysis.

    Science.gov (United States)

    Mhaskar, Rahul; Kumar, Ambuj; Miladinovic, Branko; Djulbegovic, Benjamin

    2017-12-18

    7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I 2 = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of

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

    Science.gov (United States)

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

    2011-01-01

    Legg-Calvé-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.

  7. 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.

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Persistence with denosumab and persistence with oral bisphosphonates for the treatment of postmenopausal osteoporosis: a retrospective, observational study, and a meta-analysis.

    Science.gov (United States)

    Karlsson, L; Lundkvist, J; Psachoulia, E; Intorcia, M; Ström, O

    2015-10-01

    The objectives of this study were to estimate persistence with denosumab and put these results in context by conducting a review of persistence with oral bisphosphonates. Persistence with denosumab was found to be higher than with oral bisphosphonates. This study had two objectives: to analyse persistence in Swedish women initiating denosumab for treatment of postmenopausal osteoporosis (PMO) and to put these findings in context by conducting a literature review and meta-analysis of persistence data for oral bisphosphonates. The study used the Swedish Prescribed Drug Register and included women aged at least 50 years initiating denosumab between May 2010 and July 2012. One injection of denosumab was defined as 6-month persistence. Women were considered persistent for another 6 months if they filled their next prescription within 6 months + 56 days and survival analysis applied to the data. A literature search was conducted in PubMed to identify retrospective studies of persistence with oral bisphosphonates and pooled persistence estimates were calculated using a random-effects model. The study identified 2,315 women who were incident denosumab users. Mean age was 74 years and 61% had been previously treated for PMO. At 12 and 24 months, persistence with denosumab was 83% (95% CI, 81-84%) and 62% (95% CI, 60-65%), respectively. The literature search identified 40 articles for inclusion in the meta-analysis. At 12 and 24 months, persistence with oral bisphosphonates ranged from 10% to 78% and from 16% to 46%, with pooled estimates of 45% and 30%, respectively. These data from the Swedish Prescribed Drug Register and literature review suggest that persistence was higher with denosumab than with oral bisphosphonates.

  11. Effects of bisphosphonates to treat osteoporosis in children with cerebral palsy: a meta-analysis.

    Science.gov (United States)

    Kim, Min Jeong; Kim, Soo-Nyung; Lee, In-Sik; Chung, Sochung; Lee, Joonchul; Yang, YouNa; Lee, Inho; Koh, Seong-Eun

    2015-11-01

    In childhood and adolescence, some patients with cerebral palsy (CP) have long-term limited mobility, which can lead to secondary osteoporosis, Prevention and treatment strategies have been evaluated for the management of low bone mineral density (BMD) and fragility fractures. Currently, however, there are no established guidelines for the stratification and individualization of therapeutic interventions. Recently, an increasing number of studies have reported on the use of bisphosphonates to increase BMD in various pediatric conditions, and bisphosphonates have been suggested as a method to treat osteoporosis and prevent fractures. We performed the current meta-analysis to assess the effects of bisphosphonates on increasing BMD in children who have CP with secondary osteoporosis. A search of PubMed, Cochrane, and Embase from inception to April 2014 was performed with the following keywords: (bone disease, metabolic OR osteoporosis OR osteopenia) AND (child OR pediatric OR adolescent) AND (cerebral palsy) AND (bisphosphonate). Four studies were ultimately included in the meta-analysis: one randomized, double-blinded, placebo-controlled study and three case-controlled studies. The Z-score of lumbar spine was significantly improved after bisphosphonates treatment compared with pre-treatment values (standardized mean difference [SMD], 0.799; 95% confidence interval [CI], 0.499-1.100; pBisphosphonates have a significant effect on improving BMD in children with CP. Further standardization of treatment protocols including treatment dosage and duration needs to be established, and long-term follow up studies are needed.

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

    Directory of Open Access Journals (Sweden)

    Saidapur

    2015-08-01

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

  13. Teriparatide treatment in an adult patient with hypophosphatasia exposed to bisphosphonate and revealed by bilateral atypical fractures.

    Science.gov (United States)

    Righetti, Morgane; Wach, Jean; Desmarchelier, Romain; Coury, Fabienne

    2017-12-12

    Atypical femoral fractures are defined as atraumatic fractures located in the subtrochanteric region or femoral shaft. They have been mainly reported in patients taking bisphosphonates. We report the case of a 67-year-old female with osteoporosis treated by alendronate during ten years. Radiographies showed atypical femoral fractures. Serum levels of total and bone-specific alkaline phosphatase were low. In order to accelerate bone healing, teriparatide was introduced. After one year of teriparatide treatment, pain and functional difficulty have decreased, and alkaline phosphatase levels were normalized. In view of this history of recurrent fractures, of atypical femoral fractures, of early spontaneous loss of teeth, and of low serum total and bone-specific alkaline phosphatase levels, the diagnosis of hypophosphatasia has been considered and confirmed by genetic research. Other conditions than exposure to anti-resorptive therapies may promote atypical femoral fractures, such as in conditions associated with abnormal bone structures, as hypophosphatasia, a rare inherited bone metabolism disorder. A few case reports have reported adult hypophosphatasia treated by teriparatide with a good efficacy on bone pain and consolidation but with mixed results on biological markers. Teriparatide may be therefore a treatment option in adult hypophosphatasia. ALP levels should be carefully checked among osteoporotic patients and specially before introducing a bone resorption inhibitor. Low alkaline phosphatase levels have to be taken into account and an evocative history of hypophosphatasia has to be sought because this condition may expose patients to develop atypical femoral fractures during bisphosphonate treatment. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

  14. [Deprescribing long-term treatments with bisphosphonates for osteoporosis in primary care in the Basque Country (Spain)].

    Science.gov (United States)

    Etxeberria, Arritxu; Iribar, Josune; Hernando, Javier; Idarreta, Ignacia; Vergara, Itziar; Mozo, Carmela; Vrotsou, Kalliopi; Belzunegui, Joaquín; Lekuona, Arantxa

    To evaluate the impact of a multifactorial intervention to promote bisphosphonate deprescription after over 5 years of use (BF5y) in a health care organisation (HCO) in Gipuzkoa (Spain) and to compare it with the standard intervention in other HCOs in the Basque Health Service-Osakidetza. An 8-month follow-up study (results from before and after) to assess the impact of two interventions. All patients from Osakidetza receiving BF5y treatment (electronic prescription) in July 2013 were included. The standard intervention (9 HCOs) consisted of mailing a consensus statement on BF5y deprescribing and facilitating patient identifiers with BF5y prescription for review by the primary care physician. The multifactorial intervention (Gipuzkoa) also included a local consensus with leading specialists and training sessions in health centres. 18,725 patients were included; 94.7% were women. Standard intervention deprescribing rates ranged from 26.4% (Bilbao) to 49.4% (Araba), being 37.2% overall. The multifactorial intervention deprescribing rate was 44.6%, 7.4% (p <0.0001; 95% confidence interval [95%CI]: 5.4-9.4) higher than standard intervention. Changes to other treatments were less common with the multifactorial intervention, with a difference of 3.7% (p <0.0001; 95%CI: -2.2 to -5.2). Standard and multifactorial interventions are very effective in reducing unnecessary treatments with bisphosphonates. The multifactorial intervention is more effective than the standard one, although more complex to implement. Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

  15. The Relationship of Parathyroidectomy and Bisphosphonates With Fracture Risk in Primary Hyperparathyroidism: An Observational Study.

    Science.gov (United States)

    Yeh, Michael W; Zhou, Hui; Adams, Annette L; Ituarte, Philip H G; Li, Ning; Liu, In-Lu Amy; Haigh, Philip I

    2016-06-07

    The comparative effectiveness of surgical and medical treatments on fracture risk in primary hyperparathyroidism (PHPT) is unknown. To measure the relationship of parathyroidectomy and bisphosphonates with skeletal outcomes in patients with PHPT. Retrospective cohort study. An integrated health care delivery system. All enrollees with biochemically confirmed PHPT from 1995 to 2010. Bone mineral density (BMD) changes and fracture rate. In 2013 patients with serial bone density examinations, total hip BMD increased transiently in women with parathyroidectomy (4.2% at bisphosphonates (3.6% at 8 years). In 6272 patients followed for fracture, the absolute risk for hip fracture at 10 years was 20.4 events per 1000 patients who had parathyroidectomy and 85.5 events per 1000 patients treated with bisphosphonates compared with 55.9 events per 1000 patients without these treatments. The risk for any fracture at 10 years was 156.8 events per 1000 patients who had parathyroidectomy and 302.5 events per 1000 patients treated with bisphosphonates compared with 206.1 events per 1000 patients without these treatments. In analyses stratified by baseline BMD status, parathyroidectomy was associated with reduced fracture risk in both osteopenic and osteoporotic patients, whereas bisphosphonates were associated with increased fracture risk in these patients. Parathyroidectomy was associated with fracture risk reduction in patients regardless of whether they satisfied criteria from consensus guidelines for surgery. Retrospective study design and nonrandom treatment assignment. Parathyroidectomy was associated with reduced fracture risk, and bisphosphonate treatment was not superior to observation. National Institute on Aging.

  16. Self-assembling nanoparticles for the release of bisphosphonates in the treatment of human cancers [WO2012042024].

    Science.gov (United States)

    Gou, Jingxin; Zhang, Keru; Tang, Xing

    2012-11-01

    The focus of this patent was to manipulate the pharmacokinetic profile of an amino-bisphosphonate (zoledronic acid, ZOL) to make it desirable for anti-tumor uses. This patent disclosed a unique drug loading strategy that was inspired by gene delivery vehicles based on similar materials (calcium phosphate, CaP). The promise of this drug delivery system (DDS) lies not only in a 44% in vivo inhibition of tumor growth compared with free drug, but also in the low toxicity of the drug which guarantees a dosage regimen with higher doses and longer course of treatment. Also, the disclosed DDS has the potential to be further upgraded. In this patent evaluation, the state of the art in the field of CaP-based drug carrier and the novelty of this invention will be discussed.

  17. 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], PComplex Regional Pain Syndrome type 1. Other studies are needed to determine their effectiveness. Copyright © 2017. Published by Elsevier SAS.

  18. Tumour macrophages as potential targets of bisphosphonates

    Science.gov (United States)

    2011-01-01

    Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use. Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to

  19. How do bisphosphonates affect fracture healing?

    Science.gov (United States)

    Kates, Stephen L; Ackert-Bicknell, Cheryl L

    2016-01-01

    Bisphosphonates (BPs) have been in use for many years for the treatment of osteoporosis, multiple myeloma, Paget's disease, as well as a variety of other diseases in which there is reduced bone mineral density. Given that bisphosphonates inhibit bone resorption, an important stage of fracture healing; this class of compounds has been widely studied in preclinical models regarding their influence on fracture healing. In animal models, bisphosphonate treatment is associated with a larger fracture callus, coincident with a delay in remodeling from primary woven bone to lamellar bone, but there is no delay in formation of the fracture callus. In humans, de novo use of bisphosphonate therapy after fracture does not appear to have a significant effect on fracture healing. Rarely, patients with long term use of Bisphosphonates may develop an atypical fracture and delay in fracture healing has been observed. In summary, bisphosphonates appear safe for use in the setting of acute fracture management in the upper and lower extremity in humans. While much remains unknown about the effects on healing of long-term bisphosphonates, use prior to "typical" fracture, in the special case of atypical fracture, evidence suggests that bisphosphonates negatively influence healing. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. 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...... incident subtrochanteric fractures with those sustaining other hip fractures. Subjects were bisphosphonate-naive or had a bisphosphonate washout period of 6-24 months and subsequently received an annual infusion of zoledronic acid 5 mg or placebo after low-trauma hip-fracture repair. In total, 2,127 men...... with other qualifying hip fractures reported prior bisphosphonate use. Only one further subtrochanteric fracture occurred in each treatment group over an average 2-year patient follow-up. Subtrochanteric fractures are not uncommon in bisphosphonate-naive patients. Extreme difficulties with mobility may...

  1. Changes in quality of life in patients with postmenopausal osteoporosis receiving weekly bisphosphonate treatment: a 2-year multicenter study in Japan.

    Science.gov (United States)

    Hagino, Hiroshi; Soen, Satoshi; Sugimoto, Toshitsugu; Endo, Naoto; Okazaki, Ryo; Tanaka, Kiyoshi; Nakamura, Toshitaka

    2018-03-09

    We investigated changes in quality of life (QOL), including pain, in Japanese women aged ≥ 55 years who were diagnosed as having osteoporosis at 265 centers across Japan and treated continuously with once-weekly bisphosphonates for 24 months. In 2650 evaluable patients, a significant improvement in QOL was observed from 3 months after enrollment onward and maintained throughout the 2-year observation period. A significant improvement in scores was observed for all domains of the Euro QOL 5 Dimension (EQ-5D), and the "pain", "health perception", and "posture, figure" domains of the Japanese Osteoporosis QOL Questionnaire (JOQOL). Factors identified as significantly contributing to QOL change were "fractures within the year before enrollment", "presence of spondylosis deformans", "presence of osteoarthritis", "use of activated vitamin D 3 ", and "age" based on the JOQOL, and "presence of spondylosis deformans", "use of activated vitamin D 3 ", and "age" based on the EQ-5D. The results suggested that the patients' perception of treatment effects, such as improvement in pain, contributes to treatment continuation. Osteoporosis patients should be informed that continuous treatment with once-weekly bisphosphonates can lead to a significant improvement in QOL regardless of concomitant locomotor diseases, to encourage them to remain on treatment. In conclusion, continuous bisphosphonate treatment improved the QOL even in patients with locomotor diseases, and the concomitant use of activated vitamin D 3 may also facilitate further improvement in QOL.

  2. Current state of orthodontic patients under bisphosphonate therapy.

    Science.gov (United States)

    Krieger, Elena; Jacobs, Collin; Walter, Christian; Wehrbein, Heinrich

    2013-04-04

    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. 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. 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. 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.

  3. Effect of bisphosphonate as an adjunct treatment for chronic periodontitis on gingival crevicuar fluid levels of nuclear factor-κB ligand (RANKL) and osteoprotegerin in postmenopausal osteoporosis.

    Science.gov (United States)

    Özden, Feyza O; Sakallioğlu, Elif E; Demir, Esra; Bilgici, Birşen; Tunçel, Özgür K; Gökosmanoğlu, Feyzi; Atmaca, Ayşegül

    2017-01-01

    Osteoporosis and periodontal disease are linked by an altered receptor activator of nuclear factor κB ligand and osteoprotegerin ratio (RANKL/OPG), and medical treatment with bisphosphonate (BP) may help control these molecules. The effect of BP on clinical findings and gingival crevicular fluid (GCF) values of RANKL and OPG using enzyme-linked immunosorbent assays was evaluated in postmenopausal women; 13 patients with both chronic periodontitis and osteoporosis (group A), 12 systemically healthy patients with chronic periodontitis (group B), 12 periodontally healthy patients with osteoporosis (group C), and 10 systemically and periodontally healthy individuals (group D). Recordings were repeated at the end of months 1, 6, and 12 in groups A, B, and C. At the baseline, groups A and B exhibited the lowest OPG values (P periodontal treatment, OPG values were markedly increased at the end of 6th month in group A and 12th month in group B (P 0.05) or during the observation period (P > 0.008). The use of BP may be effective in preventing periodontal breakdown by controlling the levels of these markers in osteoporosis as an adjunct to periodontal treatment.

  4. Inhibition of bone resorption by bisphosphonates interferes with orthodontically induced midpalatal suture expansion in mice.

    Science.gov (United States)

    Koehne, Till; Kahl-Nieke, Bärbel; Amling, Michael; Korbmacher-Steiner, Heike

    2018-01-18

    Craniofacial sutures are important growth sites for skull development and are sensitive to mechanical stress. In order to determine the role of bone resorption in stress-mediated sutural bone growth, midpalatal suture expansion was performed in mice receiving alendronate, an anti-resorptive bisphosphonate. The midpalatal sutures of 8-week-old C57BL/6 mice were expanded by orthodontic wires over the period of 2 weeks. Mice with maxillary expansion without drug treatment as well as untreated animals served as controls. Skulls were analyzed with micro-computed tomography (micro-CT), immunohistochemistry and histology. Maxillary expansion in mice without drug treatment resulted in an increase of TRAP-positive osteoclasts. In contrast, no increase in osteoclasts was observed in expanded sutures of mice with bisphosphonate treatment. Double calcein labeling demonstrated rapid bone formation on the oral edges of the expanded sutures in mice without bisphosphonate treatment. Less bone formation was observed in bisphosphonate-treated mice after expansion. Histology revealed that the sutural architecture was reestablished in expanded sutures of mice without bisphosphonate treatment. In contrast, the sutural architecture was disorganized and the cartilage had an irregular form, following expansion in bisphosphonate-treated mice. Finally, micro-CT imaging demonstrated that the total amount of maxillary expansion was significantly lower in mice with bisphosphonate treatment as compared to those of mice without drug treatment. In conclusion, our results indicate that osteoclast-mediated bone resorption is needed for maxillary suture expansion and reorganization of sutural architecture. Orthodontic palatal expansion can be complicated in patients with inherited or drug-induced diseases of osteoclast dysfunction.

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

    Science.gov (United States)

    Kim, Dae Hyun; Rogers, James R; Fulchino, Lisa A; Kim, Caroline A; Solomon, Daniel H; Kim, Seoyoung C

    2015-01-01

    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 osteoporosis

  6. Oral bisphosphonates and colon cancer

    DEFF Research Database (Denmark)

    Eiken, Pia; Vestergaard, Peter

    2015-01-01

    Bisphosphonates (BPs) are widely used as the main treatment for osteoporosis. In vitro and animal studies suggest that use of BPs may have a potential for colorectal cancer (CRC) prevention. Safety and efficacy in terms of osteoporosis prevention have only been evaluated in randomized controlled...

  7. [Bisphosphonates and osteonecrosis of the jaw].

    Science.gov (United States)

    Schirmer, I; Peters, H; Reichart, P A; Dürkop, H

    2005-07-01

    Since 2003, reports have been published on necrosis of the jaw bones possibly being associated with the administration of bisphosphonates. Bisphosphonates are highly active inhibitors of osteoclasts which have been used prophylactically or symptomatically in the treatment of plasmocytoma, bone metastasis of malignant disease, tumor-associated hypercalcaemia and in the treatment of osteoporosis. Due to the importance of this side effect of bisphosphonates, we report six cases. Six patients (two women and four men) with a median age of 69 years (range 55-37) were diagnosed with osteonecrosis of the maxilla and/or mandible. These osteonecroses did not react adequately to local treatment and systemic therapy with antibiotics. Four patients suffered from plasmocytoma and two patients had a history of metastasising breast cancer. Besides cytostatic chemotherapies, all patients received bisphosphonates over an extended period. Bisphosphonates are considered an important standard in the treatment of plasmocytoma and bone metastasis due to malignancies. Since 2003, several reports have been published describing patients in whom therapy resistant osteonecrosis of jaw bones occurred either after dental extractions or spontaneously. Until then, unknown side effects of bisphosphonate therapy had been suspected. Since patients with malignant diseases receive cytostatic therapy and a range of other drugs, including bisphosphonates, enhancement of the side effects may be presumed. The probable association of the therapeutic use of bisphosphonates and the occurence of jaw bone necrosis has to be studied in further investigations. Patients receiving bisphosphonates should be followed-up regularly to avoid the occurrence of extended osteonecrotic lesions, which should be diagnosed early and treated adequately.

  8. Modulation of paraoxonase 1 (PON1) activity and protein N-homocysteinylation by bisphosphonates in rats.

    Science.gov (United States)

    Rusek, Marta; Pastryk, Jolanta Elżbieta; Bełtowski, Jerzy

    2016-11-25

    Bisphosphonates are potent antiresorptive agents commonly used in the treatment of osteoporosis. As osteoporosis and atherosclerosis share some common risk factors and frequently coexist in the same patients, we examined the effect of bisphosphonates on paraoxonase 1 (PON1) - the high density lipoprotein-associated enzyme with potent anti-atherosclerotic activity. Bisphosphonates were administered orally to male adult rats for 4 weeks and then PON1 activity and some related biochemical parameters were measured in plasma. Clodronate, alendronate, ibandronate and pamidronate reduced PON1 activity toward synthetic (paraoxon, phenyl acetate) and natural (homocysteine thiolactone) substrates. The most marked effect was observed in animals receiving ibandronate. In contrast, risedronate increased PON1 activity toward these 3 substrates and zoledronate increased PON1 activity toward phenyl acetate but had no effect on its activity toward paraoxon and homocysteine thiolactone. Bisphosphonates had no effect on total plasma homocysteine and protein-bound homocysteine thiolactone. In addition, total plasma cholesterol, HDL-cholesterol, plasma triglycerides and alanine aminotransferase activity did not differ between groups. Bisphosphonates have differential effects on PON1 activity. Risedronate could be particularly useful in patients with high cardiovascular risk and PON1 deficiency. Bisphosphonates have no effect on plasma homocysteine and protein N-homocysteinylation as well as on the lipid profile. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Osteoporosis-pseudoglioma syndrome: three novel mutations in the LRP5 gene and response to bisphosphonate treatment.

    Science.gov (United States)

    Tüysüz, B; Bursalı, A; Alp, Z; Suyugül, N; Laine, C M; Mäkitie, O

    2012-01-01

    Osteoporosis-pseudoglioma (OPPG) syndrome is a rare disorder characterized by congenital or infancy-onset visual loss and severe juvenile osteoporosis. OPPG is caused by homozygous mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. We present three novel homozygous LRP5 mutations found in 3 unrelated Turkish children with consanguineous parents, along with clinical phenotypes and response to treatment with bisphosphonates (bisP). The LRP5 gene was analyzed by direct sequencing after PCR amplification. Mutation screening for LRP5 revealed homozygous nonsense R1002X mutation in the first patient and homozygous missense mutations V336M and G507S in the second and third patient, respectively. The parents were heterozygous for these mutations. The patients' eye symptoms began during the first months of life but the OPPG diagnoses were made based on skeletal deformities and osteopenia after 4 years of age. The patients' bone mineral density Z scores were very low and consistent with osteopenia. All patients were treated with bisP for 3.5-7 years. We report three novel LRP5 mutations in 3 Turkish patients with OPPG. We show that the response of bisP therapy has improved the lumbar spinal bone mineral density Z scores and the patients' quality of life as the bone pains decreased. Copyright © 2012 S. Karger AG, Basel.

  10. Bisphosphonates for Paget's disease of bone in adults.

    Science.gov (United States)

    Corral-Gudino, Luis; Tan, Adrian Jh; Del Pino-Montes, Javier; Ralston, Stuart H

    2017-12-01

    included participants who had elevated alkaline phosphatase levels whether or not bone pain was present. Mean follow-up was six months.Bisphosphonates versus placeboBisphosphonates tripled the proportion (31% versus 9%) of participants whose bone pain disappeared (RR 3.42, 95% confidence interval (CI) 1.31 to 8.90; 2 studies, 205 participants; NNT 5, 95% CI 1 to 31; moderate-quality evidence). This result is clinically important. Data were consistent when pain change was measured as any reduction (RR 1.97, 95% CI 1.29 to 3.01; 7 studies, 481 participants).There was uncertainty about differences in incident fractures: 1.4% fractures occurred in the bisphosphonates group and none in the placebo group (RR 0.89, 95% CI 0.18 to 4.31; 4 studies, 356 participants; very low-quality evidence).None of the studies reported data on orthopaedic surgery, quality of life or hearing thresholds.Results regarding adverse effects and treatment discontinuation were uncertain. There was a 64% risk of mild gastrointestinal adverse events in intervention group participants and 48% in the control group (RR 1.32, 95% CI 0.91 to 1.92; 6 studies, 376 participants; low-quality evidence). The likelihood of study participants discontinuing due to adverse effects was slightly higher in intervention group participants (4.4%) than the control group (4.1%) (RR 1.01, 95% CI 0.41 to 2.52; 6 studies, 517 participants; low-quality evidence). Zoledronate was associated with an increased risk of transient fever or fatigue (RR 2.57, 95% CI 1.21 to 5.44; 1 study, 176 participants; moderate-quality evidence).Bisphosphonates versus active comparatorMore participants reported pain relief with zoledronate than pamidronate (RR 1.30, 95% CI 1.10 to 1.53; 1 study, 89 participants; NNT 5, 95% CI 3 to 11) or risedronate (RR 1.36, 95% CI 1.06 to 1.74; 1 study, 347 participants; NNT 7, 95% CI 4 to 24; very low quality evidence). This result is clinically important.There was insufficient evidence to confirm or exclude

  11. Strontium ranelate treatment in a postmenopausal woman with osteonecrosis of the jaw after long-term oral bisphosphonate administration: a case report.

    Science.gov (United States)

    Pan, Whei-Lin; Chen, Pi-Lun; Lin, Cho-Ying; Pan, Yi-Chun; Ju, Yuh-Ren; Chan, Chiu-Po; Hsu, Robert Ww

    2017-01-01

    Bisphosphonates (BPs) suppress bone resorption and increase bone strength, thus reducing the risk of fracture. Oral BPs are widely used for the prevention and treatment of osteoporosis and osteopenia. Here, we describe the case of a postmenopausal woman who took oral alendronate for >3 years for osteoporosis. The patient presented at the clinic with sharp jaw pain and swelling on the left mandible 4 months after extraction of the third molar. Clinical examinations identified an inflamed mucosal opening with pus over an area of necrotic bone. Initial images of cone beam computed tomography revealed a sequestrum at the extracted socket. The condition did not improve after 1 week of antibiotic treatment; therefore, the alendronate treatment was terminated and the patient was prescribed strontium ranelate instead. The patient gradually recovered and, at the 2-year follow-up, the site of BP-related osteonecrosis of the jaw healed completely as determined by both clinical and cone beam computed tomography measures. The bone mineral densities in the femoral neck and lumbar spine improved after 1 year, and were maintained at the 3-year follow-up. The serum C-terminal cross-linking telopeptide values also gradually increased from the initial 130 pg/mL to 320 pg/mL at the 3-year follow-up. Taken together, this case supports the use of strontium ranelate as an alternative treatment for postmenopausal women who receive long-term oral BP treatments and are at risk for serious complications of BP-related osteonecrosis of the jaw.

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

    Science.gov (United States)

    Katsumi, Hidemasa; Tanaka, Yutaro; Hitomi, Kaori; Liu, Shu; Quan, Ying-Shu; Kamiyama, Fumio; Sakane, Toshiyasu; Yamamoto, Akira

    2017-08-17

    To improve the transdermal bioavailability and safety of alendronate (ALN), a nitrogen-containing bisphosphonate, we developed self-dissolving microneedle arrays (MNs), in which ALN is loaded only at the tip portion of micron-scale needles by a dip-coating method (ALN(TIP)-MN). We observed micron-scale pores in rat skin just after application of ALN(TIP)-MN, indicating that transdermal pathways for ALN were created by MN. ALN was rapidly released from the tip of MNs as observed in an in vitro release study. The tip portions of MNs completely dissolved in the rat skin within 5 min after application in vivo. After application of ALN(TIP)-MN in mice, the plasma concentration of ALN rapidly increased, and the bioavailability of ALN was approximately 96%. In addition, the decrease in growth plate was effectively suppressed by this efficient delivery of ALN in a rat model of osteoporosis. Furthermore, no skin irritation was observed after application of ALN(TIP)-MN and subcutaneous injection of ALN, while mild skin irritation was induced by whole-ALN-loaded MN (ALN-MN)-in which ALN is contained in the whole of the micron-scale needles fabricated from hyaluronic acid-and intradermal injection of ALN. These findings indicate that ALN(TIP)-MN is a promising transdermal formulation for the treatment of osteoporosis without skin irritation.

  13. Effect of oral bisphosphonates for osteoporosis on development of skeletal metastases in women with breast cancer: results from a pharmaco-epidemiological study.

    Science.gov (United States)

    Kremer, Richard; Gagnon, Bruno; Meguerditchian, Ari N; Nadeau, Lyne; Mayo, Nancy

    2014-11-01

    Treatment with bisphosphonates in women with breast cancer and established bone metastasis delays further skeletal-related events. Evidence is emerging that bisphosphonates are beneficial for secondary prevention of bone metastasis. The study aimed to estimate the effect of oral bisphosphonates for treatment or prevention of osteoporosis on development of bone metastasis in a population of women with breast cancer. A historical cohort of 21664 women diagnosed with breast cancer was created from health administrative data in Quebec, Canada. The primary outcome was time to develop bone metastasis; exposure was bisphosphonate use prediagnosis, postdiagnosis, both, or neither and a cumulative index of drug exposure. The sample was stratified according to stage (0-II or III) at time of diagnosis. Cox proportional hazards tested the effect of bisphosphonate use on time to develop bone metastases. Taking bisphosphonates postdiagnosis of breast cancer only or continuing bisphosphonates started prior to diagnosis after diagnosis was associated with a reduction in risk of bone metastasis from 45% to 28% in women with local disease at diagnosis. In women with regional disease, postdiagnosis bisphosphonate use, with or without prediagnosis use, reduced risk by almost 50%. A statistically significant dose-response trend was observed relating increased use to lower risk (slope = 0.94, 95% confidence interval = 0.90 to 0.99). Bisphosphonates were also associated with a decreased risk of all-cause mortality similar to that of the development of bone metastasis. Low-dose oral bisphosphonates administered for prevention or treatment of postmenopausal osteoporosis were associated with lower risk of skeletal metastasis in patients with early- or more advanced-stage breast cancer. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. Bisphosphonates for advanced prostate cancer.

    Science.gov (United States)

    Macherey, Sascha; Monsef, Ina; Jahn, Franziska; Jordan, Karin; Yuen, Kwok Keung; Heidenreich, Axel; Skoetz, Nicole

    2017-12-26

    The prevalence and incidence of pain and skeletal complications of metastatic bone disease such as pathologic fractures, spinal cord compression and hypercalcemia is high and an important contributor to morbidity, poor performance status and decreased quality of life. Moreover, pathologic fractures are associated with increased risk of death in people with disseminated malignancies. Therefore, prevention of pain and fractures are important goals in men with prostate cancer at risk for skeletal complications. To assess the effects of bisphosphonates in men with bone metastases from prostate cancer. We identified studies by electronic search of bibliographic databases including the Cochrane Controlled Trials Register and MEDLINE on 13 July 2017 and trial registries. We handsearched the Proceedings of American Society of Clinical Oncology (to July 2017) and reference lists of all eligible trials identified. This is an update of a review last published in 2006. We included randomized controlled studies comparing the effectiveness of bisphosphonates in men with bone metastases from prostate cancer. Two review authors independently extracted data and assessed the quality of trials. We defined the proportion of participants with pain response as the primary end point; secondary outcomes were skeletal-related events, mortality, quality of life, adverse events, analgesic consumption and disease progression. We assessed the quality of the evidence for the main outcomes using the GRADE approach. We included 18 trials reporting on 4843 participants comparing the effect of bisphosphonate administration to control regimens. there was no clear difference in the proportion of participants with pain response (RR 1.15, 95% CI 0.93 to 1.43; P = 0.20; I 2 = 0%; 3 trials; 876 participants; low quality evidence). In absolute terms, bisphosphonates resulted in a pain response in 40 more participants per 1000 (19 fewer to 114 more). bisphosphonates probably reduced the incidence of

  15. Adverse Effects of Bisphosphonates

    DEFF Research Database (Denmark)

    Abrahamsen, Bo

    2010-01-01

    Use of bisphosphonates has been growing steadily in the last decade. This follows the introduction of simpler dosing regimes, the availability of lower-priced generics, and concerns about the safety of hormone-replacement therapy. Bisphosphonates have a relatively good safety record...... events in bisphosphonate-treated patients was based on published information from case reports, case series, claims databases, national databases, surveys, adverse event reporting databases, and single or pooled clinical trials. The most common acute adverse events with bisphosphonates for osteoporosis...... are gastrointestinal discomfort and acute influenza-like illness. Renal complications are very rare with oral bisphosphonates and rare with i.v. bisphosphonates when used appropriately. Based on our current knowledge, skeletal events in the form of osteonecrosis of the jaw and atypical fragility fractures are rare...

  16. Adverse effects of bisphosphonates

    DEFF Research Database (Denmark)

    Abrahamsen, Bo

    2010-01-01

    Use of bisphosphonates has been growing steadily in the last decade. This follows the introduction of simpler dosing regimes, the availability of lower-priced generics, and concerns about the safety of hormone-replacement therapy. Bisphosphonates have a relatively good safety record...... events in bisphosphonate-treated patients was based on published information from case reports, case series, claims databases, national databases, surveys, adverse event reporting databases, and single or pooled clinical trials. The most common acute adverse events with bisphosphonates for osteoporosis...... are gastrointestinal discomfort and acute influenza-like illness. Renal complications are very rare with oral bisphosphonates and rare with i.v. bisphosphonates when used appropriately. Based on our current knowledge, skeletal events in the form of osteonecrosis of the jaw and atypical fragility fractures are rare...

  17. Adjuvant bisphosphonates in early breast cancer

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Shikiar Richard

    2006-07-01

    Full Text Available Abstract Background The Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q is a new measure of patient satisfaction with bisphosphonate treatment for osteoporosis. The objective of this study was to evaluate the psychometric characteristics of the OPSAT-Q. Methods The OPSAT-Q contains 16 items in four subscales: Convenience, Confidence with Daily Activities, Side Effects, and Overall Satisfaction. All four subscale scores and an overall composite satisfaction score (CSS can be computed. The OPSAT-Q, Osteoporosis Targeted Quality of Life (OPTQoL, and sociodemographic/clinical questionnaires, including 3 global items on convenience, functioning and side effects, were self-administered to women with osteoporosis or osteopenia recruited from four US clinics. Analyses included item and scale performance, internal consistency reliability, reproducibility, and construct validity. Reproducibility was measured using the intraclass correlation coefficient (ICC via a follow-up questionnaire completed by participants 2 weeks post baseline. Results 104 women with a mean age of 65.1 years participated. The majority were Caucasian (64.4%, living with someone (74%, and not currently employed (58.7%. 73% had osteoporosis and 27% had osteopenia. 80% were taking weekly bisphosphonates and 18% were taking daily medication (2% missing data. On a scale of 0–100, individual patient subscale scores ranged from 17 to 100 and CSS scores ranged from 44 to 100. All scores showed acceptable internal consistency reliability (Cronbach's alpha > 0.70 (range 0.72 to 0.89. Reproducibility ranged from 0.62 (Daily Activities to 0.79 (Side Effects for the subscales; reproducibility for the CSS was 0.81. Significant correlations were found between the OPSAT-Q subscales and conceptually similar global measures (p Conclusion The findings from this study confirm the validity and reliability of the OPSAT-Q and support the proposed composition of four subscales and a composite

  19. [Osteomyelitis of the jaw in breast cancer patients receiving bisphosphonate therapy].

    Science.gov (United States)

    Tomihara, Kei; Nagai, Itaru; Yamaguchi, Akira; Miyazaki, Akihiro; Dehari, Hironari; Abe, Masato; Nakamori, Kenji; Komai, Kiyoto; Nakai, Mitsuyoshi; Hiratsuka, Hiroyoshi

    2008-01-01

    Osteonecrosis of the jaw is a severe new complication in cancer patients with bone metastases receiving bisphosphonate. Currently, there is no effective treatment for bisphosphonate-related osteonecrosis of the jaw, and the pathogenesis of this complication has not been completely elucidated. It has been shown that a potential risk factor for the complication is dentoalveolar trauma including extraction of teeth during bisphosphonate therapy. Attention should be paid to dental care in patients prior to the initiation of bisphosphonate therapy, and extraction of teeth during bisphosphonate therapy should be avoided to prevent this complication. Therefore, the communication between general physicians prescribing bisphosphonate and dentists is important.

  20. Bisphosphonates for cardiovascular risk reduction : A systematic review and meta-analysis

    NARCIS (Netherlands)

    Kranenburg, Guido; Bartstra, Jonas W.; Weijmans, Maaike; de Jong, Pim A.; Mali, Willem P.; Verhaar, Harald J.; Visseren, Frank L J; Spiering, Wilko

    2016-01-01

    BACKGROUND AND AIMS: Bisphosphonates might be effective in reducing cardiovascular events due to their ability to reduce calcification in arterial walls. We aimed to investigate the effects of treatment with bisphosphonates on the prevention of atherosclerotic processes and cardiovascular disease.

  1. Criteria for the prescription of oral bisphosphonates for the treatment of osteoporosis in a series of women referred for tooth extraction

    Science.gov (United States)

    Fernández-Feijoo, Javier; Fernández-Montenegro, Paula; González-Mosquera, Antonio; Vázquez-García, Emma; Diz-Dios, Pedro

    2012-01-01

    Objective: To evaluate the criteria for the prescription of oral bisphosphonates (OB) in a series of women with osteoporosis referred for tooth extraction. Study design: The study included 38 postmenopausal women on treatment with OBs. The following variables were analysed: age, weight, height, type of OB and duration of treatment, bone densitometry and risk factors for osteoporosis. In addition, the osteoporosis self-assessment tool (OST) was administered and collagen type I C-telopeptide (CTX) levels were measured. Results: Bone densitometry had only been performed in six patients (15.7%) before starting OB treatment. Based on the results of the OST, nine (23.6%) of the participants presented a low risk of osteoporosis. CTX levels were measured in 23 patients: 11 (47.8%) presented values below 150 pg/ml. Conclusion: Although all patients in the present series were on treatment with OBs, a large percentage did not satisfy the criteria for the initiation of treatment for postmenopausal osteoporosis. Key words:Osteoporosis, oral bisphosphonates, osteonecrosis of the jaws. PMID:22322496

  2. Current state of orthodontic patients under Bisphosphonate therapy

    Science.gov (United States)

    2013-01-01

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

  3. Understanding bisphosphonates and osteonecrosis of the jaw: uses and risks.

    Science.gov (United States)

    Rosini, S; Rosini, S; Bertoldi, I; Frediani, B

    2015-09-01

    Bisphosphonates are chemically stable analogs of pyrophosphate compounds, which have been used to treat multiple disorders of calcium metabolism. Although bisphosphonates have been employed for many years and have demonstrated an excellent safety profile, severe osteonecrosis of the jaw (ONJ) has been described in patients with bone metastases who have been treated with bisphosphonates. In this review we describe the reasons for ONJ and discuss the varying effects of different bisphosphonates on the development of ONJ. Bisphosphonates tend to accumulate in bone, subject to remodeling (such as the jaw) and can affect osteoclast-mediated bone resorption and osteoclast formation, leading to the osteonecrosistic phenomenon. Risk factors for previously -treated patients include the type of bisphosphonates (amino or non-amino), length of treatment and route of administration, the presence of co-morbidities and/or treatment with immune-suppressing drugs, and the presence of other risk factors in addition to the type of intervention required. In oncological patients currently in treatment with receiving intravenous bisphosphonates, greater consideration must be taken depending on the length of treatment already undertaken and concomitant therapies. In these patients, a preventive dental surgery visit and examination of the case would be advisable prior to beginning treatment with bisphosphonates. Practical approaches in the prevention of ONJ include thorough pre-treatment evaluation and performing any preventative procedures (treat periodontal conditions, extract loose teeth, provide protective and endodontic therapies); initiating amino-bisphosphonates only after any gum tissue damage has healed; establishing a regimented check-up schedule and hygieneic precautions the patient can take; and during bisphosphonate treatment conduct any dental procedures in the least invasive manner during bisphosphonate treatment.

  4. Use of bisphosphonates and raloxifene and risk of deep venous thromboembolism and pulmonary embolism

    DEFF Research Database (Denmark)

    Vestergaard, P; Schwartz, K; Pinholt, E M

    2010-01-01

    Prior studies have associated raloxifene and strontium ranelate with deep venous thromboembolism and pulmonary embolism. In a cohort study, we observed an increased risk also with the bisphosphonates. However, the increase was present already before the start of bisphosphonates pointing...

  5. Bisphosphonate-Related Osteonecrosis of the Jaw: Historical, Ethical, and Legal Issues Associated With Prescribing

    Science.gov (United States)

    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. PMID:25031978

  6. Bisphosphonates in breast cancer.

    Science.gov (United States)

    Mathew, Aju; Brufsky, Adam

    2015-08-15

    Bisphosphonates are osteoclast inhibitors, currently being used in oncology to prevent or delay bone morbidity in cancer. Oral and intravenous formulations of bisphosphonates have been found to be efficacious in preventing skeletal-related events such as bone pain, pathologic fractures, spinal cord compression and hypercalcemia of malignancy, in patients with bone metastatic breast cancer. Bisphosphonates are also used to prevent bone loss associated with anti-estrogen therapy using aromatase inhibitors. In addition to its role in preventing bone resorption, several pre-clinical studies have noted an anti-tumor role as well. Recent research effort has particularly focused on investigating an adjuvant role for bisphosphonates in early breast cancer. Recently, few randomized trials have found a beneficial effect for adjuvant use of the aminobisphosphonate, zoledronate, in older patients who are post-menopausal. This review article will summarize the various clinical studies investigating the role of bisphosphonates in breast cancer. © 2014 UICC.

  7. Bisphosphonates for osteoporosis in people with cystic fibrosis.

    Science.gov (United States)

    Conwell, Louise S; Chang, Anne B

    2014-03-14

    Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis. We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 13 January 2014.Additional searches of PubMed were performed on 13 January 2014. Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis. Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data. Nine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7

  8. The role of bisphosphonates in breast cancer: Actions of bisphosphonates in animal models of breast cancer

    Science.gov (United States)

    Padalecki, Susan S; Guise, Theresa A

    2002-01-01

    The skeleton is the most common site of breast cancer metastases. These bone metastases are usually osteolytic and cause significant morbidity. Bisphosphonates, potent inhibitors of bone resorption, reduce skeletal morbidity in breast cancer patients with bone metastases. Animal studies with bisphosphonates are crucial to understanding the mechanisms by which these compounds affect bone and tumor cells in vivo. Such animal models of breast cancer that are used to test the efficacy of bisphosphonates are discussed. These studies may offer insight into the treatment of other tumor types that frequently metastasize to bone. PMID:11879558

  9. 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...

  10. Efficacy and Safety of Bisphosphonates for Osteoporosis or Osteopenia in Cardiac Transplant Patients: A Meta-Analysis.

    Science.gov (United States)

    Zhao, J; Wang, C; Hu, Z

    2015-12-01

    After cardiac transplantation (CTP), the loss of bone mass is accelerated and there is an increased risk for bone fractures. Bisphosphonates are commonly used for preventing loss of bone mass after CTP. However, no systematic evaluation of the treatment efficacy of bisphosphonates after CTP has been reported. The aim of this meta-analysis was to assess the effectiveness and safety of bisphosphonates for osteoporosis or osteopenia after CTP. An electronic database search including Medline, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies up to March 2015. We included randomized controlled trials (RCTs) and nonrandomized prospective comparative studies that were concerned with bisphosphonates for osteoporosis after CTP. Statistical analyses were conducted with the use of Review Manager 5.1.6. Three RCTs and 3 nonrandomized prospective studies involving 425 participants were included. Eight and 12 months after CTP, compared with the control groups, vertebral bone mineral density (BMD) in patients treated with bisphosphonates was ∼0.06 g/cm(2) higher than in control patients (weighted mean difference [WMD], 0.06 g/cm(2); 95% CI, 0.03-0.08 g/cm(2); P bisphosphonates than in control patients; however, this difference was not statistically significant (WMD, 0.03 g/cm(2); 95% CI, 0-0.05 g/cm(2); P = .06). No bisphosphonate treatment-related serious adverse reactions were found in the patients. In the early stage after CTP, bisphosphonates effectively reduced the loss of bone mass, especially in vertebral BMD. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Intravenous bisphosphonates and vitamin D in the treatment of bone marrow oedema in professional athletes.

    Science.gov (United States)

    Simon, Maciej J K; Barvencik, Florian; Luttke, Moritz; Amling, Michael; Mueller-Wohlfahrt, Hans-Wilhelm; Ueblacker, Peter

    2014-06-01

    The goal of this retrospective study was to evaluate the safety and efficacy of ibandronate for bone marrow oedema (BMO) syndrome and stress fracture cases, and to demonstrate an additional field of therapeutic importance-the high-performance athlete. This retrospective study included twenty-five high-performance athletes. Sixty per cent of the athletes were European soccer players and 40.0% other high-class international athletes (3 women and 22 men with an average age of 25.0±4.2), with BMO of the lower trunk or extremity diagnosed by magnetic resonance imaging (MRI). The treatment regimen consisted of high-dose vitamin D supplementation and intravenous ibandronate therapy. The time between the onset of pain and proper diagnosis of BMO was 106.3±104.1 days. Excellent pain reduction (pain at rest and under strain) and improved mobility was reported within the first two weeks after the first ibandronate administration by sixteen patients (64%). The time from first treatment until return to competition (RTC) was on average 102.6±65.2 days in total. If the time from onset of pain until diagnosis was within 40 days, the RTC was significantly reduced (p≤0.05) to almost 50% (63.8±48.1 days) when compared to the athletes with later diagnosis (124.4±63.2 days). The here-applied therapy regimen of intravenous BPs application and vitamin D supplementation in BMO syndrome has a beneficial effect for high-performance athletes. An early diagnosis and rapid treatment start can reduce the RTC significantly. An optimal bone metabolism with sufficient daily calcium and vitamin D intake is crucial and should not only be strived for the professional but also for the recreational athlete. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Bisphosphonates and their influence on fracture healing: a systematic review.

    Science.gov (United States)

    Molvik, H; Khan, W

    2015-04-01

    Bisphosphonates are commonly used in osteoporosis, but concerns have been raised about possible negative effects on fracture healing. We systematically reviewed the literature and found that bisphosphonates significantly prolong union times of distal radius fractures but not femoral fractures. The timing of bisphosphonate introduction does not affect fracture union time. Bisphosphonates are the most commonly prescribed drugs in patients suffering from and at higher risk of developing osteoporosis. However, concerns have been raised as to whether these drugs have a negative effect on fracture healing. The aim of this systematic review is to explore further these concerns. A literature review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All relevant articles found via MEDLINE, Cochrane, CINAHL, EMBASE and Google Scholar were screened. Studies with information on bisphosphonates' effect on fracture healing in humans were included and systematically reviewed. Patients with distal radius fractures on bisphosphonates had a significantly longer union time compared with controls, but not patients with femoral fractures. No correlation between timing of bisphosphonate introduction and union time for fractures was found. Although one study reported a higher humeral non-union associated with bisphosphonate introduction following the fracture, there was no evidence that bisphosphonate introduction, timing or dose resulted in a significant delay in union following other fractures. This systematic review has shown that bisphosphonates significantly prolong union times of distal radius fractures. Some clinical findings are in contrast with preclinical studies highlighting the need to develop better animal models to study osteoporosis, treatment and fracture healing. There is also a need for more well-constructed studies looking at the clinical effect of bisphosphonate on fracture healing in a large number

  13. Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene

    DEFF Research Database (Denmark)

    Vestergaard, P; Schwartz, F; Rejnmark, L

    2010-01-01

    Prior studies have suggested an association between bisphosphonate use and subtrochanteric fractures. This cohort study showed an increased risk of subtrochanteric and femoral shaft fractures both before and after the start of drugs against osteoporosis including bisphosphonates. This may suggest...

  14. [The treatment of Paget's disease of bone with second-generation bisphosphonates via intravenous infusion].

    Science.gov (United States)

    Arboleya, L; Sánchez, J; Iglesias, G; Arranz, J L

    1993-12-01

    We compared the biochemical effects and safety of pamidronate (30 mg a day for 3 consecutive days) versus clodronate (300 mg a day for 3 consecutive days) via intravenous infusion in 14 patients with Paget's disease of bone (PDB). Both drugs induced a decrease in serum alkaline phosphatase levels as well as the elimination of hydroxyproline from urine, an effect most marked in the group treated with pamidronate. The response was maintained for 6 months after the infusion in the majority of the patients. No relevant side effects were found, except post-infusion febricula and in one patient, self-limiting thrombopenia 6 months after the infusion. We conclude that the intravenous infusion of either of the two drugs may constitute a safe and effective alternative for treatment of PDB with marked biochemical activity or resistant to conventional therapy.

  15. High doses of bisphosphonates reduce osteoblast-like cell proliferation by arresting the cell cycle and inducing apoptosis.

    Science.gov (United States)

    Manzano-Moreno, Francisco Javier; Ramos-Torrecillas, Javier; De Luna-Bertos, Elvira; Ruiz, Concepción; García-Martínez, Olga

    2015-04-01

    The study objective was to evaluate the effect on osteoblast growth of high concentrations of three nitrogen-containing bisphosphonates (pamidronate, alendronate, and ibandronate) and one non-nitrogen-containing bisphosphonate (clodronate), using the MG-63 cell line as an osteoblast model, in order to determine the role of osteoblasts in bisphosphonate-related osteonecrosis of the jaw (BRONJ). Osteoblasts were incubated in culture medium with different doses of pamidronate, alendronate, ibandronate or clodronate. The proliferative capacity of the osteoblasts was determined by spectrophotometry (MTT-based) at 24 h of culture. Flow cytometry was used to determine the percentage of cells in each cell cycle phase (G0/G1, G2/M, and S) and to discriminate apoptotic cell death from necrotic cell death in the cell cycle at 24 h of treatment. All the bisphosphonates assayed produced a significant and dose-dependent reduction in MG-63 proliferation at the high doses assayed (10(-4) and 5 × 10(-5) M) in comparison with controls (p bisphosphonates significantly arrested the cell cycle in phase G0/G1 at doses of 10(-4) and 5 × 10(-5) M, increasing the percentage of cells in this phase (p bisphosphonates can reduce the proliferation of MG-63 osteoblast-like cells by arresting the cell cycle and inducing apoptosis/necrosis. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  16. Effect of Bisphosphonates on the Rapidly Growing Male Murine Skeleton

    Science.gov (United States)

    Zhu, Eric D.; Louis, Leeann; Brooks, Daniel J.; Bouxsein, Mary L.

    2014-01-01

    Bisphosphonates are effective for preventing and treating skeletal disorders associated with hyperresorption. Their safety and efficacy has been studied in adults where the growth plate is fused and there is no longitudinal bone growth and little appositional growth. Although bisphosphonate use in the pediatric population was pioneered for compassionate use in the treatment of osteogenesis imperfecta, they are being increasingly used for the treatment and prevention of bone loss in children at risk of hyperresorptive bone loss. However, the effect of these agents on the growing skeleton in disorders other than osteogenesis imperfecta has not been systematically compared. Studies were, therefore, undertaken to examine the consequences of bisphosphonate administration on the growth plate and skeletal microarchitecture during a period of rapid growth. C57Bl6/J male mice were treated from 18 to 38 days of age with vehicle, alendronate, pamidronate, zoledronate, or clodronate at doses selected to replicate those used in humans. Treatment with alendronate, pamidronate, and zoledronate, but not clodronate, led to a decrease in the number of chondrocytes per column in the hypertrophic chondrocyte layer. This was not associated with altered hypertrophic chondrocyte apoptosis or vascular invasion at the growth plate. The effects of pamidronate on trabecular microarchitecture were less beneficial than those of alendronate and zoledronate. Pamidronate did not increase cortical thickness or cortical area/total area relative to control mice. These studies suggest that bisphosphonate administration does not adversely affect skeletal growth. Long-term investigations are required to determine whether the differences observed among the agents examined impact biomechanical integrity of the growing skeleton. PMID:24422540

  17. Bisphosphonates in the management of postmenopausal osteoporosis – optimizing efficacy in clinical practice

    Science.gov (United States)

    Bock, Oliver; Felsenberg, Dieter

    2008-01-01

    Nitrogen-containing bisphosphonates are potent inhibitors of osteoclastic bone resorption. With their individually proven efficacy to significantly reduce the incidence of vertebral and/or non-vertebral fractures and with their overall beneficial safety profile, alendronate, ibandronate, risedronate, and zoledronate are considered today a treatment of first choice in postmenopausal osteoporosis. However, treatment effects in an individual patient and cost-effectiveness in public health perspective are vitally dependent on the long-term patient adherence as well as on compliance and persistence. As compliance and persistence with daily oral bisphosphonates are shown to be suboptimal in many patients, leading to an increased fracture incidence in non-compliant patients, there is a need to improve overall adherence for bisphosphonate treatment in order to achieve maximum treatment effects. One option is to extend dosing intervals to weekly (alendronate, risedronate) or monthly (ibandronate) oral regimens. Less frequent oral regimens are generally preferred by majority of patients. Another alternative is intravenous, instead of oral application (ibandronate, zoledronate). Treatment acceptance could be further improved by IV bisphosphonates with their benefit of only quarterly, or even once-yearly, application. Treatment decisions should be based on anti-fracture efficacy data first. In addition, to ensure best possible patient adherence and maximum treatment benefits, physicians should consider individual patient conditions affecting compliance and persistence as well as patient preferences. PMID:18686751

  18. Bisphosphonate-related osteonecrosis of jaw (BRONJ: an anti-angiogenic side-effect?

    Directory of Open Access Journals (Sweden)

    Petcu Eugen B

    2012-07-01

    Full Text Available Abstract Bisphosphonates are recommended in the treatment of osteoporosis and some cancers, in which case they prevent the appearance of bone metastasis. The patients taking bisphosphonates are at increased risk of developing bisphosphonate-related osteonecrosis of jaw (BRONJ which is characterised by the presence of an un-healing wound after dental surgery. BRONJ might represent an anti-angiogenic side effect. However, the real number of patients with BRONJ might be higher than currently recorded. Considering the differential diagnosis which includes various primary and secondary cancers, a correct histopathological diagnosis is very important. The morphological criteria for diagnosis of BRONJ are highlighted in this material. Virtual Slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1813972972323288

  19. Can long-term bisphosphonate use causes low-energy fractures? A case report.

    Science.gov (United States)

    Dandinoğlu, T; Akarsu, S; Karadeniz, M; Tekin, L; Arıbal, S; Kıralp, M Z

    2014-02-01

    Bisphosphonates are inorganic pyrophosphate analog which accumulate on the bone surface, cause osteoclast apoptosis, and inhibit bone resorption. The nitrogen-containing bisphosphonates continue to be the drug of choice for the treatment of osteoporosis in both men and women. Although histomorphometric studies including bone biopsies have not shown any evidence of microcracks, recent studies have revealed that potent bisphosphonates are responsible for the oversuppression of bone turnover leading to microdamages, reduced bone strength, and increased fracture risk. There are individual cases reporting atypical femoral fractures and severely suppressed bone turnover along with long-term (≥ 5 years) use of biphosphonates. In this study, we report on a 74-year-old woman with a history of continuous alendronate use for nearly 16 years who presented to the emergency department with right proximal humerus and left femur fracture.

  20. Short-term bisphosphonate treatment reduces serum 25(OH vitamin D3 and alters values of parathyroid hormone, pentosidine, and bone metabolic markers

    Directory of Open Access Journals (Sweden)

    Kamimura M

    2017-02-01

    Full Text Available Mikio Kamimura,1 Shigeharu Uchiyama,2 Yukio Nakamura,2,3 Shota Ikegami,2 Keijiro Mukaiyama,2 Hiroyuki Kato2 1Center for Osteoporosis and Spinal Disorders, Kamimura Orthopaedic Clinic, Matsumoto, Japan; 2Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan; 3Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, Japan Abstract: This study aimed to clarify the effects of short-term bisphosphonate (BP administration in Japanese osteoporotic patients retrospectively. Daily minodronate (MIN at 1 mg/day (MIN group or weekly risedronate (RIS at 17.5 mg/week (RIS group was primarily prescribed for each patient. We analyzed the laboratory data of 35 cases (18 of MIN and 17 of RIS before the start of treatment and at 4 months afterward. The changes in 25(OHD3, whole parathyroid hormone (PTH, serum pentosidine, and the bone turnover markers urinary cross-linked N-telopeptide of type I collagen (NTX, serum tartrate-resistant acid phosphatase (TRACP-5b, bone-specific alkaline phosphatase (BAP, and undercarboxylated osteocalcin were evaluated. Overall, serum 25(OHD3 was significantly decreased from 21.8 to 18.4 ng/mL at 4 months, with a percent change of –14.7%. Whole PTH increased significantly from 23.4 to 30.0 pg/mL, with a percent change of 32.1%. Serum pentosidine rose from 0.0306 to 0.0337 µg/mL, with a percent change of 15.2%. In group comparisons, 25(OHD3 and pentosidine showed comparable changes in both groups after 4 months of treatment, whereas whole PTH became significantly more increased in the MIN group. All bone turnover markers were significantly decreased at 4 months in both groups. Compared with the RIS group, the MIN group exhibited significantly larger value changes for urinary NTX, serum TRACP-5b, and BAP at the study end point. This study demonstrated that serum 25(OHD3 became significantly decreased after only 4 months of BP treatment in Japanese osteoporotic patients and

  1. Bisphosphonates and Atypical Fractures of Femur

    Directory of Open Access Journals (Sweden)

    Tero Yli-Kyyny

    2011-01-01

    Full Text Available Bisphosphonates are the most widely prescribed medicines for the treatment of osteoporosis and have generally been regarded as well-tolerated and safe drugs. Since 2005, there have been numerous case reports about atypical fractures of the femur linked to long-term treatment of osteoporosis with bisphosphonates. Some attempts to characterize pathophysiology and epidemiology of these fractures have been published as well. However, as the American Society for Bone and Mineral Research (ASBMR concluded in their task force report, the subject warrants further studies.

  2. Risks and Benefits of Bisphosphonate Therapies

    DEFF Research Database (Denmark)

    Reyes, Carlen; Hitz, Mette; Prieto-Alhambra, Daniel

    2016-01-01

    Bisphosphonates are the mainstay of osteoporosis treatment but also play a fundamental role in treating other bone diseases such as Osteogenesis Imperfecta, Pagets' disease, and in the prevention of adverse skeletal effects in certain cancers such as prostate cancer or multiple myeloma. In the last...... to reduce the risk of fracture through the inhibition of bone resorption. Other beneficial effects include pain reduction in bone metastasis and potentially a decrease in mortality. However, the chronic nature of most of these disorders implies long-term treatments, which can be associated with long......-term adverse effects. Some of the adverse effects identified include an increased risk of atypical femur fractures, osteonecrosis of the jaw, gastrointestinal side effects, or atrial fibrillation. The harm/benefit thinking and the constant update regarding these medications are vital in the day-to-day decision...

  3. The effect of radiotherapy, and radiotherapy combined with bisphosphonates or RANK ligand inhibitors on bone quality in bone metastases. A systematic review.

    Science.gov (United States)

    Groenen, Karlijn H J; Pouw, Martin H; Hannink, Gerjon; Hosman, Allard J F; van der Linden, Yvette M; Verdonschot, Nico; Tanck, Esther

    2016-05-01

    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 metastases originating from solid tumors. Pubmed, EMBASE and the Cochrane Library were searched. Any type of study design and type and dose of radiotherapy, bisphosphonates and RANKL inhibitors were allowed. 39 articles were identified. Animal studies showed that radiotherapy had similar effects on bone quality and strength as receiving no treatment, whereas adding bisphosphonates to radiotherapy restored bone quality and strength. In patient studies, bone density increased after radiotherapy and radiotherapy combined with bisphosphonates. However, due to the often non-optimal study design and study quality, it was unclear whether this increase could be attributed to these treatments. There was insufficient evidence to assess the additional effect of bisphosphonates or RANKL inhibitors. Despite the clinical experience that radiotherapy is an effective treatment for bone metastases, there was no sufficient evidence for a positive effect on bone quality and fracture risk. Animal studies showed that adding bisphosphonates to radiotherapy restored bone quality and strength, whereas this was not proven in patients. There were no studies addressing the adjunct effect of RANKL inhibitors to radiotherapy. Although associated with several methodological, practical and ethical challenges, randomized controlled trials are needed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Bisphosphonate-Functionalized Hydroxyapatite Nanoparticles for the Delivery of the Bromodomain Inhibitor JQ1 in the Treatment of Osteosarcoma.

    Science.gov (United States)

    Wu, Victoria M; Mickens, Jarrett; Uskoković, Vuk

    2017-08-09

    Osteosarcoma (OS) is one of the most common neoplasia among children, and its survival statistics have been stagnating since the combinatorial anticancer therapy triad was first introduced. Here, we report on the assessment of the effect of hydroxyapatite (HAp) nanoparticles loaded with medronate, the simplest bisphosphonate, as a bone-targeting agent and JQ1, a small-molecule bromodomain inhibitor, as a chemotherapeutic in different 2D and 3D K7M2 OS in vitro models. Both additives decreased the crystallinity of HAp, but the effect was more intense for medronate because of its higher affinity for HAp. As the result of PO 4 3- -NH + binding, JQ1 shielded the surface phosphates of HAp and pushed its surface charge to more positive values, exhibiting the opposite effect from calcium-blocking medronate. In contrast to the faster and more exponential release of JQ1 from monetite, its release from HAp nanoparticles followed a zero-order kinetics, but 98% of the payload was released after 48 h. The apoptotic effect of HAp nanoparticles loaded with JQ1, with medronate and with both JQ1 and medronate, was selective in 2D culture: pronounced against the OS cells and nonexistent against the healthy fibroblasts. While OS cell invasion was significantly inhibited by all of the JQ1-containing HAp formulations, that is, with and without medronate, all of the combinations of the targeting compound, medronate, and the chemotherapeutic, JQ1, delivered using HAp, but not HAp alone, inhibited OS cell migration from the tumor spheroids. JQ1 delivered using HAp had an effect on tumor migration, invasion, and apoptosis even at extremely low, subnanomolar concentrations, at which no effect of JQ1 per se was observed, meaning that this form of delivery could help achieve a multifold increase of this drug's efficacy. More than 80% of OS cells internalized JQ1-loaded HAp nanoparticles after 24 h of coincubation, suggesting that this augmentation of the activity of JQ1 may be due to the

  5. Bisphosphonate ISS Flight Experiment

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

    2014-01-01

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

  6. Mandibular osteonecrosis due to bisphosphonate use.

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    Şalvarcı, Ahmet; Altınay, Serdar

    2015-03-01

    Due to their efficient osteoclastic inhibitor effect in bone metabolism and antiangiogenic activity, bisphosphonates are widely used in many cancer diseases particularly in prostate cancers with bone metastasis, lung cancer, breast cancer and multiple myeloma, as well as in systemic diseases such as osteoporosis, osteopenia, Paget disease and osteogenesis imperfect for the last 13 years. Prostate cancer is a common cancer in males and it is the leading cause of bone metastasis. Mandibular metastasis is rarely encountered during the course of prostate cancer. Mandibular osteonecrosis as well has begun to be observed along with the availability of more efficient and stronger formulations developed following the use of bisphosphonates. Zolendronic acid, which has been used also by our patient, has widely come into practice as a 3(rd) generation bisphosphonate. Because of prostate cancer and widespread bone metastases, our patient has been receiving zolendronic acid with maximum androgen blockage for 4 years. Tomography of the patient, who has undergone intensive treatment because of submandibular abscess, demonstrated extensive osteonecrosis in the fovea sublingual region of the mandible corpus. In large series, although, mandibular osteonecrosis was widely seen due to bisphosphonate use for the metastases of lung and breast cancers, this rate was between 9.6% and 11% for prostate cancer within the series. Although our patient had no mandibular metastasis before, mandibular necrosis was observed due to long-term bisphosphonate use. We are going to present our patient who had this rare complication with his clinical picture.

  7. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome

    Science.gov (United States)

    Adami, S; Fossaluzza, V; Gatti, D; Fracassi, E; Braga, V

    1997-01-01

    OBJECTIVE—The reflex sympathetic dystrophy syndrome (RSDS) is a painful limb disorder, for which a consistently effective treatment has not yet been identified. The disease is associated with increased bone resorption and patchy osteoporosis, which might benefit from treatment with bisphosphonates, powerful inhibitors of bone resorption.
METHODS—Twenty patients with RSDS of foot and hand, were randomly assigned to blind administration of either alendronate intravenously (Istituto Gentili, Pisa, Italy) 7.5 mg dissolved in 250 ml saline solution or placebo saline infusions daily for three days. Two weeks later all patients had an identical treatment course with open labelled alendronate (7.5 mg/day for three days), independent from the results of the first blind treatment.
RESULTS—In the patients treated with blind alendronate the diminution in spontaneous pain, tenderness, and swelling (circumference of the affected limb) and the improvement in motion were significantly different from baseline (p<0.001), from those observed within the first two weeks in the control group (p<0.01), and from week 2 to week 4 (p<0.01). In the patients given blind placebo infusions no relevant symptomatic changes were observed after the first two weeks of follow up, but they responded to the open alendronate therapy given afterwards. In 12 patients with RSDS of the hand the ultradistal bone mineral content (BMC) of the affected arm was considerably lower than that of the controlateral arm (mean (SD)) (426(82) mg/cm versus 688(49)). Six weeks after the beginning of the trial BMC rose by 77(12) mg/cm (p<0.001) in the affected arm, but it did not change in the controlateral.
CONCLUSIONS—These results indicate that bisphosphonates should be considered for the treatment of RSDS, producing consistent and rapid remission of the disease.

 PMID:9135227

  8. 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.

  9. Bisphosphonates target B cells to enhance humoral immune responses

    Science.gov (United States)

    Tonti, Elena; Jiménez de Oya, Nereida; Galliverti, Gabriele; Moseman, E. Ashley; Di Lucia, Pietro; Amabile, Angelo; Sammicheli, Stefano; De Giovanni, Marco; Sironi, Laura; Chevrier, Nicolas; Sitia, Giovanni; Gennari, Luigi; Guidotti, Luca G.; von Andrian, Ulrich H.; Iannacone, Matteo

    2013-01-01

    Summary Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show here that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and γδ T cells, neutrophils or dendritic cells and their effect does not rely on local macrophage depletion nor does it depend upon Toll-like receptor signaling or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as a novel class of adjuvants that boost humoral immune responses. PMID:24120862

  10. 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.)

  11. Bisphosphonates Target B Cells to Enhance Humoral Immune Responses

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    Elena Tonti

    2013-10-01

    Full Text Available Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show here that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens, and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and γδ T cells, neutrophils, or dendritic cells, and their effect does not rely on local macrophage depletion, Toll-like receptor signaling, or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as an additional class of adjuvants that boost humoral immune responses.

  12. Efficacy of bisphosphonates against hip fracture in elderly patients with stroke and Parkinson diseases: meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Zhang, Weiwei; Zhu, Chen; Sun, Mengwen; Ge, Yuhao; Yan, Guang

    2014-01-01

    Stroke and Parkinson disease cause disability and immobilization that increase the risk for fractures. The purpose of the present research was to clarify the efficacy of 3 different bisphosphonates against hip fracture in elderly patients with these neurologic diseases. A literature search was performed in Medline, Embase, CBMdisc, and the Cochrane Library until March 1, 2014, with respect to strictly conducted randomized controlled trials (RCTs) and a meta-analysis was conducted. Every study was evaluated using the Jadad scale. Eight RCTs met the criteria including 5 RCTs for stroke and 3 for Parkinson disease. According to the results of RCTs, the relative risks (95% confidence interval [CI]) for hip fracture with bisphosphonates treatment compared with control treatment were .20 (.07-.54) for stroke and .26 (.13-.52) for Parkinson disease. Overall, the total relative risk (95% CI) for hip fracture with bisphosphonates treatment was .24 (.14-.42), suggesting hip fracture risks with bisphosphonates treatment were reduced significantly in elderly patients compared with the control group in the 2 neurologic diseases (heterogeneity, .86; P = 1.00 and overall effect, 4.99; P bisphosphonates treatment, bone mineral density, intact parathyroid hormone, and 1,25-dihydroxyvitamin D increased, and serum ionized calcium, urinary deoxypyridinoline decreased compared with the placebo group. No severe adverse events were reported for bisphosphonates treatment. The results of a meta-analysis of strictly conducted RCTs suggest that there is efficacy against hip fracture with bisphosphonates treatment in patients with stroke and Parkinson disease. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  13. Bisphosphonates: the first 40 years.

    Science.gov (United States)

    Russell, R Graham G

    2011-07-01

    The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in 1969, so it is timely after 40years to review the history of their development and their impact on clinical medicine. This special issue of BONE contains a series of review articles covering the basic science and clinical aspects of these drugs, written by some of many scientists who have participated in the advances made in this field. The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story, and is a paradigm of a successful journey from 'bench to bedside'. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate (PPi), and it was studies on the role of PPi as the body's natural 'water softener' in the control of soft tissue and skeletal mineralisation that led to the need to find inhibitors of calcification that would resist hydrolysis by alkaline phosphatase. The observation that PPi and BPs could not only retard the growth but also the dissolution of hydroxyapatite crystals prompted studies on their ability to inhibit bone resorption. Although PPi was unable to do this, BPs turned out to be remarkably effective inhibitors of bone resorption, both in vitro and in vivo experimental systems, and eventually in humans. As ever more potent BPs were synthesised and studied, it became apparent that physico-chemical effects were insufficient to explain their biological effects, and that cellular actions must be involved. Despite many attempts, it was not until the 1990s that their biochemical actions were elucidated. It is now clear that bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be

  14. Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement.

    Science.gov (United States)

    Anagnostis, Panagiotis; Paschou, Stavroula A; Mintziori, Gesthimani; Ceausu, Iuliana; Depypere, Herman; Lambrinoudaki, Irene; Mueck, Alfred; Pérez-López, Faustino R; Rees, Margaret; Senturk, Levent M; Simoncini, Tommaso; Stevenson, John C; Stute, Petra; Trémollieres, Florence A; Goulis, Dimitrios G

    2017-07-01

    Bisphosphonates and denosumab are used extensively in the treatment of postmenopausal osteoporosis. Despite their proven efficacy in the reduction of vertebral and non-vertebral fractures, their optimal duration of use has not been determined. The occurrence of adverse effects, such as osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF), has raised the issue of bisphosphonate or denosumab discontinuation ("drug holiday") after a certain treatment period. To assess the effect of bisphosphonate and denosumab discontinuation on fracture risk, as well as its possible benefits in reducing the risk of adverse effects. Systematic review and consensus of expert opinion. Discontinuation of bisphosphonates should be considered in all patients who have beentreated for more than five years with alendronate, risedronate or zoledronic acid. In view of the limited evidence, no robust recommendations can be made for ibandronate and denosumab. If the patient has not experienced fractures before or during therapy and the fracture risk is low, a "drug holiday" canbe recommended. Although there is no solid evidence, 1-2 years for risedronate, 3-5 years for alendronate and 3-6 years for zoledronic acid are suggested. After this time, the patient should be reassessed. If a new fracture is experienced, or fracture risk has increased or BMD remains low (femoral neck T-score ≤-2.5), anti-osteoporotic treatment should be resumed. In the case of denosumab discontinuation, close monitoring is suggested, due to the possibility of rebound fractures. Copyright © 2017. Published by Elsevier B.V.

  15. Bisphosphonates in juvenile dermatomyositis with dystrophic calcinosis.

    Science.gov (United States)

    Tayfur, Asli Celebi; Topaloglu, Rezan; Gulhan, Bora; Bilginer, Yelda

    2015-07-01

    Our primary objective was to retrospectively analyze whether bisphosphonates initiated in combination with immunosuppressive drugs and/or intravenous immunoglobulin (IVIG) resulted in a radiological and clinical improvement of dystrophic calcinosis in six female juvenile dermatomyositis (JDM) patients. Medical records of the patients were reviewed. All six patients met the Bohan and Peter diagnostic criteria for JDM. A resolution of calcinosis was observed in four of the six patients with JDM following the use of bisphosphonates and intensive immunosuppressive therapy with or without IVIG. Bisphosphonates were unable to either decelerate the progression of calcinosis or improve calcinosis in cases 5 and 6. In case 5, it took a relatively long time to control the disease activity despite the appropriate immunsuppressive treatment and she experienced multiple flares of active JDM. Case 6 had a long duration of severe active disease before treatment initiation. No important adverse event was observed. Early commencement of aggressive immunosuppressive agents in combination with bisphosphonate is a choice for the treatment of calcinosis in JDM patients. Concomitant use of IVIG may have an additional effect on the resolution of calcinosis.

  16. A case of osteonecrosis of the jaw in a breast cancer patient with bone metastases receiving long-term treatment with bisphosphonates.

    Science.gov (United States)

    Mouri, Yukako; Yoshida, Miwa; Nakano, Shogo; Yorozuya, Kyoko; Fujii, Kimihito; Fukutomi, Takashi; Nakaoka, Toshiaki; Yamada, Shiro; Hara, Kazuo

    2009-01-01

    Bisphosphonates (BPs) are often used for the treatment of several diseases such as osteoporosis, cancer-associated hypercalcemia, and osteolytic bone metastasis. Recently, there have been reports of osteonecrosis of the jaw (ONJ) in cancer patients whose treatment regimens include BPs. In this case report, we describe complications and treatment of ONJ in a breast cancer patient with bone metastases who received long-term treatment with BPs. A 70-year-old woman underwent modified radical mastectomy on her left breast cancer and received oral 5-fluorouracil derivatives for 2 years in another hospital. Eleven years after the surgery, she came to our hospital complaining of spinalgia and was diagnosed with recurrent breast cancer with multiple metastases to the stomach, liver, multiple lymph nodes, and spine. After surgery for spine metastases, she was given a combination therapy of trastuzumab (initial bolus: 170 mg/body, followed by two or more cycles of 85 mg/body) every week, docetaxel (100 mg/body) every 3 weeks, and BPs (90 mg/body) every 4 weeks. About 1 year and 4 months later, she complained of pain in her right maxilla; biopsy revealed ONJ. Medical oncologists need to recognize ONJ as a serious side effect of BP treatment; dentists and oral and maxillofacial surgeons need to thoroughly consult patients regarding the administration of BPs and have them make an informed consent.

  17. A postmenopausal osteoporotic woman losing bone mineral density despite bisphosphonates

    Directory of Open Access Journals (Sweden)

    Lai PSM

    2013-10-01

    Full Text Available Bisphosphonates are pyrophosphate analogues, with a strong affinity for bones. They inhibit bone resorption and are currently the first choice of treatment for osteoporosis. Bisphosphonates should be taken in a specific manner and for at least one year to be effective in the maintenance and improvement of bone mineral density (BMD, as well as for protection against fractures. We report a case of a postmenospausal osteoporotic woman who lost BMD despite being on bisphosphonate therapy for eight years, highlighting issues that a primary care doctor needs to address before deciding on the next best option.

  18. Risk of fracture and the concomitant use of bisphosphonates with osteoporosis-inducing medications.

    Science.gov (United States)

    Nyandege, Abner N; Slattum, Patricia W; Harpe, Spencer E

    2015-04-01

    To review the literature on the concomitant use of bisphosphonates and medications that can influence bone metabolism and potentially attenuate bisphosphonate antifracture efficacy. MEDLINE and CINAHL were searched for articles published in English through December 2014 using the following terms: bisphosphonates, bone density conservation agents, acid-suppressive therapy, levothyroxine, thiazolidinediones (TZDs), selective serotonin reuptake inhibitors (SSRIs), bone fractures. Studies were included if they reported results of concomitant use of any listed medications with bisphosphonates and risk of fractures and focused on women. Articles that focused generally on the use of one of the listed medications and fractures without explicitly examining the potential antifracture efficacy or attenuation of bisphosphonates were excluded. A total of 6 relevant studies were identified. Four epidemiological studies reported a statistically significant dose-dependent increase in the risk of fractures when bisphosphonates and acid-suppressive drugs were used together. One post hoc analysis of clinical trial data suggested no attenuation of the antifracture effects of bisphosphonates when used concomitantly with acid-suppressive therapy. One study involving bisphosphonates and SSRIs noted a statistically significant association between fracture risk and SSRI use. No study examining TZDs or levothyroxine with bisphosphonates was identified. Existing research suggests potential attenuation of bisphosphonate antifracture efficacy among patients taking acid-suppressive medications. Based on their pharmacological actions, TZDs, SSRIs, and levothyroxine have similar implications. The paucity of evidence in the literature associating the attenuation of bisphosphonate antifracture efficacy when combined with other medications suggests that further investigation is needed. © The Author(s) 2015.

  19. BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW AND DENTAL IMPLANTS

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    Ala Hassan A. Qamheya

    2016-01-01

    Full Text Available Bisphosphonate (BP is one of the possible riskfactors in the osteonecrosis of the jaw (ON J. Surgical interventions during or after the course of treatment by using BPs may expose the patient under this risk. Animal studies, human studies, case reports, and systematic reviews are used to show the relationship between the use of bisphosphonates and dental implants. In this review data about bisphosphonaterelated osteonecrosis of the jaw (BRON J: incidence, prevention and treatment modalities for the patients who are scheduled for dental implant treatment plan and who have been already treated by dental implants will be investigated. Various views for the relationship between dental implants and bisphosphonates will be analyzed depending on the multifactors: duration, route of uptake, dosage of the drug and patient’s other medications that affect the effects of bisphosphonate. All patients treated with this drug must be informed about the risk of implant loss or possibility of osteonecrosis.

  20. Role of bisphosphonates in postmenopausal women with breast cancer.

    Science.gov (United States)

    Gnant, Michael

    2014-04-01

    Data suggest that bisphosphonates protect bone health and may have anticancer activity in postmenopausal women during adjuvant breast cancer therapy. However, key questions remain surrounding the role of adjuvant bisphosphonates in breast cancer, including patient populations deriving benefit, timing/scheduling of therapy, and specific clinical benefits. PubMed, Embase, and San Antonio Breast Cancer Symposium databases provide study results that address these issues in postmenopausal women. Review of these data would aid physicians in providing optimal management of breast cancer in postmenopausal women. For example, recent data reinforce use of intravenous bisphosphonates concurrently with adjuvant endocrine therapy to ameliorate bone loss in recently postmenopausal or osteopenic postmenopausal women with early breast cancer. In contrast, clinical data for oral bisphosphonates have not provided support for using anti-osteoporosis doses in this setting, and the optimal dose is unclear. Additionally, current clinical data show improvements in disease outcomes with bisphosphonates in many studies, although not in all patient subsets. Strong support for the potential adjuvant anticancer benefits from bisphosphonates has been demonstrated in women with established menopause (i.e., very low circulating estrogen levels). Initiating bisphosphonates early and concomitantly with adjuvant therapy generally provided the greatest benefits. However, questions remain such as schedule of treatment and relative potency among the intravenous bisphosphonates and elucidation of the role of oral bisphosphonates, as well as ongoing studies that might provide clarification. This review addresses these controversies in the context of translational research, which may provide the rationale for ongoing studies and evolving treatment paradigms in this area. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. [Atypical fracture of metatarsal bone in a patient with multiple myeloma who was treated long-term with bisphosphonates].

    Science.gov (United States)

    Adam, Z; Sprláková-Puková, A; Chaloupka, R; Krejčí, M; Pour, L; Král, Z; Mayer, J

    2013-11-01

    The first reports found in professional literature on the use of bisphosphonates as a treatment date back to 1972. We found the first report on the use of a bisphosphonate comprising nitrogen in its molecule in a publication from 1990. Some of the adverse effects of the particular types of bisphosphonates were described in the registration studies. At least two serious adverse effects of this group of medicines had not been described until 2000. We found the first description of jaw osteonecrosis in relation to the longterm application of bisphosphonates in a publication from 2002 and we found the first description of an atypical bone fracture originating without a corresponding traumatic event in a location with no presence of an osteolytic focus in an article from 2006. These so  called atypical fractures, which are also called fractures without a corresponding traumatic event (low energy fractures), have been described to have occurred in femurs, in the pelvis and less frequently in the metatarsal area. "Atypical fractures" are linked to longterm administration of bisphosphonates, which significantly increases the bone density and impedes osteolysis but it simultaneously increases the fragility of bones and decreases their flexibility. The definition of an atypical fracture of the skeleton emphasises the fact that such fractures occur with an inadequately minimal force (energy) in the aforementioned predilection locations. In the following text we are describing a patient who has been treated for a multiple myeloma with an atypical fracture of the Metatarsal bone 2. This fracture occurred during a regular walk without any excessive load and the patient could not recall any corresponding injury or longer walking. The patient had been administered bisphosphonates for 34 months before the atypical metatarsal fracture occurred. The metatarsal bone fracture was treated through a nonweight  bearing regime for the sole and the pain diminished within a single month

  2. 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

  3. 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).

  4. Bioactive glass combined with bisphosphonates provides protection against biofilms formed by the periodontal pathogen Aggregatibacter actinomycetemcomitans.

    Science.gov (United States)

    Hiltunen, Anna K; Skogman, Malena E; Rosenqvist, Kirsi; Juvonen, Helka; Ihalainen, Petri; Peltonen, Jouko; Juppo, Anne; Fallarero, Adyary

    2016-03-30

    Biofilms play a pivotal role in the progression of periodontitis and they can be treated with antiseptics (i.e. chlorhexidine) or antibiotics, but these therapeutic alternatives are unable of ameliorating periodontal alveolar bone loss, which has been, on the other hand, successfully treated with bone-preserving agents. The improved bone formation achieved in animal models by the combination of two such agents: bioactive glass (BAG) and bisphosphonates has attracted the interest for further exploring dental applications. However, the antimicrobial effects that may result from combining them have not been yet investigated. Here, our aim was to explore the anti-biofilm effects that could result from combining BAG with bisphosphonates, particularly in a dental biofilm model. The experiments were performed with an oral cavity single-specie (Aggregatibacter actinomycetemcomitans) biofilm assay, which was optimized in this contribution. Risedronate displayed an intrinsic anti-biofilm effect, and all bisphosphonates, except clodronate, reduced biofilm formation when combined with BAG. In particular, the anti-biofilm activity of risedronate was significantly increased by the combination with BAG. Since it has been proposed that some of the antimicrobial effects of BAG are caused by local pH changes, studies of pH variations were performed to gain a mechanistic understanding. However, the observed anti-biofilm effects could not be explained with lowered pHs. Overall, these results do provide further support for the promising use of bisphosphonate-BAG combinations in dental applications. These findings are particularly relevant for patients undergoing cancer chemotherapy, or osteoporotic patients, which are known to be more vulnerable to periodontitis. In such cases, bisphosphonate treatment could play a double positive effect: local treatment of periodontitis (in combination with BAG) and systemic treatment of osteoporosis, prevention of hypercalcemia and metastases

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

    DEFF Research Database (Denmark)

    Hermann, Anne Pernille; Abrahamsen, Bo

    2013-01-01

    Bisphosphonates are widely used globally as the main treatment for osteoporosis. Both safety and efficacy have only been rigorously evaluated in studies of relatively short duration (3-5 years), with smaller extension studies. The evidence for benefit beyond five years in intervention studies...... is limited and does not include proven efficacy against nonvertebral fractures. Observational studies suggest a sustained benefit against hip fractures. Bisphosphonates are stored in the skeleton for months to years, depending on the degree of bone turnover and the binding properties of the bisphosphonate...... in question. The effects of continued treatment on bone strength is not known but there are concerns that osteonecrosis of the jaw and atypical femur fractures may stem from long term bisphosphonate use....

  6. Local Administration of Bisphosphonate-soaked Hydroxyapatite for the Treatment of Osteonecrosis of the Femoral Head in Rabbit

    Directory of Open Access Journals (Sweden)

    Jin-Hui Ma

    2016-01-01

    Conclusions: Local administration of HA soaked in a low-dose ZOL solution increased new bone formation while inhibiting bone resorption in an animal model of ONFH, which might provide new evidence for joint-preserving surgery in the treatment of ONFH.

  7. 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.

  8. Bisphosphonate-Related Osteonecrosis of the Jaw Mimicking Bone Metastasis

    OpenAIRE

    Bhatt, Geetika; Bhatt, Aashish; Dragun, Anthony E.; Li, Xiao-Feng; Civelek, A. Cahid

    2014-01-01

    Osteonecrosis of the jaw is usually a potential complication of bisphosphonate therapy. In a cancer patient, this disease entity can be misdiagnosed as a metastatic lesion. Our aim is to make clinicians aware of bisphosphonate associated osteonecrosis of the jaw to prevent misdiagnosis and initiate proper treatment at the earliest. We present the case of a breast cancer patient with multiple bony metastases and a jaw lesion presumed to be metastases. After no response to palliative radiation,...

  9. Bisphosphonate-related osteonecrosis of the jaw in patients with breast cancer.

    Science.gov (United States)

    Piccioli, Andrea

    2015-01-01

    Bisphosphonate represents a well-established treatment option in the management of metastatic bone disease and bone loss/osteoporosis in women with breast cancer. These drugs reduce osteoclast. Some bisphosphonate also have osteoblastic function leading to a reducted bone turnover and thereby skeletal-related events. The aim of this review is to evaluate the bisphosphonate-related osteonecrosis of the jaw in patients with breast cancer. Based on the proven effect of bone protection during adjuvant endocrine therapy, new treatment guidelines recommend the routine use of bisphosphonates to prevent bone loss during adjuvant therapy, which may likely become the standard practice.

  10. Bisphosphonate therapy for spinal osteoporosis in Hajdu-Cheney syndrome - new data and literature review.

    Science.gov (United States)

    Pittaway, James F H; Harrison, Christopher; Rhee, Yumie; Holder-Espinasse, Muriel; Fryer, Alan E; Cundy, Tim; Drake, William M; Irving, Melita D

    2018-04-04

    Hajdu-Cheney syndrome (HCS) (#OMIM 102500) is a rare, autosomal dominant condition that presents in early childhood. It is caused by mutations in the terminal exon of NOTCH2, which encodes the transmembrane NOTCH2 receptor. This pathway is involved in the coupled processes of bone formation and resorption. The skeletal features of HCS include acro-osteolysis of the digits and osteoporosis commonly affecting vertebrae and long bones. Fractures are a prominent feature and are associated with significant morbidity. There is no specific treatment, but with both acro-osteolysis and generalized osteoporosis, it is possible that anti-resorptive treatment might be of benefit. However, to date only a few case reports have evaluated the effectiveness of bisphosphonate treatment. We describe the clinical features, treatment regimens and response to bisphosphonate treatment in 7 newly described patients aged 6-39 with HCS, and pooled the data with that from 8 previously published cases (a total of 17 courses of treatment in 15 individuals). The mean lumbar spine bone mineral density (BMD) z-score before treatment was - 2.9 (SD 1.2). In 14 courses of treatment (82%), there was an increase in BMD with bisphosphonate treatment, but the impact (in terms of change in spinal BMD z-score) appeared to be less with advancing age (p = 0.01). There was no evidence that acro-osteolysis was prevented. Although individual response is variable and age-related, the data support a role for bisphosphonates in preventing or treating spinal osteoporosis in HCS, but bone loss from the lumbar spine may be rapid after cessation.

  11. Inflammatory eye reactions with bisphosphonates and other osteoporosis medications

    DEFF Research Database (Denmark)

    Clark, Emma M; Durup, Darshana

    2015-01-01

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

  12. Uptake of a fluorinated bisphosphonate by cultured bones

    Energy Technology Data Exchange (ETDEWEB)

    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.

  13. 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......-2005). SUBJECTS: Fracture patients beginning bisphosphonates (n = 15 795) were matched with unexposed fracture patients of the same age, sex and fracture type (n = 31 590). RESULTS: Incidence rates of AF were 16.5/1000 person years in untreated fracture patients and 20.6/1000 person years in bisphosphonate users...... increased even in patients who stopped therapy after the first packet and (ii) risks were not increased by high adherence. Bisphosphonate-exposed patients were at increased risk of hospital-treated AF [adjusted HR: 1.13 (1.01-1.26)], but the risk amongst bisphosphonate users was inversely proportional...

  14. Oral Bisphosphonates and Improved Survival of Breast Cancer.

    Science.gov (United States)

    Rennert, Gad; Pinchev, Mila; Gronich, Naomi; Saliba, Walid; Flugelman, Anath; Lavi, Idit; Goldberg, Hadassah; Fried, Georgeta; Steiner, Mariana; Bitterman, Arie; Landsman, Keren; Rennert, Hedy S

    2017-04-01

    Purpose: Bisphosphonates are used for treatment or prevention of osteoporosis and of bone metastases. The use of oral bisphosphonates was suggested to be associated with reduced risk of developing breast cancer, and their positive influence on breast cancer survival was only demonstrated with third-generation bisphosphonates. We studied the association of use of oral bisphosphonates after breast cancer diagnosis on overall and breast cancer survival. Experimental Design: A nested case-control analysis was performed using data from the population-based Breast Cancer in Northern Israel Study (BCINIS). Participants were postmenopausal women with newly diagnosed breast cancer insured by Clalit. Use of second-generation bisphosphonates (alendronate and/or risedronate) was identified using computerized prescription records. The analysis was restricted to women who did not use bisphosphonates prior to diagnosis. Results: In a cohort of 3,731 postmenopausal women with breast cancer, followed up for an average of 70 months, there were 799 cases of death which were matched to 15,915 control periods of living breast cancer cases. Use of bisphosphonates after diagnosis for at least 18 months was significantly more common among survivors than among their matched controls who died, adjusted for tumor stage/grade (overall survival: OR = 0.63, 0.41-0.96, P = 0.03; breast cancer-specific survival: OR = 0.28, 0.09-0.91, P = 0.035). A similar advantageous effect, but statistically underpowered, was found in estrogen receptor (ER)-positive, ER-negative, and HER2neu-positive tumors. Conclusions: The use of oral bisphosphonates, by postmenopausal, probably osteoporotic, women initiated after diagnosis of breast cancer was associated with a significant improvement in overall and breast-specific odds of survival. Clin Cancer Res; 23(7); 1684-9. ©2016 AACR . ©2016 American Association for Cancer Research.

  15. Questioning the association between bisphosphonates and atypical femoral fractures.

    Science.gov (United States)

    Pazianas, Michael; Kim, Se-min; Yuen, Tony; Sun, Li; Epstein, Sol; Zaidi, Mone

    2015-01-01

    Bisphosphonates are the first-line treatment for osteoporosis. Structurally, they are stable analogues of pyrophosphate and therefore exhibit a high affinity for bone mineral. They reduce bone loss by attenuating the ability of the osteoclast to resorb bone, decreasing activation frequency, and the rate of remodeling. Large prospective randomized placebo-control trials provide unequivocal evidence for a reduction in the incidence of fractures. Impressively, 40 years since their first use in patients, the safety profile of bisphosphonates has been equally reassuring. Questions have arisen lately as to whether bisphosphonates could cause atypical fractures, a rare type of atraumatic or minimal trauma femur fracture occurring below the great trochanter. This question has prompted calls for a broader examination of the long-term effects of bisphosphonate use. An attempt by the Food and Drug Administration to garner consensus and provide definitive views was not successful. This has led to continued anxiety among treating physicians and patients alike, resulting in an overall reduction in prescriptions for bisphosphonates and for osteoporosis therapies in general. Here, we provide an overview of the current data on atypical fractures and bisphosphonate use. © 2014 New York Academy of Sciences.

  16. The Frequency of and Risk Factors for the Use of Bisphosphonates in the Adjuvant Setting of Primary Breast Cancer in Germany.

    Science.gov (United States)

    Fick, Eva-Maria; Katalinic, Alexander; Waldmann, Annika

    2015-10-01

    The aim of this cross-sectional health care study (use of bisphosphonates in primary tumors of the mammae, EBisMa) is to determine how often bisphosphonate medication is used in patients with non-metastatic primary breast cancer treatment, but who do not suffer from osteoporosis. Furthermore, we describe patients' characteristics and the most frequently used type of bisphosphonate in adjuvant therapy. The study population included primary breast cancer patients of four breast centers in northern Germany. Data on bisphosphonate therapy were collected by use of patient questionnaires; clinical data were extracted from the registers. Patients with and without prescribed bisphosphonate adjuvant treatment were tested for statistically significant differences regarding their characteristics. Four hundred seventy-four of 663 contacted patients participated in the study. Thirty-nine out of 474 patients (9.6%) were on adjuvant bisphosphonate therapy. Zoledronic acid was the most frequently reported bisphosphonate used for prevention of bone metastases. Compared to patients who did not report bisphosphonate medication, women who did report bisphosphonate therapy had a significantly higher advanced tumor stage (p Bisphosphonates are rarely used in the adjuvant treatment of primary breast cancer. Patients with advanced tumor stage were more likely to use bisphosphonates in the adjuvant treatment of primary breast cancer. Further research is needed to identify patients who may benefit most from adjuvant bisphosphonate treatment.

  17. Calcium Phosphates as Delivery Systems for Bisphosphonates

    Directory of Open Access Journals (Sweden)

    Adriana Bigi

    2018-01-01

    Full Text Available Bisphosphonates (BPs are the most utilized drugs for the treatment of osteoporosis, and are usefully employed also for other pathologies characterized by abnormally high bone resorption, including bone metastases. Due to the great affinity of these drugs for calcium ions, calcium phosphates are ideal delivery systems for local administration of BPs to bone, which is aimed to avoid/limit the undesirable side effects of their prolonged systemic use. Direct synthesis in aqueous medium and chemisorptions from solution are the two main routes proposed to synthesize BP functionalized calcium phosphates. The present review overviews the information acquired through the studies on the interaction between bisphosphonate molecules and calcium phosphates. Moreover, particular attention is addressed to some important recent achievements on the applications of BP functionalized calcium phosphates as biomaterials for bone substitution/repair.

  18. Bisphosphonates do not Alter the Rate of Secondary Mineralization

    Energy Technology Data Exchange (ETDEWEB)

    R Fuchs; M Faillace; M Allen; R Phipps; L Miller; D Burr

    2011-12-31

    Bisphosphonates function to reduce bone turnover, which consequently increases the mean degree of tissue mineralization at an organ level. However, it is not clear if bisphosphonates alter the length of time required for an individual bone-modeling unit (BMU) to fully mineralize. We have recently demonstrated that it takes {approx}350 days (d) for normal, untreated cortical bone to fully mineralize. The aim of this study was to determine the rate at which newly formed trabecular BMUs become fully mineralized in rabbits treated for up to 414 d with clinical doses of either risedronate (RIS) or alendronate (ALN). Thirty-six, 4-month old virgin female New Zealand white rabbits were allocated to RIS (n=12; 2.4 {mu}g/kg body weight), ALN (n=12; 2.4 {mu}g/kg body weight), or volume-matched saline controls (CON; n=12). Fluorochrome labels were administered at specific time intervals to quantify the rate and level of mineralization of trabecular bone from the femoral neck (FN) by Fourier transform infrared microspectroscopy (FTIRM). The organic (collagen) and inorganic (phosphate and carbonate) IR spectral characteristics of trabecular bone from undecalcified 4 micron thick tissue sections were quantified from fluorescently labels regions that had mineralized for 1, 8, 18, 35, 70, 105, 140, 210, 280, and 385 d (4 rabbits per time point and treatment group). All groups exhibited a rapid increase in mineralization over the first 18 days, the period of primary mineralization, with no significant differences between treatments. Mineralization continued to increase, at a slower rate up, to 385 days (secondary mineralization), and was not different among treatments. There were no significant differences between treatments for the rate of mineralization within an individual BMU; however, ALN and RIS both increased global tissue mineralization as demonstrated by areal bone mineral density from DXA. We conclude that increases in tissue mineralization that occur following a period

  19. Bisphosphonates do not alter the rate of secondary mineralization

    Energy Technology Data Exchange (ETDEWEB)

    Fuchs R. K.; Miller L.; Faillace M.E.; Allen M.R.; Phipps R.J. and Burr D.B.

    2011-05-18

    Bisphosphonates function to reduce bone turnover, which consequently increases the mean degree of tissue mineralization at an organ level. However, it is not clear if bisphosphonates alter the length of time required for an individual bone-modeling unit (BMU) to fully mineralize. We have recently demonstrated that it takes {approx}350 days (d) for normal, untreated cortical bone to fully mineralize. The aim of this study was to determine the rate at which newly formed trabecular BMUs become fully mineralized in rabbits treated for up to 414 d with clinical doses of either risedronate (RIS) or alendronate (ALN). Thirty-six, 4-month old virgin female New Zealand white rabbits were allocated to RIS (n = 12; 2.4 {micro}g/kg body weight), ALN (n = 12; 2.4 {micro}g/kg body weight), or volume-matched saline controls (CON; n = 12). Fluorochrome labels were administered at specific time intervals to quantify the rate and level of mineralization of trabecular bone from the femoral neck (FN) by Fourier transform infrared microspectroscopy (FTIRM). The organic (collagen) and inorganic (phosphate and carbonate) IR spectral characteristics of trabecular bone from undecalcified 4 micron thick tissue sections were quantified from fluorescently labels regions that had mineralized for 1, 8, 18, 35, 70, 105, 140, 210, 280, and 385 d (4 rabbits per time point and treatment group). All groups exhibited a rapid increase in mineralization over the first 18 days, the period of primary mineralization, with no significant differences between treatments. Mineralization continued to increase, at a slower rate up, to 385 days (secondary mineralization), and was not different among treatments. There were no significant differences between treatments for the rate of mineralization within an individual BMU; however, ALN and RIS both increased global tissue mineralization as demonstrated by areal bone mineral density from DXA. We conclude that increases in tissue mineralization that occur

  20. [Osteoprotective therapy with bisphosphonates or denosumab in patients with multiple myeloma: benefit and risks].

    Science.gov (United States)

    Adam, Zdeněk; Straub, Jan; Krejčí, Marta; Pour, Luděk; Brančíková, Dagmar; Ostřížková, Lenka; Sandecká, Viera; Štork, Martin

    Bisphosphonates have been used during the complete treatment of multiple myeloma for more than twenty years. They slow osteolysis and thereby contribute to the improvement of quality of life. Their long-term use, however, is related to 2 serious, usually later appearing complications: osteonecrosis of the jaw, occurring in 6-9 % of patients, and rarer atypical bone fractures. Both these complications are very difficult to heal, and all the more emphasis is therefore laid on prevention. This first of all includes discussion about the risk with the patient, followed by a dental checkup before the commencement of therapy and then repeated during its course, as well as reduced use of these drugs for a necessary period of time. However osteonecrosis of the jaw does not only develop as a consequence of bisphosphonate therapy. The complication is also caused by some new drugs (denosumab and others) used in cancer therapies. The text includes an overview of the drugs currently used in cancer treatment, which also increase the risk of appearance of osteonecrosis of the jaw. For patients with multiple myeloma, who achieve the complete or very good partial remission after chemotherapy, it is recommended to administer these drugs for more than 1 year after achieving the positive treatment response, but not longer than for 2 years. Only regarding those who do not reach the good treatment response, bisphosphonates are administered over the long term, as long as osteolytic activity of the disease lasts.Key words: atypical bone fractures - bisphosphonates - drug induced osteonecrosis of the jaw - multiple myeloma.

  1. Effect of antiresorptive drugs on bony turnover in the jaw: denosumab compared with bisphosphonates.

    Science.gov (United States)

    Ristow, Oliver; Gerngroß, Carlos; Schwaiger, Markus; Hohlweg-Majert, Bettina; Kehl, Victoria; Jansen, Heike; Hahnefeld, Lilian; Koerdt, Steffen; Otto, Sven; Pautke, Christoph

    2014-04-01

    Osteonecrosis of the jaw as a result of treatment with receptor activators of nuclear factor kappa-B ligand (RANKL) inhibitors (denosumab) is a new type of bony necrosis, the exact pathogenesis of which is unknown. Our aim was to find out whether the turnover of bone in the jaw is increased after denosumab has been given compared with other skeletal sites, and if that turnover might have a role in denosumab-related osteonecrosis of the jaw (DRONJ). Bone scintigraphic images of 45 female patients with breast cancer and bone metastases were analysed retrospectively, and divided into 3 groups: those given denosumab, those given a bisphosphonate, and a control group (n=15 in each). All patients had bone scintigraphy before treatment (T0) and during the course of treatment after 12 (T1) and 24 (T2) months. The data were analysed quantitatively using 6 preset bony regions of interest. There was similar turnover of bone in the mandible compared with other skeletal sites (such as the femur), while the maxilla showed significantly higher turnover. None of the bony regions investigated showed any significant changes after the bisphosphonate had been given. There was a tendency to increase bone turnover in those patients taking denosumab. The bone turnover of the jawbone is not overtly changed either by a bisphosphonate or denosumab, so it seems unlikely that oversuppression of bony turnover in the jawbones plays an important part either in the pathogenesis of DRONJ or in the bisphosphonate-related osteonecrosis of the jaw (BRONJ). Copyright © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  2. Bisphosphonate-Related Osteonecrosis of the Jaw Mimicking Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Geetika Bhatt

    2014-01-01

    Full Text Available Osteonecrosis of the jaw is usually a potential complication of bisphosphonate therapy. In a cancer patient, this disease entity can be misdiagnosed as a metastatic lesion. Our aim is to make clinicians aware of bisphosphonate associated osteonecrosis of the jaw to prevent misdiagnosis and initiate proper treatment at the earliest. We present the case of a breast cancer patient with multiple bony metastases and a jaw lesion presumed to be metastases. After no response to palliative radiation, repeat radiological imaging studies revealed osteonecrosis of the jaw. Correlating a patient’s clinical information with findings on diagnostic imaging studies, such as SPECT bone and CT scans, can help identify this potential complication of bisphosphonate treatment. Early diagnosis helps minimize unnecessary biopsies and allows for the proper treatment to be instituted.

  3. Bisphosphonate-related osteonecrosis of the jaw mimicking bone metastasis.

    Science.gov (United States)

    Bhatt, Geetika; Bhatt, Aashish; Dragun, Anthony E; Li, Xiao-Feng; Civelek, A Cahid

    2014-01-01

    Osteonecrosis of the jaw is usually a potential complication of bisphosphonate therapy. In a cancer patient, this disease entity can be misdiagnosed as a metastatic lesion. Our aim is to make clinicians aware of bisphosphonate associated osteonecrosis of the jaw to prevent misdiagnosis and initiate proper treatment at the earliest. We present the case of a breast cancer patient with multiple bony metastases and a jaw lesion presumed to be metastases. After no response to palliative radiation, repeat radiological imaging studies revealed osteonecrosis of the jaw. Correlating a patient's clinical information with findings on diagnostic imaging studies, such as SPECT bone and CT scans, can help identify this potential complication of bisphosphonate treatment. Early diagnosis helps minimize unnecessary biopsies and allows for the proper treatment to be instituted.

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

    DEFF Research Database (Denmark)

    Pazianas, Michael; Abrahamsen, Bo; Ferrari, Serge

    2013-01-01

    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...... 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......, 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...

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

    Science.gov (United States)

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

    2015-03-01

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

  6. Adherence to oral bisphosphonates: 30 more minutes in dosing instructions matter.

    Science.gov (United States)

    Vytrisalova, M; Touskova, T; Ladova, K; Fuksa, L; Palicka, V; Matoulkova, P; Horak, P; Stepan, J

    2015-01-01

    Low adherence to treatment with bisphosphonates significantly impedes its effectiveness. The objectives were: (1) to compare adherence to oral weekly and monthly bisphosphonates with emphasis on dosing instructions; and (2) to study associations between adherence and beliefs about the bisphosphonate treatment among women ≥ 55 years. A multicenter survey was performed in secondary-care patients with osteoporosis. Osteoporosis Specific Morisky Medication Adherence Scale (OS-MMAS), questions on compliance with five dosing instructions and Beliefs about Medicines Questionnaire (BMQ) Specific were used. As many as 363 questionnaires (response rate 95%) were analyzed. Respondents (mean age 69 years) were treated with weekly bisphosphonates (37%) or monthly ibandronate (63%). Based on OS-MMAS, 67% of respondents showed high adherence with no differences between the subgroups. Only 44% of respondents were compliant with all dosing instructions. Compliance with dosing instructions concerning time interval (fasting and staying upright) was 71% in weekly and 52% in monthly subgroups, respectively (p bisphosphonates.

  7. Biochemical markers for prediction of 4-year response in bone mass during bisphosphonate treatment for prevention of postmenopausal osteoporosis

    DEFF Research Database (Denmark)

    Ravn, Pernille; Thompson, Desmond E; Ross, Philip D

    2003-01-01

    Short-term changes in biochemical markers of bone turnover (bone markers) have been suggested as predictors of long-term response in bone mass during antiresorptive treatment. In the Danish cohort (n = 306) of the Early Postmenopausal Intervention Cohort (EPIC) Study (n = 1609) of oral alendronate...

  8. Biochemical markers for prediction of 4-year response in bone mass during bisphosphonate treatment for prevention of postmenopausal osteoporosis

    DEFF Research Database (Denmark)

    Ravn, Pernille; Thompson, Desmond E; Ross, Philip D

    2003-01-01

    Short-term changes in biochemical markers of bone turnover (bone markers) have been suggested as predictors of long-term response in bone mass during antiresorptive treatment. In the Danish cohort (n = 306) of the Early Postmenopausal Intervention Cohort (EPIC) Study (n = 1609) of oral alendronat...

  9. Effects of increasing age, dosage, and duration of PTH treatment on BMD increase--a meta-analysis

    DEFF Research Database (Denmark)

    Schwarz, Peter; Jorgensen, Niklas Rye; Mosekilde, Leif

    2012-01-01

    We studied the effects of increasing age, dosage, and duration of parathyroid hormone (PTH) treatment on changes in bone mineral density (BMD). Randomized placebo controlled trials on PTH treatment in men or women were retrieved from PubMed (1951 to present), Web of Science (1945 to present......), or Embase (1974 to present). The search date was November 16, 2010. All studies comparing PTH treatment to either placebo or antiresorptive drugs-for example, bisphosphonates or hormone replacement therapy-were included. A total of 214 studies were identified in the initial search, and 15 of these trials...... were included. By metaregression analysis, we found that the increase in spine BMD (Z-score) after PTH treatment was blunted by increasing age (R (2) = 0.27; 2p = 0.01, slope -0.023 Z-scores per year, 11 studies). By increasing PTH dosage (μg/d), spine BMD increased significantly (2p = 0...

  10. Determinants associated with bone mineral density increase in response to daily teriparatide treatment in patients with osteoporosis.

    Science.gov (United States)

    Niimi, Rui; Kono, Toshibumi; Nishihara, Atsushi; Hasegawa, Masahiro; Matsumine, Akihiko; Kono, Toshihiko; Sudo, Akihiro

    2014-09-01

    Several factors associated with bone mineral density (BMD) increase are reported with daily teriparatide treatment, but there has been no systematic analysis to summarize these associations. The purpose of this study was to investigate the clinical determinants associated with BMD increase to daily teriparatide treatment. This was a retrospective study. We performed an analysis of 306 patients diagnosed with osteoporosis. Teriparatide was administered at 20μg/day for 12months. The primary efficacy measure was a change in lumbar spine (LS) BMD from baseline at 12months. To determine the response variables of BMD changes, we investigated the clinical determinants using univariate and multivariate analyses. There was a 9.8±8.2% increase in LS BMD after 12months. Prior bisphosphonate treatment and baseline procollagen type I N-terminal propeptide (PINP) concentration were significantly associated with LS BMD absolute response by univariate analyses. In the multiple regression model, patients with higher baseline PINP concentration had a significantly greater LS BMD absolute increase. Prior bisphosphonate use lost its correlation in the multiple regression models. Our results showed that baseline PINP concentration was a useful predictor of LS BMD absolute increase regardless of prior treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. 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....

  12. Thirteen cases of jaw osteonecrosis in patients on bisphosphonate therapy.

    Science.gov (United States)

    Vieillard, Marie-Hélène; Maes, Jean-Michel; Penel, Guillaume; Facon, Thierry; Magro, Leonardo; Bonneterre, Jacques; Cortet, Bernard

    2008-01-01

    We report on our experience with 13 cases of jaw osteonecrosis in patients treated with amino-bisphosphonates. Data were collected by a regional observatory for jaw osteonecrosis in northern France via letters sent to all physicians likely to manage patients with this condition. All study patients were evaluated at a multidisciplinary jaw osteonecrosis clinic between June and December 2005. We identified 13 cases, in 12 women and 1 man, with a mean age of 62.6 years. Intravenous amino-bisphosphonate therapy was given for metastatic bone disease from breast cancer in 7 patients and multiple myeloma in 5 patients; the remaining patient was on oral alendronate for osteoporosis. Mean treatment duration was 24 months. A history of dental extraction was found in 11 (84.6%) patients. The mandible was involved in all 13 patients and the maxillary in 3 (23%) patients. Amino-bisphosphonate therapy was discontinued in all 13 patients. We suggest a classification scheme for the clinical and computed-tomography patterns seen in our patients. Jaw osteonecrosis is a severe complication of amino-bisphosphonate therapy. In addition to the application of published guidelines, we propose discontinuing bisphosphonate therapy whenever possible. We are evaluating our classification scheme to identify early diagnostic criteria and/or clinical and computed-tomography outcome criteria that would improve the management of patients with jaw osteonecrosis.

  13. Clinical utility of clodronate in the prevention and management of osteoporosis in patients intolerant of oral bisphosphonates.

    Science.gov (United States)

    Muratore, Maurizio; Quarta, Eugenio; Grimaldi, Antonella; Calcagnile, Fabio; Quarta, Laura

    2011-01-01

    Bisphosphonates have a long history in the treatment of osteoporosis and bone-related disease. This review focuses on the use of a specific nonaminobisphosphonate, clodronate, which appears to be much better tolerated than other bisphosphonates and free of high-risk contraindications. Specifically, this paper reviews its use in the prevention of osteoporosis in postmenopausal women, taking into account its tolerability profile and recent safety issues arising regarding the use of bisphosphonates.

  14. Clinical utility of clodronate in the prevention and management of osteoporosis in patients intolerant of oral bisphosphonates

    Science.gov (United States)

    Muratore, Maurizio; Quarta, Eugenio; Grimaldi, Antonella; Calcagnile, Fabio; Quarta, Laura

    2011-01-01

    Bisphosphonates have a long history in the treatment of osteoporosis and bone-related disease. This review focuses on the use of a specific nonaminobisphosphonate, clodronate, which appears to be much better tolerated than other bisphosphonates and free of high-risk contraindications. Specifically, this paper reviews its use in the prevention of osteoporosis in postmenopausal women, taking into account its tolerability profile and recent safety issues arising regarding the use of bisphosphonates. PMID:22087064

  15. Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials.

    Science.gov (United States)

    Giusti, Andrea

    2014-11-01

    Bisphosphonates are potent inhibitors of bone resorption, widely used for the management of osteoporosis and fracture prevention. Recent evidence suggests that bisphosphonates may have beneficial effects in the treatment of thalassemia-associated osteoporosis, a complex and multifactorial condition. Here we summarise available data about the efficacy and tolerability of bisphosphonates in beta--thalassemic patients. Randomised controlled trials (RCTs) of bisphosphonates in beta-thalassemia were identified searching PubMed. Studies were reviewed to retrieve relevant clinical information. The following variables were considered to assess the safety and efficacy of bisphosphonates-bone mineral density (BMD), markers of bone turnover, incidence of fragility fracture, bone pain, back pain, and clinical adverse events. Five RCTs were identified, investigating alendronate, clodronate, zoledronic acid and neridronate. All bisphosphonates produced a significant decrease of the markers of bone turnover. Alendronate, neridronate, and zoledronic acid significantly improved BMD at the lumbar spine, femoral neck and total hip. Zoledronic acid and neridronate were also shown to reduce bone and back pain. Probably due to the small sample sizes and to the short duration of the trials, it was not possible to establish the anti-fracture efficacy of bisphosphonates; however, they were well tolerated and adverse events were rare but expected on the basis of previous studies. Sufficient evidence exists to support the use of bisphosphonates in the management of thalassemia-associated osteoporosis (to prevent bone loss and improve the BMD). Further research is warranted to establish their anti-fracture efficacy and long-term safety.

  16. Soaking morselized allograft in bisphosphonate can impair implant fixation

    DEFF Research Database (Denmark)

    Jakobsen, Thomas; Baas, Jørgen; Bechtold, Joan E

    2007-01-01

    The use of impacted, morselized allograft is a well-established way to provide initial stability of revision joint replacements. We investigated whether rinsing morselized allograft in bisphosphonate and subsequently impacting it around experimental titanium-coated implants would further facilitate...... bisphosphonate (alendronate, 2 mg/mL) or saline (control). Unbound alendronate was not rinsed away. During the first surgery, one pair of implants (alendronate and control) was inserted into one humerus. Eight weeks later, a second pair of implants was inserted into the contralateral humerus. The first pair....... Furthermore, the alendronate treatment blocked formation of new bone and inhibited resorption of the graft material. Although limited by the specific dose of alendronate used and the omission of rinsing away excess bisphosphonate, this study warrants caution and calls for further experimental research before...

  17. 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.

  18. Bisphosphonates for cardiovascular risk reduction: A systematic review and meta-analysis.

    Science.gov (United States)

    Kranenburg, Guido; Bartstra, Jonas W; Weijmans, Maaike; de Jong, Pim A; Mali, Willem P; Verhaar, Harald J; Visseren, Frank L J; Spiering, Wilko

    2016-09-01

    Bisphosphonates might be effective in reducing cardiovascular events due to their ability to reduce calcification in arterial walls. We aimed to investigate the effects of treatment with bisphosphonates on the prevention of atherosclerotic processes and cardiovascular disease. Pubmed, Embase and the Cochrane Library were systematically reviewed by two independent investigators for randomized controlled studies published up to January 2016, in which the effect of bisphosphonates on arterial wall disease, cardiovascular events, cardiovascular mortality or all-cause mortality were reported. There was no restriction for the type of population used in the trials. Random-effects models were used to calculate the pooled estimates. 61 trials reporting the effects of bisphosphonates on the outcomes of interest were included. Bisphosphonates had beneficial effects on arterial wall disease regarding arterial calcification (pooled mean percentage difference of 2 trials -11.52 (95% CI -16.51 to -6.52, p bisphosphonate treatment on cardiovascular events was found (pooled RR of 20 trials 1.03; 95% CI 0.91-1.17, I(2) 16%), while a lower risk for cardiovascular mortality was observed in patients treated with bisphosphonates (pooled RR of 10 trials 0.81; 95% CI 0.64-1.02; I(2) 0%) although not statistically significant. Patients treated with bisphosphonates had a reduced risk of all-cause mortality (pooled RR of 48 trials 0.90; 95% CI 0.84-0.98; I(2) 53%). In this systematic review and meta-analysis it is shown that bisphosphonates reduce arterial wall calcification but have no effect on arterial stiffness or on cardiovascular events. Bisphosphonates tend to reduce the risk of cardiovascular mortality and reduce all-cause mortality in various patient groups, including osteoporosis and cancer patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  19. Design and Biological Evaluation of Delivery Systems Containing Bisphosphonates

    Directory of Open Access Journals (Sweden)

    Blessing Aderibigbe

    2016-12-01

    Full Text Available Bisphosphonates have found application in the treatment of reoccurrence of bone diseases, breast cancer, etc. They have also been found to exhibit antimicrobial, anticancer and antimalarial activities. However, they suffer from pharmacological deficiencies such as toxicity, poor bioavailability and low intestinal adsorption. These shortcomings have resulted in several researchers developing delivery systems that can enhance their overall therapeutic effectiveness. This review provides a detailed overview of the published studies on delivery systems designed for the delivery of bisphosphonates and the corresponding in vitro/in vivo results.

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

    Directory of Open Access Journals (Sweden)

    Zuzana Janovská

    2012-01-01

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

  1. Are long-term bisphosphonate users a reality?

    DEFF Research Database (Denmark)

    Abrahamsen, B

    2012-01-01

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

  2. [Osteonecrosis of the jaws by long term therapy with bisphosphonates].

    Science.gov (United States)

    Piesold, Jörn-Uwe; Al-Nawas, Bilal; Grötz, Knut A

    2006-09-01

    For several decades bisphosphonates have been used to reduce skeletal related events in patients with both osteoporosis or bone metastases. Under long term application, besides the known therapy side effects, a new clinical picture has been described within the last few years. This is osteonecrosis of the jaws, which is characterized by its difficulty in treatment. Besides exposed jaw bone, the start of the disease usually lacks any symptoms. The typical clinical symptoms then are foetor ex ore, swelling, exsudation, loosening of teeth, pain or paresthesia. Later oro-antral/nasal or oro-cutaneous fistula can develop. The X-ray shows persisting tooth sockets after extractions and later cloudy radio-lucency, sequestra or fractures. The patient exposed to bisphosphonate can be grouped according to the risk for osteonecrosis: high risk patients with intravenous bisphosphonate therapy and additional chemo-, radiation or corticoid therapy--predominantly patients with a malignant underlying disease and bone metastases low risk patients with an oral bisphosphonate therapy without additional chemo-, radiation or corticoid therapy--preferably patients with non-corticoid-induced osteoporosis. Before starting a bisphosphonate therapy possible causes of infection should be treated and risk of injuries to the mucosa should be reduced according to the individual risk profile. This is supplemented by information of the patient about the risk of necrosis and the possibilities for prevention. Regular dental recall under bisphophonate therapy is emphasised for early recognition of possible problems. Prophylaxis is recommended for the prevention of periodontal infection combined with a follow up of removable denture for possible ulcera. Generally, conservative treatment measures are preferred to surgical ones. Inevitable operations are carried out non-traumatically using broad spectrum antibiotic prophylaxis until the day of suture removal (not before day 10). Long term follow up

  3. Clinical utility of clodronate in the prevention and management of osteoporosis in patients intolerant of oral bisphosphonates

    Directory of Open Access Journals (Sweden)

    Muratore M

    2011-10-01

    Full Text Available Maurizio Muratore, Eugenio Quarta, Antonella Grimaldi, Fabio Calcagnile, Laura Quarta Department of Rheumatology, Hospital Galateo, San Cesario di Lecce, Italy Abstract: Bisphosphonates have a long history in the treatment of osteoporosis and bone-related disease. This review focuses on the use of a specific nonaminobisphosphonate, clodronate, which appears to be much better tolerated than other bisphosphonates and free of high-risk contraindications. Specifically, this paper reviews its use in the prevention of osteoporosis in postmenopausal women, taking into account its tolerability profile and recent safety issues arising regarding the use of bisphosphonates. Keywords: clodronate, bisphosphonates, osteoporosis, bone turnover, menopause, tolerability

  4. Efficacy of bisphosphonates against osteoporosis in adult men: a meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Chen, L; Wang, G; Zheng, F; Zhao, H; Li, H

    2015-09-01

    This meta-analysis of published randomized controlled trials (RCTs) aimed to analyze the efficacy of administration of bisphosphonates in men with osteoporosis. Compared with placebo, bisphosphonates could reduce the risk of vertebral and non-vertebral fractures, reduce bone-specific alkaline phosphatase (BSAP) and C-terminal telopeptide of type I collagen (CTX), and increase bone mineral density (BMD). Bisphosphonates are well-investigated antiresorptive medications, approved as first-line drugs for osteoporosis in postmenopausal women. However, there is a paucity of high-quality evidence regarding the efficacy of bisphosphonates administered for osteoporosis in adult men. The aim of this meta-analysis was to analyse the efficacy of administration of bisphosphonates in men based on published RCTs. PubMed, Embase, MEDLINE, and the Cochrane library were searched, and mean differences were calculated to evaluate the efficacy of bisphosphonates on reducing the risk of vertebral and non-vertebral fracture, reducing bone-turnover biomarkers, and increasing BMD. Nine RCTs were included and the total number of participants was 2464. Compared with placebo, the efficacy of bisphosphonates on vertebral and non-vertebral fracture risk reduction was confirmed [for vertebral fracture, RR (95 % CI) 0.36 (0.24, 0.56), P bisphosphonates on reducing BSAP [MD (95 % CI) -24.41 (-26.19, -22.62), P bisphosphonates group compared with the control group at lumbar spine, femoral neck, and total hip (P bisphosphonates could decrease the risk of vertebral and non-vertebral fractures, reduce BSAP and CTX, and increase BMD in men with osteoporosis.

  5. Risk of atrial fibrillation with use of oral and intravenous bisphosphonates.

    Science.gov (United States)

    Sharma, Abhishek; Einstein, Andrew J; Vallakati, Ajay; Arbab-Zadeh, Armin; Walker, Marcella Donovan; Mukherjee, Debabrata; Homel, Peter; Borer, Jeffrey S; Lichstein, Edgar

    2014-06-01

    Clinical studies suggest an association between bisphosphonate use and new-onset atrial fibrillation (AF). Intravenous bisphosphonates more potently increase the release of inflammatory cytokines than do oral bisphosphonates; thus, the risk of developing AF may be greater with intravenous preparations. We have evaluated incidence of new-onset AF with use of oral and intravenous bisphosphonates through a systematic review and meta-analysis of the literature. We searched PubMed, CINAHL, Cochrane Central Register of Controlled Trials, Scopus, and EMBASE databases for observational studies and randomized controlled trials (RCTs) published from 1966 to April 2013 that reported the number of patients developing AF with use of oral or intravenous bisphosphonates. The random-effects Mantel-Haenszel test was used to evaluate the relative risk of AF with use of oral and intravenous bisphosphonates. Nine studies (5 RCTs and 4 observational studies) were included in the final analysis. Pooled data from RCTs and observational studies (n = 135,347) showed a statistically significantly increased risk of new-onset AF with both intravenous (relative risk 1.40, 95% confidence interval 1.32 to 1.49) and oral (relative risk 1.22, 95% confidence interval 1.14 to 1.31) bisphosphonates. The z statistic, which assesses the difference between the 2 risk ratios, indicated higher risk of AF with intravenous bisphosphonates versus oral bisphosphonates (p = 0.03). In conclusion, pooled data from RCTs and observational studies suggest that risk of AF is increased by use of oral or intravenous bisphosphonates but further suggest that risk is relatively greater with intravenous preparations. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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

  7. Proximal femoral reconstruction for failed internal fixation of a bisphosphonate-related femur fracture

    Directory of Open Access Journals (Sweden)

    Rishabh G. Jethanandani, BSE

    2016-12-01

    Full Text Available We present a case of a bisphosphonate-related femur fracture in an elderly woman, who failed treatment with both cephalomedullary nail and proximal femoral locking plate, leading to successful treatment with total hip arthroplasty. Hardware failure should be included in the differential of patients with previous internal fixation of bisphosphonate-related femur fracture that present with hip or groin pain. Arthroplasty can be an acceptable salvage option in an active elderly patient with a bisphosphonate-related femur fracture.

  8. Bisphosphonates and their clinical implications in endodontic therapy

    NARCIS (Netherlands)

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

    2013-01-01

    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

  9. Concept, diagnosis and classification of bisphosphonate-associated osteonecrosis of the jaws. A review of the literature.

    Science.gov (United States)

    Gavaldá, C; Bagán, J-V

    2016-05-01

    Bisphosphonates (BPs) and other antiresorptive agents such as denosumab are widely prescribed for the treatment of osteoporosis and are also used in patients with multiple myeloma and metastatic breast or prostate cancer for avoiding bone reabsorption and fractures that result in increased morbidity-mortality among such individuals. We made a bibliographic search to analyze the concept, diagnosis and the different classifications for bisphosphonate-associated osteonecrosis of the jaws. Osteonecrosis of the jaws (ONJ) is an important complication of exposure to BPs or other antiresorptive agents, and although its prevalence is low, it can pose management problems. The definition, diagnosis and classification of osteonecrosis have evolved since Marx reported the first cases in 2003. The present study offers a literature review and update on the existing diagnostic methods and classification of the disorder, with a view to facilitating earlier and more effective treatment.

  10. Bisphosphonate and Implant Dentistry - Is it Safe?

    Science.gov (United States)

    Thirunavukarasu, Ananthi; Pinto, Hugo Grancho; Seymour, Kevin Guy

    2015-08-01

    Bisphosphonates are a group of drugs that are commonly used to alter bone metabolism in order to prevent bone loss in diseases such as osteoporosis and bone cancers. Unfortunately, the use of bisphosphonates has been associated with bisphosphonate-related osteonecrosis of the jaws. The debate as to whether it is wise to consider implant therapy in patients being treated with bisphosphonate therapy remains a grey area. This review will present the latest evidence and guidelines available on bisphosphonates and their possible effects on implant dentistry. The risk factors, co-morbidities, clinical presentation and findings from various imaging modalities for bisphosphonate-related osteonecrosis of the jaws are highlighted. The management of patients being treated with bisphosphonates, in whom dental implants might be considered or have already been placed, will also be discussed. Finally, the areas requiring future research are considered.

  11. Do bisphosphonates affect bone healing? A meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Xue, Deting; Li, Fangcai; Chen, Gang; Yan, Shigui; Pan, Zhijun

    2014-06-05

    Whether bisphosphonates affect indirect bone healing is still unclear. We carried out a comprehensive search strategy. Only randomized controlled trials were included. Two reviewers independently assessed methodological qualities and extracted outcome data. Analysis was performed with RevMan 5.2. Eight eligible randomized controlled trials with 2,508 patients were included. Meta-analysis results showed that no statistically significant differences were founded in indirect bone healing in short time (within 3 months) (relative risk (RR) 1.40, relative the control group; 95% CI 0.36 to 5.49) and in long-term (more than 12 months) postoperation (RR 1.0; 95% CI 0.98 to 1.02) between bisphosphonates infusion groups and control groups. There were no statistically significant differences of indirect bone healing between early and delay bisphosphonates administration groups. Bisphosphonates infusion after lumbar infusion surgery could promote bone healing and shorten fusion time in 6 months postoperation (RR 1.35; 95% CI 1.11 to 1.66). There was no clinically detectable delay to fracture healing via external callus formation following bisphosphonates treatment. Considering the benefit aspects of bisphosphonates for osteoporosis treatment, we recommend bisphosphonates infusion after fracture fixation surgery and lumbar fusion surgery.

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

    Directory of Open Access Journals (Sweden)

    Marco Antonio T. Martins

    2009-02-01

    Full Text Available Os bisfosfonatos são um grupo de medicamentos utilizados no tratamento de doenças malignas metastáticas e em outras doenças ósseas como osteoporose e doença de Paget. A despeito dos seus benefícios, uma importante complicação denominada de osteonecrose dos maxilares vem sendo observada nos pacientes usuários crônicos dos bisfosfonatos que se caracteriza clinicamente por exposições ósseas na região maxilofacial persistente, acompanhadas de osteomielite, geralmente sintomáticas e cujo tratamento é complexo. Este estudo tem por objetivo revisar a literatura sobre a osteonecrose associada ao uso dos bisfosfonatos, em especial, em oncologia, no período de 2003 a 2008. Serão apresentados e discutidos os fatores de risco, aspectos etiopatogênicos, clínicos, imagenológicos, terapêuticos e preventivos desta doença. Devido à dificuldade de tratamento da osteonecrose associada aos bisfosfonatos, o foco deve ser a prevenção, sendo o ideal a eliminação de quadros infecciosos orais antes da terapia com os bisfosfonatos ter sido iniciada e minimizar traumas em boca após o uso destes medicamentos.Bisphosphonates are drugs used in the treatment of malignant metastatic diseases and in other bone lesions such as osteoporosis and Paget´s disease. Besides their benefits, jaw osteonecrosis, an important side effect, has been observed in long-term users of these drugs. Jaw osteonecrosis is clinically characterized by prolonged maxillary and mandible bone exposure accompanied by osteomyelitis. These lesions are usually symptomatic and difficult to treat. This study has the objective of reviewing publications from 2003 to 2008 about bisphosphonate-associated jaw osteonecrosis, in particular in relation to oncology. Risk factors, and etiopathological, clinical, radiographic, therapeutic, and preventive aspects of this condition are presented and discussed. Due to the difficulty to treat this disease, the focus must be prevention, with the

  13. 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.

  14. Identification of material parameters based on Mohr-Coulomb failure criterion for bisphosphonate treated canine vertebral cancellous bone.

    Science.gov (United States)

    Wang, Xiang; Allen, Matthew R; Burr, David B; Lavernia, Enrique J; Jeremić, Boris; Fyhrie, David P

    2008-10-01

    Nanoindentation has been widely used to study bone tissue mechanical properties. The common method and equations for analyzing nanoindentation, developed by Oliver and Pharr, are based on the assumption that the material is linearly elastic. In the present study, we adjusted the constraint of linearly elastic behavior and use nonlinear finite element analysis to determine the change in cancellous bone material properties caused by bisphosphonate treatment, based on an isotropic form of the Mohr-Coulomb failure model. Thirty-three canine lumbar vertebrae were used in this study. The dogs were treated daily for 1 year with oral doses of alendronate, risedronate, or saline vehicle at doses consistent, on a mg/kg basis, to those used clinically for the treatment of post-menopausal osteoporosis. Two sets of elastic modulus and hardness values were calculated for each specimen using the Continuous Stiffness Measurement (CSM) method (E(CSM) and H(CSM)) from the loading segment and the Oliver-Pharr method (E(O-P) and H(O-P)) from the unloading segment, respectively. Young's modulus (E(FE)), cohesion (c), and friction angle (phi) were identified using a finite element model for each nanoindentation. The bone material properties were compared among groups and between methods for property identification. Bisphosphonate treatment had a significant effect on several of the material parameters. In particular, Oliver-Pharr hardness was larger for both the risedronate- and alendronate-treated groups compared to vehicle and the Mohr-Coulomb cohesion was larger for the risedronate-treated compared to vehicle. This result suggests that bisphosphonate treatment increases the hardness and shear strength of bone tissue. Shear strength was linearly predicted by modulus and hardness measured by the Oliver-Pharr method (r(2)=0.99). These results show that bisphosphonate-induced changes in Mohr-Coulomb material properties, including tissue shear cohesive strength, can be accurately

  15. Evidence on the analgesic role of bisphosphonates and denosumab in the treatment of pain due to bone metastases: A systematic review within the European Association for Palliative Care guidelines project.

    Science.gov (United States)

    Porta-Sales, Josep; Garzón-Rodríguez, Cristina; Llorens-Torromé, Silvia; Brunelli, Cinzia; Pigni, Alessandra; Caraceni, Augusto

    2017-01-01

    Bisphosphonates and denosumab are well-established therapies to reduce the frequency and severity of skeletal-related events in patients with bone metastasis. However, the analgesic effect of these medications on bone pain is uncertain. To identify, critically appraise and synthesize existing evidence to answer the following questions: 'In adult patients with metastatic bone pain, what is the evidence that bisphosphonates and denosumab are effective and safe in controlling pain?' and 'What is the most appropriate schedule of bisphosphonate/denosumab administration to control bone pain?'. This review also updates the 2002 Cochrane review 'Bisphosphonates for the relief of pain secondary to bone metastases'. Standard systematic review and narrative synthesis. MEDLINE, EMBASE and Cochrane CENTRAL databases were searched for relevant articles published through 31 January 2014. A manual search was also performed. Study inclusion criteria were: a) conducted in adult patients; b) randomized controlled trial or meta-analisys; c) reported efficacy of bisphosphonates or denosumab on pain and/or decribed side effects versus placebo or other bisphosphonate; and d) English language. The database search yielded 1585 studies, of which 43 (enrolling 8595 and 7590 patients, respectively, in bisphosphonate and denosumab trials) met the inclusion criteria. Twenty-two (79%) of the 28 placebo-controlled trials found no analgesic benefit for bisphosphonates. None of the denosumab studies assessed direct pain relief. Evidence to support an analgesic role for bisphosphonates and denosumab is weak. Bisphosphonates and denosumab appear to be beneficial in preventing pain by delaying the onset of bone pain rather than by producing an analgesic effect per se.

  16. 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

  17. Osteomyelitis Treatment with Nanometer-Sized Hydroxyapatite Particles as a Delivery Vehicle for a Ciprofloxacin- Bisphosphonate Conjugate; New Fluoroquinolone-Bisphosphonate Derivatives Show Similar Binding Affinity to Hydroxyapatite and Improved Antibacterial Activity Against Drug-Resistant Pathogens

    Science.gov (United States)

    2008-12-01

    the collagen-gentamicin sponge (Stemberger et al., 1997). Since then, CP and hydroxyapatite (HA) carriers have been added, and successfully used...performance against drug-resistant microorganisms of clinical interest such as MRSA and A. baumannii. Further study of this E43 is necessary to determine...H., Bader, F., Rahn, H., Ascherl, R., 1997: Local treatment of bone and soft tissue infections with the collagen-gentamicin sponge , Eur. J. Surg

  18. Liquid chromatography-mass spectrometry analysis of five bisphosphonates in equine urine and plasma.

    Science.gov (United States)

    Wong, April S Y; Ho, Emmie N M; Wan, Terence S M; Lam, Kenneth K H; Stewart, Brian D

    2015-08-15

    Bisphosphonates are used in the management of skeletal disorder in humans and horses, with tiludronic acid being the first licensed veterinary medicine in the treatment of lameness associated with degenerative joint disease. Bisphosphonates are prohibited in horseracing according to Article 6 of the International Agreement on Breeding, Racing and Wagering (published by the International Federation of Horseracing Authorities). In order to control the use of bisphosphonates in equine sports, an effective method to detect the use of bisphosphonates is required. Bisphosphonates are difficult-to-detect drugs due to their hydrophilic properties. The complexity of equine matrices also added to their extraction difficulties. This study describes a method for the simultaneous detection of five bisphosphonates, namely alendronic acid, clodronic acid, ibandronic acid, risedronic acid and tiludronic acid, in equine urine and plasma. Bisphosphonates were first isolated from the sample matrices by solid-phase extractions, followed by methylation with trimethylsilyldiazomethane prior to liquid chromatography - tandem mass spectrometry analysis using selective reaction monitoring in the positive electrospray ionization mode. The five bisphosphonates could be detected at low ppb levels in 0.5mL equine plasma or urine with acceptable precision, fast instrumental turnaround time, and negligible matrix interferences. The method has also been applied to the excretion study of tiludronic acid in plasma and urine collected from a horse having been administered a single dose of tiludronic acid. The applicability and effectiveness of the method was demonstrated by the successful detection and confirmation of the presence of tiludronic acid in an overseas equine urine sample. To our knowledge, this is the first reported method in the successful screening and confirmation of five amino- and non-amino bisphosphonates in equine biological samples. Copyright © 2015 Elsevier B.V. All rights

  19. ATYPICAL FEMORAL FRACTURES AFTER LONG-TERM BISPHOSPHONATES THERAPY: CASE REPORT.

    Science.gov (United States)

    Găleşanu, Corina; Mocanu, Veronica; Buzdugă, C; Florescu, A; Zaharia, V; Lisnic, V

    2016-01-01

    We present a 77-year-old woman with no histor of trauma, or associated with low-energy trauma, admitted to our clinic after three weeks of a left femoral fracture threated in Orthopedic Clinic. The patient was in treatment with bisphosphonates over 10 years for osteoporosis. The causal re lationship between prolonged bisphosphonate use and the occurrence of atypical femora fractures (AFF) has not yet been established. For the patient at high risk of fracture, it may be beneficial to continue bisphosphonate treatment beyond five years. The absolute risk of atypical femoral fractures is low (about 100 cases per 100,000 person-years among long term users). For most people with osteoporosis, the proven fragility-fracture risk-reduction. benefits of bisphosphonates outweigh the risks of AFF.

  20. The role of bisphosphonates in breast cancer: Development of bisphosphonates

    Science.gov (United States)

    Fleisch, Herbert

    2002-01-01

    Bisphosphonates are synthetic compounds characterized by a P–C–P group, and are thus analogs of inorganic pyrophosphate. They are used in medicine mainly to inhibit bone resorption in diseases like osteoporosis, Paget's disease and tumor bone disease. They have been used for over a century in industry, and only in 1968 was it shown that bisphosphonates have biological effects. These effects consist mainly of an inhibition of bone resorption and, when given in large amounts, an inhibition of ectopic and normal calcification. While the latter effect is the consequence of a physical-chemical inhibition of calcium phosphate crystal formation, the former is due to a cellular effect involving both apoptosis of the osteoclasts and a destruction of the osteoclastic cytoskeleton, inducing a decrease in osteoclast activity. The biochemical basis of these effects for the nitrogen-containing compounds is an inhibition of the mevalonate pathway caused by the inhibition of farnesylpyrophosphate synthase, which leads to a decrease of the formation of isoprenoid lipids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. The other bisphosphonates are incorporated into the phosphate chain of ATP-containing compounds so that they become non-hydrolyzable. The new P–C–P-containing ATP analogs inhibit cell function and may lead to apoptosis and death of osteoclasts. PMID:11879557

  1. Bisphosphonate induced osteonecrosis of jaw in breast cancer patients: A systematic review

    OpenAIRE

    Varun, BR; Sivakumar, TT; Nair, Bindu J; Joseph, Anna P

    2012-01-01

    Background: Bisphosphonate therapy is widely used for the treatment of bone metastasis in breast cancer patients. Aim: The aim of this study is to estimate the overall prevalence of bisphosphonate induced osteonecrosis of jaw (BONJ) in breast cancer patients with bone metastasis. Materials and Methods: A literature review was conducted to search and evaluate all the articles that contained original data on the prevalence of BONJ in breast cancer patients from the year 2003-2009. Pubmed search...

  2. 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......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 bisphosphonates used for osteoporosis....

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

    Science.gov (United States)

    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.

  4. Osteonecrosis of the jaw and bisphosphonate use in breast cancer patients.

    Science.gov (United States)

    Kyrgidis, Athanassios; Triaridis, Stefanos; Vahtsevanos, Kostantinos; Antoniades, Kostantinos

    2009-08-01

    It is renowned that breast cancer patients suffer from a number of cancer-related skeletal events, while drugs recently added to the practitioners' quiver, such as aromatase inhibitors, intensify the need to preserve bone mass in this group of patients. Bisphosphonates are potent inhibitors of both normal and pathologic bone resorption. Besides their apoptotic and antiproliferative activity on osteoclasts, bisphosphonates can also exert various effects on macrophages, keratinocytes and fibroblasts. Bisphosphonate-related osteonecrosis of the jaw is a complication that emerged after broad clinical use of bisphosphonates, and which has not yet been adequately described in a clinical trial setting. The purpose of this review is to critically reflect the incidence, etiopathogenesis, prevention and treatment of osteonecrosis of the jaw. Succinct suggestions are provided to ensure clinicians prevent and detect the complications early.

  5. 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.

  6. Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid.

    Science.gov (United States)

    Brown, Janet E; Ellis, Susan P; Lester, James E; Gutcher, Sandra; Khanna, Tina; Purohit, Om-Prakesh; McCloskey, Eugene; Coleman, Robert E

    2007-09-15

    Bisphosphonates play a central role in the management of bone loss due to a range of disorders, including metastatic bone disease, cancer treatment-induced bone loss, and postmenopausal osteoporosis. With potent bisphosphonates, such as zoledronic acid, it may be possible to maintain efficacy with relatively infrequent administration. Sixty-six patients who were osteopenic at >1 year following curative cancer therapy received a single i.v. 4 mg dose of the bisphosphonate zoledronic acid. Bone mineral density (BMD) was measured using double-beam X-ray absorptiometry scan and the bone resorption marker N-telopeptide of type II collagen was determined using a chemiluminescence ELISA assay. The single dose of zoledronic acid induced mean increases in bone BMD at the lumbar spine of 3.1%, 5.2%, and 5.3% and at the total hip of 2.7%, 3.5%, and 4.3% after 12, 24, and 36 months of follow-up, respectively (P < 0.001 at all time points). By 36 months, 84% of patients had achieved increase in BMD at the spine and 90% at the hip. The mean percentage decrease in the bone resorption marker N-telopeptide was approximately 58% at 6 weeks and 42%, 33%, and 31% at 12, 24, and 36 months, respectively (P < 0.001). A single dose of zoledronic acid in patients with low BMD results in a sustained increase in BMD and a corresponding decrease in bone resorption. Very infrequent administration of zoledronic acid may have clinical benefits in terms of convenience, reduced toxicity, improved compliance, and cost.

  7. Bilateral distal fibula fractures in a woman on long-term bisphosphonate therapy.

    Science.gov (United States)

    Murray, J C; Audet, M C; Bédard, M; Michou, L

    2016-02-01

    We report the case of a 53-year-old female, treated by bisphosphonate for 12 years, who presented atraumatic fractures of both fibulas. Her X-rays showed bilateral distal fibula fractures with radiological features similar to atypical femur fractures. The distal fibula should be considered as a potential site for stress fractures in bisphosphonate users. Bisphosphonates are the most widely used drugs in the treatment of osteoporosis. During the last decade, the occurrence of atypical fractures, mostly subtrochanteric and diaphyseal femoral fractures, has been acknowledged in patients with long-term use of bisphosphonates. We report the case of a 53-year-old female on alendronate therapy for the past 12 years who presented with a few months history of atraumatic right, and subsequently left, lateral ankle pain. Her X-rays showed bilateral distal fibula fractures with radiological features similar to atypical femur fractures. She had been treated conservatively with walking boots and her treatment with bisphosphonate had been stopped 5 months prior to the fractures. Callus was progressively seen on serial follow-up X-rays, and both fractures healed completely within a reasonable period of 1 year. Investigations did not reveal any secondary causes of osteoporosis or metabolic bone disorders. To our knowledge, this is the first reported case of bilateral distal fibula fractures in a patient on long-term bisphosphonate therapy.

  8. Atypical femoral fractures related to bisphosphonate therapy

    Directory of Open Access Journals (Sweden)

    Tarun Pankaj Jain

    2012-01-01

    Full Text Available Bisphosphonates (BP are a commonly prescribed class of drugs for the prevention of osteoporosis-related fractures. Paradoxically, however, they have recently been linked to atypical fractures in the shaft of the femur. Since many physicians including radiologists, are not aware of this entity, the incidence is likely underreported. These fractures usually occur in the sub-trochanteric region of the femur in the setting of low-energy trauma. It starts as a fracture line involving the lateral cortex and then progresses medially to give rise to a complete fracture. The fracture line is usually transverse, and there is a medial spike associated with a complete fracture. These fractures can be bilateral. Awareness of these atypical fractures and their radiological appearance should enable their early and accurate detection and thus lead to specific treatment.

  9. 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.

  10. The cell cycle arrest and the anti-invasive effects of nitrogen-containing bisphosphonates are not mediated by DBF4 in breast cancer cells.

    Science.gov (United States)

    Mansouri, Mahdieh; Mirzaei, Seyed Abbas; Lage, Hermann; Mousavi, Seyyedeh Soghra; Elahian, Fatemeh

    2014-04-01

    Recent work has shown that a DBF4 analog in yeast may be a target of nitrogen-containing bisphosphonates. DBF4 is an essential protein kinase required for DNA replication from primary eukaryotes to humans and appears to play a critical role in the S-phase checkpoint. It is also required for cell migration and cell surface adhesion. The effects of Pamidronate, risedronate, or zoledronate on cell viability and DBF4 expression were measured via MTT assays and western blotting. In addition, FACS cell cycle analyses and invasion assays were conducted in cells in the presence of nitrogen-containing bisphosphonates to identify any correlations between DBF4 expression and S-phase arrest or anti-invasive effects of the bisphosphonates. Zoledronate transiently down-regulated DBF4 expression in all three cell lines in the first 24 h of the experiment, but after 72 h, DBF4 expression returned to the control levels in all treated cells. Following treatment of the tumor cells with the bisphosphonates, the number of cells in S-phase was increased. Pamidronate and zoledronate showed anti-invasive effects in BT20 cells. The anti-invasive effects of pamidronate, risedronate and zoledronate appeared after 48 h of exposure. In MDA-MB231 cells a reduction of invasiveness was only observed after 72 h of the pamidronate exposure. We finally concluded that the anti-invasive and cell cycle arrest-inducing effects of nitrogen-containing bisphosphonates are not DBF4 mediated, and other mediators are therefore needed to explain the observed complex behaviors. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  11. Long-term follow-up of jaw osteomyelitis associated with bisphosphonate use in a tertiary-care center.

    Science.gov (United States)

    Pigrau-Serrallach, Carlos; Cabral-Galeano, Evelyn; Almirante-Gragera, Benito; Sordé-Masip, Roger; Rodriguez-Pardo, Dolors; Fernandez-Hidalgo, Nuria; Larrosa-Escartín, Nieves; Bescos-Atín, Socorro; Pahissa-Berga, Albert

    2014-01-01

    This study reviews our experience in bisphosphonate-associated jaw osteomyelitis (BJOM), focusing on the incidence, etiology, treatment, and long-term outcome. Retrospective review of the clinical histories adult patients diagnosed with BJOM (1995-2008) in a tertiary hospital. BJOM was found in 30 of 132 (22.7%) consecutive patients with jaw osteomyelitis. The percentage of BJOM cases increased from 8.7% (4/46) in 1995-2005 to 30.2% (26/86) in 2005-2008. Symptoms appeared in a median of 2.5 years after intravenous use, and 4.5 years after oral exposure. Viridans group streptococci were isolated in 83.3% of cases. Actinomyces spp. was found in 16 (39.0%) of 41 bone histologies. All included patients received a median of 6 months of appropiate antibiotic therapy and a surgical procedure (debridament and/or sequestrectomy). Thirteen of 27 cases (48.1%) with long-term follow-up (median 22 months, IQR 25-75 17-28) failed. Clinical failure defined as, persistent infection or relapse, was more frequent in patients receiving intravenous than oral bisphosphonates (11/16 [68.8%] vs. 2/11 [18.2%]; P < .05) and in cases with Actinomyces spp. (7/10 [70.0%] vs6/17 [35.3%]; P = .08). Bisphosphonate therapy is now a frequent cause of JO. BJOM is difficult to cure and relapses are common, particularly in patients exposed to intravenous bisphosphonates. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  12. Novel actions of bisphosphonates in bone: Preservation of osteoblast and osteocyte viability

    Science.gov (United States)

    Bellido, Teresita; Plotkin, Lilian I.

    2010-01-01

    Bisphosphonates stop bone loss by inhibiting the activity of bone resorbing osteoclasts. However, the effect of bisphosphonates on bone mass cannot completely explain the reduction in fracture incidence observed in patients treated with these agents. Recent research efforts provided an explanation to this dichotomy by demonstrating that part of the beneficial effect of bisphosphonates on the skeleton is due to prevention of osteoblast and osteocyte apoptosis. Work of our group, independently confirmed by other investigators, demonstrated that bisphosphonates are able to prevent osteoblast and osteocyte apoptosis in vitro and in vivo. This pro-survival effect is strictly dependent on the expression of connexin (Cx)43, as demonstrated in vitro using cells lacking Cx43 or expressing dominant negative mutants of the protein as well as in vivo using Cx43 osteoblast/osteocyte-specific conditional knock-out mice. Remarkably, this Cx43-dependent survival effect of bisphosphonates is independent of gap junctions and results from opening of Cx43 hemichannels. Hemichannel opening leads to activation of the kinases Src and extracellular signal-regulated kinases (ERKs), followed by phosphorylation of the ERK cytoplasmic target p90RSK kinase and its substrates BAD and C/EBPβ, resulting in inhibition of apoptosis. The anti-apoptotic effect of bisphosphonates is separate from the effect of the drugs on osteoclasts, as analogs that lack anti-resorptive activity are still able to inhibit osteoblast and osteocyte apoptosis in vitro. Furthermore, a bisphosphonate analog that does not inhibit osteoclast activity prevented osteoblast and osteocyte apoptosis and the loss of bone mass and strength induced by glucocorticoids in mice. Preservation of the bone forming function of mature osteoblasts and maintenance of the osteocytic network, in combination with lack anti-catabolic actions, open new therapeutic possibilities for bisphosphonates in the treatment of osteopenic conditions in

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

    DEFF Research Database (Denmark)

    Pazianas, Michael; Clark, Emma M; Eiken, Pia Agnete

    2013-01-01

    Ocular inflammatory reactions have been described in patients on bisphosphonate treatment. We estimated the incidence rate of ocular inflammation at 3 and 12 months in patients treated for osteoporosis using a register based cohort linked to prescription data (hospitals and private practice......) and hospital data. Between Jan 1, 1997 and Dec 31, 2007, a total of 88,202 patients beginning osteoporosis therapy were identified. Of those patients, 82,404 (93%) began oral bisphosphonates and 5798 (7%) non-bisphosphonates. Topical eye steroids (TES) Within the first year of treatment, 4,769 (5...

  14. Bisphosphonates and pathologic complete response to taxane and anthracycline-based neoadjuvant chemotherapy in patients with breast cancer

    Science.gov (United States)

    Chavez-MacGregor, Mariana; Brown, Erika; Lei, Xiudong; Litton, Jennifer; Meric-Bernstram, Funda; Mettendorf, Elizabeth; Hernandez, Leonel; Valero, Vicente; Hortobagyi, Gabriel N.; Gonzalez-Angulo, Ana Maria

    2011-01-01

    Purpose Several studies have suggested that bisphosphonates have an antitumor effect. We sought to evaluate whether the use of bisphosphonates increased the rates of pathological complete response (pCR) in breast cancer patients. Methods We identified 1449 breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy between 1995 and 2007 at M.D. Anderson Cancer Center. We also identified those patients that while receiving chemotherapy received bisphosphonates for osteopenia or osteoporosis. Primary outcome was the proportion of patients achieving a pCR. Groups were compared using the chi-squared test. A multivariable logistic regression model was fit to examine the relationship between the use of bisphosphonates and pCR. An exploratory survival analysis using the Kaplan-Meier method was performed; groups were compared using the log-rank test. Results From the 1449 patients included, 39 (2.7%) received bisphosphonates. Those receiving bisphosphonates were older (pbisphosphonate group and 16% in the non-bisphosphonate group (p=.11). In the multivariable model, patients treated with bisphosphonates tended to have higher rates of pCR (OR 2.18; 95%CI 0.90–5.24); however the difference was not statistically significant. With a median follow up of 55 months (3–145), no differences in recurrence or in survival were observed. Conclusions The use of bisphosphonates at the time of neoadjuvant chemotherapy was not associated with a statistically significant increase in the rates of pCR. The observed estimates suggest a positive effect; however, the small proportion of patients receiving bisphosphonates likely affected the power to detect a statistically significant difference. PMID:21590688

  15. The effects of bisphosphonate on the remodeling of different irregular bones in mice.

    Science.gov (United States)

    Su, Jiansheng; Feng, Mu; Han, Wenfei; Zhao, Hang

    2015-09-01

    We aimed to compare the effects of bisphosphonate on the remodeling of irregular bones (the jaw and ilium) in mice after trauma. To verify the feasibility of modeling osteonecrosis, 20 mice were injected intraperitoneally with zoledronate and dexamethasone (ZOL&DEX group), dexamethasone (DEX group), or phosphate-buffered saline (PBS) [control (CTR) group]. Mice then underwent extraction of the right maxillary first molar and creation of an artificial bony cavity in the ilium. Bone sections were stained with H&E for morphological studies. To further compare differences between the maxilla and the ilium caused by similar traumas, 80 mice were injected intraperitoneally with ZOL&DEX or PBS. Pathological progression at the injury sites was assessed at 1 day and at 1, 3, and 8 weeks after trauma using micro-computed tomography (CT), H&E and immunohistochemistry analyses, high-performance liquid chromatography-mass spectrometry, and enzyme-linked immunosorbent assay. Only the ZOL&DEX model group effectively developed osteonecrosis. Bony sequestra, osseous sclerosis, unhealed mucosa, and radiopaque alveolar bone were found in the maxilla. In the ilium, there was a lower frequency of osteonecrotic disease and osseous sclerosis, and less suppression of bone remodeling than in the maxilla following long-term bisphosphonate administration. Zoledronate levels were higher in the maxilla. ZOL&DEX treatment suppressed the levels of RANKL and IL-17, but induced an upregulation of osteoprotegerin and FAM20C in both bones. Accumulation of bisphosphonate may increase the incidence of osteonecrosis. The RANKL/OPG pathway and IL-17 and FAM20C cytokines play key roles in the progression of pathologically abnormal bone remodeling. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Uptake of free, calcium-bound and liposomal encapsulated nitrogen containing bisphosphonates by breast cancer cells.

    Science.gov (United States)

    Zlatev, Hristo P; Auriola, Seppo; Mönkkönen, Jukka; Määttä, Jorma A

    2016-04-30

    We have examined the uptake routes by which breast cancer cells internalize different formulations of nitrogen containing bisphosphonates (N-BPs). Cell viability was assessed with the tetrazolium colorimetric test (MTT assay) after treatment with different N-BP formulations in the presence or absence of inhibitors for different endocytosis mechanisms. Intracellular formation of isopentenyl pyrophosphate (IPP) and triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (ApppI), were quantified with mass spectrometry (ES-LTQ-MS) as surrogate markers for N-BP efficacy. Direct quantification intracellular [(14)C]-labeled zoledronic acid was done with liquid scintillation counting. The main uptake route for all the different formulations of nitrogen containing bisphosphonates was shown to be dynamin dependent endocytosis, which was significantly enhanced with calcium. This uptake mechanism was mostly caveolin and clathrin independent in MCF7 cells, but more clathrin dependent in T47D cells. Liposome encapsulation of the drug shifted the uptake mechanism to be more dependent on caveolin in both the cell lines. The cytotoxicity of N-BPs and the concentrations of formed intracellular ApppI and IPP were significantly increased by calcium chelation and liposome encapsulation, the latter being the most potent formulation. Nitrogen containing bisphosphonates require active endocytosis for cellular uptake and in the breast cancer cells the mechanism is uniformly dynamin dependent for all the formulations tested. This differs e.g. from the previous observations on macrophages, which mostly utilize macropinocytosis. Liposomal formulation was found to prolong the duration of the drug effect in cells. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Cost-effectiveness of bisphosphonates for prevention of fracture related to glucocorticoid-induced osteoporosis in Malaysia.

    Science.gov (United States)

    Mohd-Tahir, Nurul-Ain; Thomas, Paraidathathu; Mohamed-Said, Mohd-Shahrir; Makmor-Bakry, Mohd; Li, Shu-Chuen

    2018-03-01

    Glucocorticoid therapy is associated with an appreciable risk of bone loss leading to fractures that require expensive treatments. This study aimed to evaluate the cost-effectiveness of bisphosphonates for prevention of hip fracture in glucocorticoid-induced osteoporosis (GIOP) in Malaysia. Retrospective data were collected from GIOP patients referred to the Universiti Kebangsaan Malaysia Medical Centre. Fracture events and direct medical costs were compared between bisphosphonates and calcium/vitamin D combination. Fracture events were reported in 28 out of 93 included patients, with hip and vertebral fractures representing 42.9% and 35.7%, respectively. Overall, the use of bisphosphonates could not be considered cost-effective for treatment of all GIOP patients. The presence of certain fracture risk factors was able to modify the cost-effectiveness of bisphosphonates. Bisphosphonates was considered cost-effective if started in patients more than 60 years old. However, the use of bisphosphonates was not cost-effective in GIOP patients with secondary osteoporosis. The incremental cost-effectiveness ratios (ICER) of bisphosphonates in patients with risk factors of previous fracture or rheumatoid arthritis were Malaysian Ringgits (MYR) 108 603.40 and MYR 25 699.21, respectively. Fracture risk factors of age, previous fracture, rheumatoid arthritis and secondary osteoporosis may modify the cost-effectiveness outcomes of bisphosphonates. Bisphosphonates would be considered cost-effective in patients more than 60 years old as compared to calcium/vitamin D treatments. Further evaluation of the impact of fracture risk factors in larger populations would provide more precise information to better assist rational and economical use of anti-osteoporosis treatment in GIOP patients. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  18. Carpal Tunnel Syndrome Associated with Oral Bisphosphonates. A Population-Based Cohort Study.

    Science.gov (United States)

    Carvajal, Alfonso; Martín Arias, Luis H; Sáinz, María; Escudero, Antonio; Fierro, Inmaculada; Sauzet, Odile; Cornelius, Victoria R; Molokhia, Mariam

    2016-01-01

    Bisphosphonates are widely used to prevent osteoporotic fractures. Some severe musculoskeletal reactions have been described with this medication; among them, some cases of carpal tunnel syndrome. Thus, the aim of this study was to explore whether bisphosphonates may be associated with this syndrome. A cohort study was conducted to compare exposed to unexposed women; the exposed group was that composed of women having received at least one prescription of an oral bisphosphonate. For the purpose, we used information from The Health Improvement Network (THIN) database. The outcome of interest was defined as those women diagnosed with carpal tunnel syndrome. A survival analysis was performed; the Cox proportional hazard model was used to calculate hazard ratios and 95% confidence intervals, and to adjust for identified confounding variables. Out of a sample of 59,475 women older than 51 years, 19,825 were treated with bisphosphonates during the period studied. No differences in age distribution or mean follow-up time were observed between the two groups in comparison. Overall, there were 572 women diagnosed with carpal tunnel syndrome, 242 (1.2%) in the group exposed to bisphosphonates, and 330 (0.8%) in the unexposed. An adjusted hazard ratio of developing carpal tunnel syndrome of 1.38 (95%CI, 1.15-1.64) was found for women exposed to bisphosphonates; no significant changes in the hazard ratios were found when considering different levels of bisphosphonate exposure. An increased risk of carpal tunnel syndrome is associated with the use of bisphosphonates in postmenopausal women.

  19. Osteoporosis and bisphosphonate-related osteonecrosis of the jaw bone.

    Science.gov (United States)

    Villa, Alessandro; Castiglioni, Stefano; Peretti, Alessandro; Omodei, Marco; Ferrieri, Giovanni B; Abati, Silvio

    2011-01-01

    The aim of this longitudinal study is to present data from 76 female patients treated with bisphosphonates (BPs) for postmenopausal osteoporosis and referred to the Unit of Oral Diagnosis and Day Surgery of the University of Milano for diagnosis and treatment. All patients received a thorough oral examination. The diagnosis of osteonecrosis of the jaw bone (ONJ) was made from radiographic and clinical findings. 9% of individuals had BRONJ at first visit. Patients with dental or periodontal abscess were significantly more likely to develop BRONJ (OR: 2.9, 95% CI 0.5-15.9). Patients with osteoporosis receiving BPs may develop BRONJ, especially in the presence of an active infectious process in the mouth. Clinicians should carefully follow up on individuals receiving bisphosphonates therapy to avoid the occurrence of osteonecrotic lesions.

  20. Patterns of bisphosphonates utilization in patients under age 45 in a large cohort of commercial insurance beneficiaries in the United States.

    Science.gov (United States)

    Xie, Jing; Tong, Angela; Kim, Seoyoung C

    2015-01-01

    The effectiveness and safety of bisphosphonates treatment used in the young population have not been well studied. Despite insufficient data on effectiveness and safety of bisphosphonates in young patients, bisphosphonates are still considered in younger patients at high risk for osteoporosis or fracture. The objectives of this study were to identify bisphosphonate initiators aged 10-45 years and describe their clinical characteristics and to assess time trends of bisphosphonate use over the past decade in a large U.S. population-based cohort. Using the medical and pharmacy claims data from a U.S. commercial insurance (2003-2012), patients aged 10-45 years without malignancy who initiated an oral or intravenous bisphosphonate after at least 1 year of insurance enrollment were selected. Baseline demographics, comorbidities, medications and health care utilization were assessed in the year prior to initiating a bisphosphonate. The trend of bisphosphonate use over time was examined. There were 9,082 bisphosphonate initiators (0.02% of the same age group in the population). The mean age was 38.1 years and 79.6% female. Osteoporosis was the most common diagnosis (41.2%). At baseline, 10.8% had a diagnosis of fracture and 29.0% had a bone mineral density measured. Of those who used glucocorticoids (39%) at baseline, the mean 1-year cumulative prednisone-equivalent dose was 2,669 milligrams. The use of bisphosphonates in the young population significantly decreased over the past decade (pbisphosphonates was uncommon and significantly decreased over the past decade in the U.S. While most patients initiating bisphosphonates had a diagnosis of osteoporosis and fracture in the preceding year, some had no recorded claims with a diagnosis of fracture, osteoporosis, or long-term glucocorticoids use at baseline. Future research is needed to examine the effectiveness and safety of bisphosphonates in young patients at risk for osteoporosis.

  1. Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study.

    Science.gov (United States)

    Naylor, K E; Jacques, R M; Paggiosi, M; Gossiel, F; Peel, N F A; McCloskey, E V; Walsh, J S; Eastell, R

    2016-01-01

    We used bone turnover markers to identify women who responded to bisphosphonate treatment for osteoporosis. Response was more likely with alendronate and ibandronate than risedronate. There was a greater decrease in bone markers if baseline bone turnover markers were higher and if the patient took more than 80 % of her medication. Biochemical response to bisphosphonate therapy can be assessed using either a decrease in bone turnover marker beyond the least significant change (LSC) or a reduction to within a reference interval (RI). We compared the performance of these target responses and determined whether response was related to the type of bisphosphonate, compliance and baseline bone turnover markers. Biochemical responses to three oral bisphosphonates were assessed in an open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53-84 years), randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. The LSC for each marker was derived within the study population, whereas RIs were obtained from a control group of healthy premenopausal women (age 35-40 years). Over 70 % of women achieved a target response for serum CTX and PINP, irrespective of the approach used. The percentage decrease at 12 weeks was greater for women with baseline PINP above the RI -63 % (difference 13 %, 95 % CI 0 to 27.1, P = 0.049) and good compliance -67 % (difference 15.9 %, 95 % CI 6.3 to 25.5, P = 0.001). Responders had a greater increase in spine bone density compared to nonresponders; for example 6.2 vs. 2.3 % (difference 3.9 %, 95 % CI 1.6 to 6.3, P = 0.0011) for PINP LSC. The magnitude of change in bone markers was greater with ibandronate and alendronate than risedronate. Both approaches to response identified similar proportions of women as responders. Nonresponders had smaller increases in BMD, and we suggest that biochemical assessment of response is a useful tool for the management of women with

  2. Stress fracture of the ulna associated with bisphosphonate therapy and use of walking aid.

    Science.gov (United States)

    Chiang, G S H; Grace, C S H; Koh, K W B; Kelvin, K W B; Chong, T W; Wei, C T; Tan, B Y; Yeow, T B

    2014-08-01

    We report a case of a stress fracture of the ulna secondary to long-term bisphosphonate therapy and walking cane. Physicians need to have a high index of suspicion of stress fractures occurring in patients complaining of chronic upper limb pain if they are on bisphosphonate therapy and are using walking aids. Stress fractures of the upper extremities are rare and are usually associated with athletes; however, a few recent case reports have shown an association between stress fractures of the upper extremities and the use of walking aids. The association between increased incidence of upper extremity stress fractures and the use of both bisphosphonates and walking aids in patients has not been well studied, with only one previously reported case. Here, we report a case of a complete stress fracture of the ulna in a 77-year-old female, premorbidly ambulant with walking cane, on long-term bisphosphonates without any pre-existing medical conditions which could result in secondary causes of bone loss. Investigations did not reveal any causes of pathological fracture. This fracture is attributed to the use of long-term bisphosphonate therapy in conjunction with the use of a walking cane. This case highlights the importance of entertaining the possibility of such fractures occurring in any patient who is on bisphosphonate therapy presenting with stress fractures of the upper extremity.

  3. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel.

    Science.gov (United States)

    Hadji, P; Coleman, R E; Wilson, C; Powles, T J; Clézardin, P; Aapro, M; Costa, L; Body, J-J; Markopoulos, C; Santini, D; Diel, I; Di Leo, A; Cameron, D; Dodwell, D; Smith, I; Gnant, M; Gray, R; Harbeck, N; Thurlimann, B; Untch, M; Cortes, J; Martin, M; Albert, U-S; Conte, P-F; Ejlertsen, B; Bergh, J; Kaufmann, M; Holen, I

    2016-03-01

    Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus. The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with a T score of 18,000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of {sup 186}Re-MAG3-conjugated bisphosphonate ({sup 186}Re-MAG3-HBP), an agent for treatment of painful bone metastases

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Kazuma [Kyoto University, Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto (Japan)]|[Kanazawa University, Advanced Science Research Center, Kanazawa (Japan); Mukai, Takahiro [Kyoto University, Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto (Japan)]|[Kyushu University, Graduate School of Pharmaceutical Sciences, Fukuoka (Japan); Kawai, Keiichi [Kanazawa University, Graduate School of Medical Sciences, Kanazawa (Japan)]|[University of Fukui, Biomedical Imaging Research Center, Yoshida, Fukui (Japan); Takamura, Norito [Kyushu University of Health and Welfare, School of Pharmaceutical Sciences, Nobeoka (Japan); Hanaoka, Hirofumi; Saji, Hideo [Kyoto University, Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto (Japan); Hashimoto, Kazuyuki [Japan Atomic Energy Agency, Tokai-mura, Ibaraki (Japan); Shiba, Kazuhiro; Mori, Hirofumi [Kanazawa University, Advanced Science Research Center, Kanazawa (Japan)

    2009-01-15

    We have developed a {sup 186}Re-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate ({sup 186}Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of {sup 186}Re-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of {sup 99m}Tc-MAG3 and drugs with high affinity for serum protein produced competitive displacement at specific binding sites and enhanced total clearance and tissue distribution. The displacement effects of several protein-binding inhibitors on the protein binding of {sup 186}Re-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering {sup 186}Re-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline. The protein binding of {sup 186}Re-MAG3-HBP in rat serum, human serum, and a human serum albumin solution was significantly decreased by the addition of ceftriaxone, which has high affinity for binding site I on serum albumin. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of {sup 186}Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone. The findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein. (orig.)

  5. Risk of atrial fibrillation associated with use of bisphosphonates and other drugs against osteoporosis: a cohort study

    DEFF Research Database (Denmark)

    Vestergaard, Peter; Schwartz, Kristoffer; Pinholt, Else Marie

    2010-01-01

    We studied the association between bisphosphonate use and risk of atrial fibrillation or flutter and the effect of confounders such as heart and lung disease in a nationwide retrospective cohort from Denmark. All users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n.......98-1.10; alendronate HR = 1.05, 95% CI 0.96-1.15). In patients using etidronate (12.5% vs. 3.8%) and alendronate (11.4% vs. 4.6%) major differences were present in prevalence of COPD at start of treatment compared to matched controls. In conclusion, oral bisphosphonates do not seem to be associated with an excess risk...

  6. Influence of patient training on persistence, compliance, and tolerability of different dosing frequency regimens of bisphosphonate therapy: An observational study in Turkish patients with postmenopausal osteoporosis

    Directory of Open Access Journals (Sweden)

    Ülkü Akarırmak

    2016-08-01

    Conclusion: Our findings revealed remarkably high rates for persistence and compliance with bisphosphonate treatment in postmenopausal osteoporosis, with no impact of training on compliance and persistence rates. Longer persistence and better compliance rates were achieved with the monthly bisphosphonate regimen when compared to the weekly regimen.

  7. Indomethacin treatment reduces microglia activation and increases ...

    Indian Academy of Sciences (India)

    2016-07-14

    Jul 14, 2016 ... the SVZ and migration to the ischaemic striatum following stroke. [Lopes RS, Cardoso MM, Sampaio AO, Barbosa Jr MS, Souza CC, da Silva MC, Ferreira EMN, Freire MAM, Lima RR and Gomes-Leal W 2016. Indomethacin treatment reduces microglia activation and increases numbers of neuroblasts in the ...

  8. Indomethacin treatment reduces microglia activation and increases ...

    Indian Academy of Sciences (India)

    Indomethacin treatment reduces microglia activation and increases numbers of neuroblasts in the subventricular zone and ischaemic striatum after focal ischaemia. ROSANA S LOPES MARCELO M CARDOSO ARTHUR O SAMPAIO MARIO SANTOS BARBOSA Jr CELICE C SOUZA MICHELLE C DA SILVA ELANE ...

  9. [A case of osteonecrosis of the lower jaw due to bisphosphonates in a breast cancer patient with bone metastasis].

    Science.gov (United States)

    Kubo, Norio; Katayama, Kazuhisa; Ishizaki, Akiko; Morinaga, Nobuhiro; Negishi, Takeshi; Kuwano, Hiroyuki

    2008-11-01

    Recently, osteonecrosis of the jaw (ONJ) with bisphosphonates is frequently reported. ONJ due to bisphosphonate is an adverse event in the treatment of breast cancer with bone metastasis. We report a case of ONJ due to bisphosphonates. A 66-year-old woman was admitted to our hospital due to right advanced breast cancer with bone metastasis. She received neo-adjuvant chemotherapy consisting of paclitaxel 70 mg/m2, qw, trastuzumab 2 mg/m2, qw. After chemotherapy, we performed modified mastectomy for local control. Postoperative adjuvant chemotherapy was added with bisphosphonate for bone metastasis of breast cancer. After bisphosphonate was used 14 times, she had a pain and pus-discharge in her lower jaw. The dentists' diagnosis was ONJ. We treated her with antibiotics and local minor curettage. The inflammatory symptoms almost disappeared. In this case, the administration of bisphosphonates was thought to be a major risk factor for ONJ. We think that special precautions for ONJ should be taken in patients administered bisphosphonates for bone metastasis of breast cancer.

  10. [Bisphosphonate-associated osteonecrosis of the jaw].

    Science.gov (United States)

    Abu-Id, M H; Açil, Y; Gottschalk, J; Kreusch, T

    2006-03-01

    Bisphosphonates (BP) are widely used in patients with osteoporosis or malignant tumors with bony metastases such as breast cancer and plasmocytoma because of their potency to affect osteoclasts and bone resorption. Osteonecrosis of the jaw (ONJ) has been described as a potential side effect since 2003. After a review of the literature we present results of a questionnaire, which was sent to departments of oral and maxillofacial surgery (OMFS) in German-speaking countries. We present 349 patients from the literature, 54 patients from the departments of OMFS and 19 cases from our own department. These patients ware analyzed depending on their disease, their medication, localization of the affected area, histological signs and therapeutic outcome. Of 73 patients, 68 (93%) were treated with pamidronate or zoledronate; 69 (94%) patients suffered from malignant diseases, 3 (5%) had osteoporosis, and 1 (1%) had Paget's disease. In 57 (78%) patients the ONJ affected the mandible, in 12 (16%) the maxilla and in 4 (5%) both jaws. A previous tooth extraction was reported in 38 (52%) patients, and in 35 (48%) ONJ occurred spontaneously. Histological findings were similar to osteomyelitis with a high number of actinomyces colonies. Nine (12%) patients received non-surgical treatment only, 52 (71%) patients underwent minor surgical procedures (e. g. decortication) and 19 (26%) patients underwent marginal or segmental resection of the jaw. Considering all treatment modalities, healing was achieved in 55; the most effective was marginal and segmental resection (88%). Though millions of patients receive BP treatment only a few suffer from ONJ. The incidence in cancer patients with pamidronate and zoledronate therapy is 4%-10%. Because of the similarity to "phossy jaw", seen in patients dealing with white phosphorus in the nineteenth century, some authors call the new entity "bis-phossy jaw". As the pathogenesis of ONJ is not clear we recommend that the descriptive term

  11. Adjuvant Bisphosphonates for Postmenopausal Breast Cancer

    Science.gov (United States)

    A summary of a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer that shows the drugs can reduce the rate of disease recurrence in bone.

  12. Pharmacokinetics of bisphosphonates in rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Luurila, S.; Kautiainnen, S.; Ylitalo, P.; Ylitalo, R. [Univ. of Tamperer, Dept. of Pharmacological Sciences, Tampere (Finland)

    1999-01-01

    Clodronate, pamidronate and etidronate are commonly used bisphosphonates, which accumulate extensively in arteries and some other tissues. We compared their pharmacokinetics in rabbits with those of tiludronate, the drug newly introduced to clinical use. The {sup 14}C-labelled drugs were given intravenously and plasma drug levels were monitored for up to 24 hr. The dose-related plasma concentrations of tiludronate and etidronate were clearly higher and decreased more slowly than those of clodronate and pamidronate (P<0.001). Already at 5 min., the concentrations of tiludronate and etidronate were higher than those of clodronate and pamidronate (P=0.016). At 24 hr, plasma concentration of tiludronate was 12{+-}6.6%, of etidronate 18{+-}2.5%, of clodronate 0.8{+-}0.2%, and of pamidronate 1.4{+-}0.4% of the dose per body weight. With the same dose (25 mg/kg), absolute AUC{sub 0-24hr} for tiludronate and etidronate was 9-11 times larger than for clodronate. AUC{sub 0-24hr} for pamidronate (2.5 mg/kg) was 11% of that for clodronate. Plasma clearance of tiludronate and etidronate was 9-15 times slower than that of clodronate and pamidronate. At 24 hr, the mean tissue-to-plasma ratio of tiludronate for aorta was 1.2-1.6. For bone, spleen, liver and kidneys the ratio varied from 5.4 to 52.6. The results suggest that 1) tiludronate and etidronate are removed from plasma much slower than clodronate and pamidronate, and 2) the potential of tiludronate to concentrate in arteries and bone is generally smaller than previously found with the other bisphosphonates. (au) 26 refs.

  13. Closure of an open wound associated with bisphosphonate-related osteonecrosis of the jaw in a breast cancer patient.

    Science.gov (United States)

    Soolari, Nafiseh; Soolari, Ahmad

    2011-01-01

    Many clinicians will not treat patients presenting with bisphosphonate-related osteonecrosis of the jaw following long-term use of bisphosphonates because of the lack of predictable outcomes. MATERICAL AND METHODS: The patient presented with pain from a nonhealing lesion in the posterior maxilla following extraction of the maxillary right third molar. The lesion had not responded to any conventional dental treatment. The patient had suffered from breast cancer, and her treatment included several years of therapy with Zometa (zoledronic acid), a bisphosphonate. The patient stopped taking Zometa and commenced rinsing with phosphate buffer-stabilized 0.1% chlorine dioxide-containing mouthwash. After 5 months, changes in the morphology of the lesion were noted and the soft tissue had closed over the open wound. Cessation of bisphosphonate therapy and usage of a phosphate buffer-stabilized 0.1% chlorine dioxide-containing mouthwash lessened the patient's pain and resulted in closure of the soft tissue lesion.

  14. 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.

  15. 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

  16. Clinical utility of clodronate in the prevention and management of osteoporosis in patients intolerant of oral bisphosphonates

    OpenAIRE

    Muratore, Maurizio; Quarta, Eugenio; Grimaldi, Antonella; Calcagnile, Fabio; Quarta, Laura

    2011-01-01

    Maurizio Muratore, Eugenio Quarta, Antonella Grimaldi, Fabio Calcagnile, Laura Quarta Department of Rheumatology, Hospital Galateo, San Cesario di Lecce, Italy Abstract: Bisphosphonates have a long history in the treatment of osteoporosis and bone-related disease. This review focuses on the use of a specific nonaminobisphosphonate, clodronate, which appears to be much better tolerated than other bisphosphonates and free of high-risk contraindications. Specifically, this paper reviews its use...

  17. Radiologic Findings of Oral Bisphosphonate-Related Osteonecrosis of the Maxilla, Complicated by Actinomycosis: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yi Kyung; Kim, Hyung Jin; Kim, Eun Hee; Chung, Seung Kyu; Hong, Jong Rak [Samsung Medical Center, Seoul (Korea, Republic of)

    2010-01-15

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare, but serious complication, which has recently been more frequently reported. However, this entity is unfamiliar to radiologists. We report a case of BRONJ complicated by actinomycosis following a tooth extraction in a 68-year-old woman who has been treated with oral bisphosphonate for treatment of osteoporosis over the last 3 years and 3 months

  18. Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis?

    Science.gov (United States)

    Ristow, Oliver; Gerngroß, Carlos; Schwaiger, Markus; Hohlweg-Majert, Bettina; Kehl, Victoria; Jansen, Heike; Hahnefeld, Lilian; Otto, Sven; Pautke, Christoph

    2014-05-01

    The pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is not completely understood. The most popular hypothesis has suggested that the bone turnover (BT) in the jawbone is greater than that in other sites and that this turnover will be overly suppressed by bisphosphonates. Using bone scintigraphy, a simple tool for the quantitative evaluation of bone metabolism and blood flow, the goals of the present study were to determine whether the rate of bone remodeling is greater in the jaw and whether the bone BT in the jaw is differentially altered after bisphosphonate intake compared with that in other skeletal sites. The bone scintigraphies of 90 female patients with breast cancer were retrospectively analyzed (n = 45 with bisphosphonate intake; n = 45 without bisphosphonate intake [control group]). All patients in the study group had undergone bone scintigraphy before therapy and during the treatment (course after 12 and 24 months). The data were quantitatively analyzed using 6 predetermined regions of interest. The bone BT of the mandible was similar to that of the femur and significantly reduced compared with that of the maxilla (P .05). The finding that the mandible had significantly lower bone BT than that of the maxilla and that two thirds of BRONJ cases occur in the mandible were inconsistent with the investigated hypothesis. Furthermore, the bone BT in the jawbone was not overly suppressed by bisphosphonates. Thus, it is unlikely that over suppression of bone BT is the exclusive causation playing a role in the pathomechanism of BRONJ. Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  19. The relationship between the chemistry and biological activity of the bisphosphonates.

    Science.gov (United States)

    Ebetino, Frank H; Hogan, Anne-Marie L; Sun, Shuting; Tsoumpra, Maria K; Duan, Xuchen; Triffitt, James T; Kwaasi, Aaron A; Dunford, James E; Barnett, Bobby L; Oppermann, Udo; Lundy, Mark W; Boyde, Alan; Kashemirov, Boris A; McKenna, Charles E; Russell, R Graham G

    2011-07-01

    The ability of bisphosphonates ((HO)(2)P(O)CR(1)R(2)P(O)(OH)(2)) to inhibit bone resorption has been known since the 1960s, but it is only recently that a detailed molecular understanding of the relationship between chemical structures and biological activity has begun to emerge. The early development of chemistry in this area was largely empirical and based on modifying R(2) groups in a variety of ways. Apart from the general ability of bisphosphonates to chelate Ca(2+) and thus target the calcium phosphate mineral component of bone, attempts to refine clear structure-activity relationships had led to ambiguous or seemingly contradictory results. However, there was increasing evidence for cellular effects, and eventually the earliest bisphosphonate drugs, such as clodronate (R(1)=R(2)=Cl) and etidronate (R(1)=OH, R(2)=CH(3)), were shown to exert intracellular actions via the formation in vivo of drug derivatives of ATP. The observation that pamidronate, a bisphosphonate with R(1)=OH and R(2)=CH(2)CH(2)NH(2), exhibited higher potency than previously known bisphosphonate drugs represented the first step towards the later recognition of the critical importance of having nitrogen in the R(2) side chain. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates took place particularly in the 1980s, but still with an incomplete understanding of their structure-activity relationships. A major advance was the discovery that the anti-resorptive effects of the nitrogen-containing bisphosphonates (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their potency as inhibitors of the enzyme farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids utilized in sterol synthesis and for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular targets

  20. Incidence and Predictors of Multiple Fractures Despite High Adherence to Oral Bisphosphonates

    DEFF Research Database (Denmark)

    Hawley, Samuel; Javaid, M Kassim; Rubin, Katrine H

    2016-01-01

    Oral bisphosphonates (BPs) are highly effective in preventing fractures and are recommended first-line therapies for patients with osteoporosis. We identified the incidence and predictors of oral BP treatment failure, defined as the incidence of ≥2 fractures while on treatment (≥2 FWOT) among users...

  1. 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...

  2. 3-Keto-1,5-bisphosphonates Alleviate Serum-Oxidative Stress in the High-fat Diet Induced Obesity in Rats.

    Science.gov (United States)

    Lahbib, Karima; Aouani, Iyadh; Cavalier, Jean-François; Touil, Soufiane

    2015-09-01

    Obesity has become a leading global health problem owing to its strong association with a high incidence of oxidative stress. Many epidemiologic studies showed that an antioxidant supplementation decreases the state of oxidative stress. In the present work, a HFD-induced rat obesity and oxidative stress were used to investigate the link between fat deposition and serum-oxidative stress markers. We also studied the effect of a chronic administration of 3-keto-1,5-bisphosphonates 1 (a & b) (40 μg/kg/8 weeks/i.p.). Exposure of rats to HFD during 16 weeks induced fat deposition, weight gain and metabolic disruption characterized by an increase in cholesterol, triglyceride and glycemia levels, and a decrease in ionizable calcium and free iron concentrations. HFD also induced serum-oxidative stress status vocalized by an increase in ROS (H2 O2 ), MDA and PC levels, with a decrease in antioxidant enzyme activity (CAT, GPx, SOD). Importantly, 3-keto-1,5-bisphosphonates corrected all the deleterious effects of HFD treatment in vivo, but it failed to inhibit lipases in vitro and in vivo. These studies suggest that 3-keto-1,5-bisphosphonates 1 could be considered as safe antioxidant agents that should also find other potential biological applications. © 2014 John Wiley & Sons A/S.

  3. Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk factors in patients with breast cancer and gynecological malignancies.

    Science.gov (United States)

    Fehm, T; Beck, V; Banys, M; Lipp, H P; Hairass, M; Reinert, S; Solomayer, E F; Wallwiener, D; Krimmel, M

    2009-03-01

    Since 2003, multiple cases of bisphosphonate-induced osteonecrosis of the jaw (ONJ) were reported. The aim of this study was to describe the incidence and risk factors of ONJ in patients with breast cancer or gynecological malignancies receiving bisphosphonates (BP). ONJ was recorded for all patients with breast cancer or gynecological malignancies treated with intravenous bisphosphonates at the Department of Gynecology and Obstetrics, University Hospital Tuebingen during April, 1999 and May, 2006. 10 of 345 (2.9%) patients with breast cancer or gynecological malignancies developed ONJ while receiving bisphosphonate therapy. Six patients with ONJ had a history of recent dental procedures. All patients had received zoledronic acid as part of their bisphosphonate regimen. Time of exposure to bisphosphonates and the number of treatment cycles were significant risk factors for the development of ONJ (p<0.001). In patients diagnosed with ONJ the mean number of treatment cycles was 27+/-18 cycles. However, the mean number of treatment cycles in patients without manifestation of ONJ was 12+/-12 cycles. Length of exposure to BPs and the cumulative dose of given BPs seem to be the most important risk factors for the development of ONJ followed by dental procedures.

  4. Bisphosphonates for prevention of osteopenia in kidney-transplant recipients: a systematic review of randomized controlled trials.

    Science.gov (United States)

    Wang, J; Yao, M; Xu, J-h; Shu, B; Wang, Y-j; Cui, X-j

    2016-05-01

    We conducted a systematic review of randomized controlled trials (RCTs) of bisphosphonates for the prevention of osteopenia in kidney-transplant recipients. Bisphosphonates improved bone mineral density at the lumbar spine and femoral neck after 12 months. However, additional well-designed RCTs are required to determine the optimal treatment strategy. Osteopenic-osteoporotic syndrome is a bone complication of renal transplantation. Bisphosphonates, calcitonin, and vitamin D analogs may be used to prevent or treat osteoporosis or bone loss after renal transplantation. However, there is currently no widely recognized strategy for the prevention of corticosteroid-induced osteoporosis. This study aims to assess the available evidence to guide the targeted use of bisphosphonates for reducing osteoporosis and bone loss in renal-transplant recipients. We searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE for randomized controlled trials of bisphosphonates for osteoporosis or bone loss after renal transplantation. A total of 352 abstracts were identified, of which 55 were considered for evaluation and 9 were included in the final analysis. The primary outcome measure was change in the bone mineral density (BMD) of the lumbar spine and femoral neck after 12 months. Data extraction was performed independently by two investigators. BMD at the lumbar spine was improved after treatment with bisphosphonates [9 trials; 418 patients; weighted mean difference (WMD), 0.61; 95 % confidence interval (CI), 0.16-1.06]. Eight trials (406 patients) that reported changes in BMD at the femoral neck also showed improved outcomes after treatment with bisphosphonates (WMD, 0.06; 95 % CI, 0.03-0.09). Bisphosphonates improve BMD at the lumbar spine and femoral neck after 12 months in renal-transplant recipients.

  5. Oral bisphosphonate use and total knee/hip implant survival

    DEFF Research Database (Denmark)

    Prieto-Alhambra, Daniel; Lalmohamed, Arief; Abrahamsen, Bo

    2014-01-01

    OBJECTIVE: Aseptic loosening is the most common cause of revision arthroplasty. Bisphosphonates could minimize this through their antiresorptive effects. This study was undertaken to investigate the association between bisphosphonate use and implant survival. METHODS: A retrospective cohort study...

  6. Challenge test to bisphosphonates in patients with hypersensitivity reactions to drugs.

    Science.gov (United States)

    Minciullo, Paola Lucia; Allegra, Alessandro; D'Angelo, Anna; Musolino, Caterina; Gangemi, Sebastiano

    2015-01-01

    Bisphosphonates are a commonly used class of drugs with known efficacy in the prevention and treatment of postmenopausal and steroid-induced osteoporosis, Paget's disease of bone, hypercaelcemia of malignancy, osteolytic lesions of multiple myeloma, and bone metastases. Nitrogen-containing bisphosphonates have a favourable tolerability and safety profile, cutaneous reactions have been reported. This is a retrospective case series study, based on the analysis of data from 1429 patients admitted to the Allergy and Clinical Immunology Division of the University of Messina between January 2011 and December 2012. Most patients had previous adverse drug reactions (ADRs) and referred to us for a challenge test with an alternative drug. We observed six patients with a past history of adverse drug reaction who needed to be tested for bisphosphonates: three patients for risedronate, two for clodronate and one for alendronate. In two years only two patients were referred to us for an adverse reaction to bisphosphonates: one to alendronate and one to risedronate. Another patient presented a previous reaction to strontium ranelate. The other three patients reported previous hypersensitivity reactions to at least two different classes of drugs. All the patients experienced no reaction using the tested drugs. In our experience drug challenge tests for bisphosphonates are safe and reliable. Copyright © 2013 SEICAP. Published by Elsevier Espana. All rights reserved.

  7. 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

  8. Baseline mineralizing surface determines the magnitude of the bisphosphonate effect on cortical bone mineralization in postmenopausal osteoporotic patients

    Science.gov (United States)

    Misof, B.M.; Blouin, S.; Lueger, S.; Paschalis, E.P.; Recker, R.R.; Phipps, R.; Klaushofer, K.; Roschger, P.

    2017-01-01

    Purpose: To determine the effect of short- or long-term bisphosphonate treatment on cortical bone mineralization density distribution (BMDD). Methods: BMDD was assessed by quantitative backscatter electron imaging in postmenopausal osteoporosis: in paired transiliac biopsy samples (n=36) at baseline and after 3 years risedronate treatment from a clinical study, in transiliac biopsy samples from patients who were treated with either risedronate (n=31) or alendronate (n=68) for 3 to 7 years from an observational study. Outcomes were related to premenopausal reference data (n=73) and to histomorphometric mineralizing surface per bone surface (MS/BS). Results: In the clinical study, patients with lower (below cohort median) MS/BS had normal cortical CaMean at baseline. After 3 years risedronate, their CaMean was not different versus baseline but increased versus reference (+2.9%, p=0.003). Among the groups of the observational study, CaMean did not exceed reference level, was similar for alendronate versus risedronate and similar between 3 to 5 years versus longer than 5 years treatment duration. Conclusion: Baseline bone mineralizing surface appears to be important for the effect of bisphosphonate on cortical bone mineralization. In patients with lower baseline MS/BS, level of mineralization after treatment can exceed reference level. Whether this is beneficial in the long-term is unknown. PMID:28860420

  9. Pharmacovigilance of oral bisphosphonates: adverse effects manifesting in the soft tissue of the oral cavity.

    Science.gov (United States)

    Kharazmi, Mohammad; Persson, Ulf; Warfvinge, Gunnar

    2012-12-01

    It is well known that oral bisphosphonates can induce necrosis of the osseous structures of the jaws. However, there seems to be a limited awareness that oral bisphosphonates can also induce adverse effects in the soft tissues of the oral cavity, as indicated by the paucity of reported cases in the literature. Because oral bisphosphonates are widely used drugs for several skeletal conditions, it is reasonable to assume that mucosal adverse effects are more common than the small number of published cases indicates. The purpose of this study was to investigate whether this adverse effect of bisphosphonates is represented as reports from health practitioners in an adverse drug reaction database, as well as to gain knowledge about which substances are being associated with adverse drug reactions affecting the oral mucosa. The database of the Medical Products Agency-Sweden was searched for adverse effects from oral bisphosphonates manifesting in the oral and maxillofacial region. Reports of reactions limited to the soft tissues of the oral cavity were selected and further analyzed. Only those reports showing recovery or improvement after the cessation of bisphosphonate use were included in the study. A total of 83 cases of adverse reactions to oral bisphosphonates were retrieved from the search. Of these, 12 were included in the study. They were associated with the use of alendronate, etidronate and risedronate, in descending order. Sixteen percent of the reports comprising the oral and maxillofacial region were limited to the oral mucosa and reported recovery or improvement after discontinuation of the drug. Adverse effects of oral bisphosphonates with manifestations in the soft tissue of the oral cavity seem to be more common than the small number of published cases indicates. However, considering that oral bisphosphonates are widely used drugs, the incidence is still low. These adverse drug reactions are not limited to alendronate and may also be induced by

  10. Bisphosphonate-associated osteonecrosis of the jaws

    Directory of Open Access Journals (Sweden)

    Pankaj Agarwal

    2012-01-01

    Full Text Available Bisphosphonates constitute a group of drugs capable of modulating bone turnover and reduce its remodeling when an excessive resorption occurs. This is why they are indicated in a large group of bone diseases like postmenopausal osteoporosis or osteolysis associated with breast cancer or multiple myeloma. Over the last few years and due to their extensive use, many cases of complications associated with their use have been published. Among the most important possible adverse effects are the oral ones, with the appearance of ulcerations and, especially, osteonecrosis of the jaws associated with this therapy. In this paper, we have analyzed the general characteristics of these drugs and their mechanisms of action as well as the described adverse effects, especially oral and maxillofacial, have been made special reference, regarding the prevention of osteonecrosis of the jaws, heightened by cases described in the medical and odontological literature. The preventive protocol backs up the fundamental role of the odontologist in the effective prevention of this process before, during and after the treatment.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. 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.

  13. Bisphosphonate-related jaw necrosis--severe complication in maxillofacial surgery.

    Science.gov (United States)

    Eckert, A W; Maurer, P; Meyer, L; Kriwalsky, M S; Rohrberg, R; Schneider, D; Bilkenroth, U; Schubert, J

    2007-02-01

    Bisphosphonates are used as potent inhibitors in metastatic bone lesions. They can reduce skeletal burden and prevent bony metastases. They are integral in the treatment of some tumours like breast cancer, prostate cancer and multiple myeloma. As a side effect, these drugs also may cause severe jaw necrosis. Twenty-four patients with bisphosphonate-related jaw necrosis were analyzed in a clinical study. These necroses mostly appeared after administration of aminobisphosphonates. Recurrent avascular necroses were found after changing from Pramidronate to Zoledronate. All patients were treated by resection of necrotic bone. Repeated surgical interventions were required with about 25% of the patients. The management of patients with bisphosphonate-related jaw necrosis remains extremely difficult and includes surgical procedures as well as the eradicating of the necrotic bone including antibiotic therapy. The prevention of such complications consists in a minimization of dental surgical interventions and an avoidance of ulcers by dental prosthesis.

  14. 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.

  15. Bisphosphonates and Risk of Upper Gastrointestinal Cancer — A Case Control Study Using the General Practice Research Database (GPRD)

    Science.gov (United States)

    Wright, Ellen; Schofield, Peter T.; Seed, Paul; Molokhia, Mariam

    2012-01-01

    Background Concerns have been raised as to the safety of bisphosphonates; in particular a possible link between bisphosphonate use and upper gastrointestinal (GI) cancer. Two published studies using different study populations but drawn from earlier versions of the same national UK database, reached differing conclusions: one finding no evidence for an increase in the risk of gastric or oesophageal cancer in bisphosphonate users and one finding a small but significantly increased risk of oesophageal cancer linked to duration of bisphosphonate use. Methodology/ Principal Findings Design-A case control study comparing bisphosphonate prescribing in cases of upper GI cancer from 1995 to 2007 using UK primary care electronic health records (GPRD). Main Outcome Measure-Relative Risk (approximated to Odds Ratio for rare events) for oesophageal and gastric cancer development in bisphosphonate users compared to non–users. The odds of being a case of oesophageal cancer, adjusted for smoking status, were significantly increased in women who had had one or more bisphosphonate prescriptions, odds ratio 1·54 (95% CI 1·27–1·88) compared to non-users. There was no significant effect on gastric cancer in women, odds ratio adjusted for smoking status, 1.06 (95% CI 0.83–1.37) and also no apparent risk in men for either oesophageal or gastric cancer, odds ratio adjusted for smoking status 0.78 (95%CI 0.56–1.09) and 0.87 (95% CI 0.55–1.36) respectively. Conclusions/ Significance Our results support a small but significant increased risk of oesophageal cancer in women prescribed bisphosphonates and is based on the largest number of exposed cases to date in the UK. PMID:23112825

  16. Aspects of osseous, peritoneal and renal handling of bisphosphonate during peritoneal dialysis: a methodological study

    DEFF Research Database (Denmark)

    Joffe, P; Henriksen, Jens Henrik Sahl

    1996-01-01

    The accumulation of methylene bisphosphonate (MBP) in increased bone turnover is an index of the total skeletal turnover. Accordingly, a model has been described where uptake of the osseous tracer can be estimated, regardless of renal function. In the present study, the model was adapted to conti......The accumulation of methylene bisphosphonate (MBP) in increased bone turnover is an index of the total skeletal turnover. Accordingly, a model has been described where uptake of the osseous tracer can be estimated, regardless of renal function. In the present study, the model was adapted.......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

  17. Canine cancellous bone microarchitecture after one year of high-dose bisphosphonates

    DEFF Research Database (Denmark)

    Ding, Ming; Day, JS; Burr, DB

    2003-01-01

    We examined the effects of one-year high-dose bisphosphonates (risedronate 0.5 mg/kg/day or alendronate 1.0 mg/kg/day) on the three-dimensional (3-D) microstructural and mechanical properties of canine cancellous bone. A high-resolution micro-CT scanner was used to scan cubic specimens produced...... from the first lumbar vertebrae. Microstructural properties of the specimens were calculated directly from the 3-D datasets and the mechanical properties of the specimens were determined. Our data demonstrate significant microarchitectural changes in the bisphosphonate-treated cancellous bone....... Our results suggest a bone remodeling-adaptation mechanism stimulated by bisphosphonates that increases bone volume fraction, thickens trabeculae, changes trabeculae towards more plate-like, and increases mechanical properties. The secondary degree of anisotropy contributed significantly...

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

    Directory of Open Access Journals (Sweden)

    Schlegel Karl A

    2010-10-01

    Full Text Available Abstract Background Bone-destructive disease treatments include bisphosphonates and antibodies against the osteoclast differentiator, RANKL (aRANKL; however, osteonecrosis of the jaw (ONJ is a frequent side-effect. Current models fail to explain the restriction of bisphosphonate (BP-related and denosumab (anti-RANKL antibody-related ONJ to jaws. Msx-1 is exclusively expressed in craniofacial structures and pivotal to cranial neural crest (CNC-derived periodontal tissue remodeling. We hypothesised that Msx-1 expression might be impaired in bisphosphonate-related ONJ. The study aim was to elucidate Msx-1 and RANKL-associated signal transduction (BMP-2/4, RANKL in ONJ-altered and healthy periodontal tissue. Methods Twenty ONJ and twenty non-BP exposed periodontal samples were processed for RT-PCR and immunohistochemistry. An automated staining-based alkaline phosphatase-anti-alkaline phosphatase method was used to measure the stained cells:total cell-number ratio (labelling index, Bonferroni adjustment. Real-time RT-PCR was performed on ONJ-affected and healthy jaw periodontal samples (n = 20 each to quantitatively compare Msx-1, BMP-2, RANKL, and GAPDH mRNA levels. Results Semi-quantitative assessment of the ratio of stained cells showed decreased Msx-1 and RANKL and increased BMP-2/4 (all p Conclusions These results explain the sclerotic and osteopetrotic changes of periodontal tissue following BP application and substantiate clinical findings of BP-related impaired remodeling specific to periodontal tissue. RANKL suppression substantiated the clinical finding of impaired bone remodelling in BP- and aRANKL-induced ONJ-affected bone structures. Msx-1 suppression in ONJ-adjacent periodontal tissue suggested a bisphosphonate-related impairment in cellular differentiation that occurred exclusively jaw remodelling. Further research on developmental biology-related unique features of jaw bone structures will help to elucidate pathologies restricted to

  19. Bisphosphonates and Risk of Subtrochanteric, Femoral Shaft, and Atypical Femur Fracture: A Systematic Review and Meta-analysis

    Science.gov (United States)

    Gedmintas, Lydia; Solomon, Daniel H.; Kim, Seoyoung C.

    2013-01-01

    While there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral fractures (AFF). Recent published studies examining this potential association are conflicting in regards to the existence and strength of this association. We conducted a systematic review and meta-analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random-effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta-analysis: five case-control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF with adjusted RR of 1.70 (95% CI 1.22–2.37). Subgroup analysis of studies using the ASBMR-criteria to define AFF suggests a higher risk of AFF with bisphosphonate use with RR of 11.78 (95% CI 0.39–359.69) as compared to studies using mainly diagnosis codes (RR 1.62, 95% CI 1.18–2.22), although there is a wide confidence interval and severe heterogeneity (I2=96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI 1.29–2.04). This meta-analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long-term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear. PMID:23408697

  20. 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; Wei, Tzuping; Li, Wen-wu; Shi, Xiaoyou; Clark, J David; Kingery, Wade S

    2016-01-01

    BACKGROUND Bisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that anti-resorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, post-fracture cutaneous cytokine up-regulation, and adaptive immune responses in this CRPS model. METHODS Rats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by uCT and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed and skin cytokine (TNF, IL-1, IL-6) and nerve growth factor (NGF) levels were determined by EIA. Skin and sciatic nerve immunoglobulin levels were determined by EIA. RESULTS Tibia fracture rats developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression, trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by uCT, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression and elevated immunocomplex deposition in skin and nerve. Alendronate (60 μg/kg/day s.c.) or zoledronate (3 mg/kg/day p.o.) treatment for 28 days, started

  1. 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.

  2. Diagnóstico, prevención y tratamiento de la osteonecrosis de los maxilares por bisfosfonatos: Recomendaciones de la Sociedad Española de Cirugía Oral y Maxilofacial (SECOM Diagnosis, prevention, and treatment of bisphosphonate-associated osteonecrosis of the jaw: Recommendations of the Spanish Society of Oral and Maxillofacial Surgery (SECOM

    Directory of Open Access Journals (Sweden)

    L.M. Junquera

    2008-06-01

    Full Text Available Los bisfosfonatos son análogos estables de los pirofosfatos inorgánicos que han demostrado su eficacia para el tratamiento de diversas patologías, como las lesiones osteolíticas asociadas a metástasis óseas o al mieloma múltiple, la hipercalcemia maligna, la enfermedad de Paget y la osteoporosis. En la actualidad se podría hablar, al menos académicamente, de dos entidades con diferentes grados de información científica: las osteonecrosis en relación con la administración intravenosa de estos medicamentos y las osteonecrosis en relación con la administración oral de los mismos. Para el primer grupo las estrategias de prevención y tratamiento empiezan a estar consolidadas, mientras que para el segundo se precisará de una mayor documentación científica para alcanzar este objetivo. Facilitar el diagnóstico clínico y complementario de las osteonecrosis por bisfosfonatos por parte de los especialistas de la salud oral (cirujanos orales y maxilofaciales, odontólogos y estomatólogos. Los objetivos del presente artículo son explicitar las medidas preventivas más apropiadas para limitar el número de casos de esta patología, a la luz de los conocimientos actuales, detallar la forma de tratamiento más reconocida para los diferentes estadios de la osteonecrosis, una vez establecida así como proporcionar un documento para la buena praxis médica y odontológica en los pacientes que padecen esta enfermedad o estén en riesgo de sufrirla. Este documento ha sido aprobado por la Comisión Científica de la SECOM.The bisphosphonates are stable inorganic pyrophosphate analogs that have demonstrated their efficacy in the treatment of a variety of pathologies, such as osteolytic lesions associated with bony metastases or multiple myeloma, malignant hypercalcemia, Paget’s disease, and osteoporosis. Currently, two disease entities supported by different degrees of scientific evidence can be characterized, at least academically

  3. 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.

  4. Biodegradable bisphosphonate nanoparticles for imaging and therapeutic applications in osteosarcoma

    Science.gov (United States)

    Rudnick-Glick, S.; Corem-Salkmon, E.; Grinberg, I.; Gluz, E.; Margel, S.

    2015-08-01

    Osteosarcoma (OS) is amongst the most commonly diagnosed bone tumors occurring in adolescence, young adults and adults over the age of 65. Current treatment is based on a combination of surgery and chemotherapy. Chemotherapy has improved the survival rate, however it is associated with severe side effects due to the use of high dosages, nonspecific uptake and poor bone blood supply. At present bisphosphonates (BP) are widely used in the treatment of bone disorders including OS. We have engineered a unique biodegradable BP nanoparticle that possesses a dual functionality: 1) covalent attachment of a dye (e.g., NIR dye) or drug to the nanoparticles through the primary amine groups on the surface of the nanoparticle; 2) chelation to the bone mineral hydroxyapatite through the BP on the surface of the nanoparticle. Due to a high concentration of PEG in the BP nanoparticles they possess a relatively long plasma half-life time. Therefore, the nanoparticle has potential for use both in diagnosis and therapy of OS. Doxorubicin was conjugated to the free amine on the surface of the BP nanoparticles. In vitro experiments on osteosarcoma cells demonstrated that the doxorubicin-conjugated BP nanoparticles possess a higher efficacy than the free doxorubicin. Further investigation in vivo in a chicken embryo model confirmed that the doxorubicin-conjugated nanoparticle was significantly more effective in inhibiting tumor growth compared to free doxorubicin at a similar concentration. Additionally, we have shown that these BP nanoparticles preferentially target OS tumor tissue, thus increasing anti-cancer drug bioavailability at targeted site.

  5. The Effects of Bisphosphonates Used Continually or Intermittently on Fractures, Bone Mineral Density and Biochemical Parameters in Osteoporotic Patients - Original Investigation

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    Alev Çevikol

    2010-04-01

    Full Text Available Aim: The aim of this study was to evaluate the effects of bisphosphonates on new fracture development, bone mineral density and biochemical parameters in osteoporotic patients who were treated with these drugs for 5 years. Material and Methods: Thirty nine patients from our osteoporosis outpatient clinic, using bisphosphonates treatment for 5 years were included in this retrospective study. The patients were questioned in terms of demographic features, osteoporosis risk factors, spine and total hip BMD scores measured during the diagnosis and the last follow-up, duration of bisphosphonates use, adverse-effect profile and compliance to the treatment. Serum calcium, phosphorus, alkaline phosphatase levels and 24 houred-urine calcium level were examined. Patients were divided into 2 groups as the patients who were using bisphosphonates continually after diagnosis were group 1 and the patients left using bisphosphonates for some time because of several reasons treated intermittently were group 2. Results: After the diagnosis, 11 (28.2% patients received bisphosphonate treatment continually (Group 1 while 28 (71.8% used the treatment intermittently (Group 2 for 5 years. The break in bisphosphonate use in Group 2 was 1.25±0.63 years. No statistical differences were determined between the 2 groups with respect to DEXA measurement, biochemical parameters or new fracture development identified clinically (p>0.05. Conclusion: Efficacy of bisphosphonates on new fracture development identified clinically, biochemical parameters and DEXA measurement was sustained in patients using bisphosphonates regularly for 5 years, even when treatment was interrupted for approximately 1.5 years. (From the World of Osteoporosis 2010;16:1-8

  6. Bisphosphonates and evidence for association with esophageal and gastric cancer: a systematic review and meta-analysis

    Science.gov (United States)

    Wright, Ellen; Schofield, Peter T; Molokhia, Mariam

    2015-01-01

    Objectives Concerns have been raised about a possible link between bisphosphonate use, and in particular alendronate, and upper gastrointestinal (UGI) cancer. A number of epidemiological studies have been published with conflicting results. We conducted a systematic review and meta-analysis of observational studies, to determine the risk of esophageal and gastric cancer in users of bisphosphonates compared with non-users. Design We searched PubMed, MEDLINE, EMBASE, Web of Knowledge and Cochrane Database of Systematic Reviews for studies investigating bisphosphonates and esophageal or gastric cancer. We calculated pooled ORs and 95% CIs for the risk of esophageal or gastric cancer in bisphosphonate users compared with non-users. We performed a sensitivity analysis of alendronate as this was the most common single drug studied and is also the most widely used in clinical practice. Results 11 studies (from 10 papers) examining bisphosphonate exposure and UGI cancer (gastric and esophageal), met our inclusion criteria. All studies were retrospective, 6/11 (55%) case–control and 5/11(45%) cohort, and carried out using data from 5 longitudinal clinical databases. Combining 5 studies (1 from each database), we found no increased risk, OR 1.11 (95% CI 0.97 to 1.27) of esophageal cancer in bisphosphonate users compared with non-users and no increased risk of gastric cancer in bisphosphonate users, OR 0.96 (95% CI 0.82 to 1.12). Conclusion This is the fourth and most detailed meta-analysis on this topic. We have not identified any compelling evidence for a significantly raised risk of esophageal cancer or gastric cancer in male and female patients prescribed bisphosphonates. PMID:26644118

  7. Bisphosphonate complications including osteonecrosis of the jaw.

    Science.gov (United States)

    Mehrotra, Bhoomi; Ruggiero, Salvatore

    2006-01-01

    Bisphosphonate therapy has been incorporated in the standard management of patients with multiple myeloma-related bony disease. Although their efficacy in reducing skeletal related events is important in the supportive management of the myeloma patient, post-marketing experience with this class of agents, particularly the more potent intravenous agents pamidronate and zoledronic acid, have raised cautionary notes regarding the potential side effects of these agents. The focus of this session is to review the risk factors, incidence, prevention strategies and management of bisphosphonate-related osteonecrosis of the jaw. In addition, pathophysiology, incidence and monitoring for renal dysfunction during chronic therapy with these agents are reviewed.

  8. Bisphosphonates: An update to the general dentist

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    Varun Dahiya

    2013-01-01

    Full Text Available Bisphosphonates (BP, included under host modulation therapy are drugs that inhibit bone resorption and commonly prescribed to prevent skeletal related changes in malignant diseases of bone and bone diseases such as osteoporosis. The sudden rise of this group of drugs is unfortunately because of the serious complication of osteonecrosis of jaws called Bisphosphonate related osteonecrosis of jaws which leads to many dental related complications. This literature review is undertaken to review the general recommendations to the dentist and clinical implications of BP′s. The implications of BP′s use in dentistry are still being determined.

  9. The risk of second hip fracture is decreased with compliant and persistent use of bisphosphonates

    DEFF Research Database (Denmark)

    Hansen, Louise; Vestergaard, Peter; Petersen, Karin Dam

    , previously employed by the same authors in a cost of illness study, was modified to estimate the cost-effectiveness of bisphosphonate treatment is Danish fracture patients above 50 years. The model applied an incidence-based, bottom-up approach from a societal perspective and, thus, included direct...

  10. Association between refill compliance to oral bisphosphonate treatment, incident fractures, and health care costs--an analysis using national health databases

    DEFF Research Database (Denmark)

    Olsen, K R; Hansen, C; Abrahamsen, Bo

    2013-01-01

    major osteoporotic fractures, and the direct costs related to hospital care, primary care, and pharmaceutical treatment for these excess fractures reached almost 14 M DKK (2.5 M USD) for the study population which compares to a national annual excess cost of around 17 M DKK (3.1 M USD) using 2011...... prescription prevalence....

  11. 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.

  12. 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)

  13. The effect on implant fixation of soaking tricalcium phosphate granules in bisphosphonate

    DEFF Research Database (Denmark)

    Jakobsen, Thomas; Baas, Jørgen; Bechtold, Joan E

    2012-01-01

    biomechanical implant fixation and osseointegration of experimental implant grafted with β-TCP granules (Conduit) could be improved by soaking the β-TCP granules in bisphosphonate (zoledronate). In 10 dogs, a pair of titanium coated implants surrounded by a 2.5 mm gap was inserted into the proximal part of each...... tibia. The gap was grafted with β-TCP granules either soaked with zoledronate or saline. At 12 weeks, the implants were evaluated with biomechanical push-out test and histomorphometrical analysis. We found that bisphosphonate increased one of the three biomechanical parameters, but found no difference...

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

    Science.gov (United States)

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

    2016-10-01

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

  15. Efficacy of Bisphosphonates on Bone Mineral Density and Fracture Rate in Patients With Osteogenesis Imperfecta: A Systematic Review and Meta-analysis.

    Science.gov (United States)

    Shi, Chang Gui; Zhang, Ying; Yuan, Wen

    2016-01-01

    Epidemiological evidence suggests that bisphosphonates are the most promising drugs for patients with osteogenesis imperfecta (OI). However, data on this issue are controversial. We conducted a meta-analysis to assess the efficacy of bisphosphonates on bone mineral density (BMD) and fracture rate in patients with OI. Electronic databases were searched to find relevant studies. Two reviewers independently identified relevant randomized controlled trials, which evaluated the efficacy of bisphosphonates in patients with OI. Outcome measures were fracture incidence and BMD changes in different skeletal sites. A total of 9 randomized controlled trials including 557 patients were identified. Meta-analysis demonstrated a beneficial effect of bisphosphonates on spine BMD Z-score and area BMD (in grams per square centimeter) %. Patients treated with bisphosphonates had a lower risk of fracture [risk ratio (RR) = 0.80; 95% confidence interval (CI): 0.66-0.97] compared with those in control groups. In children, bisphosphonates were efficacious in reducing fractures (RR = 0.80; 95% CI: 0.66-0.97), where in adults, bisphosphonates seemed equivalent to placebo in that respect (RR = 0.82; 95% CI: 0.42-1.59), although no significant difference was noted between these 2 RRs (test of interaction, z = -0.07; P = 0.94). There was also no significant difference in reducing fractures between oral and intravenous bisphosphonates (P = 0.23). This study showed that bisphosphonates could increase the BMD and reduce the risk of facture in patients with OI. There was no enough evidence to identify any differences in efficacy between oral and intravenous bisphosphonates on fracture reduction, as well as between children and adults.

  16. Severe osteonecrosis of the jaws in a compromised patient subjected to bisphosphonate therapy

    Directory of Open Access Journals (Sweden)

    Juliana Dreyer de Menezes

    Full Text Available Bisphosphonate-related osteonecrosis of the jaws is characterized by alveolar bone exposure, especially after mucosal trauma or after surgical procedures, in patients who have previously received or who are currently receiving bisphosphonates without a history of radiation therapy in the maxillofacial region. The condition is refractory to treatment, and attempts at debridement are not completely effective in eradicating the necrotic bone. We report here a case of a severe osteonecrosis of the jaws in a 77-year-old male patient, who had been subjected to chemotherapy and treatment with zoledronic acid and corticosteroid. The patient also had comorbidities such as diabetes and periodontal disease, which might have contributed to the lesion development. Bisphosphonate-related osteonecrosis of the jaws has become a reality in dental clinical practice. Although palliative treatment aiming at controlling pain, infection and injury progression is indicated, the therapeutic strategy is still challenging. So far, the best approach available is prevention, based on oral care before, during, and after bisphosphonate therapy.

  17. Bisphosphonates use and risk of gastric cancer: an updated meta-analysis of cohort and case-control studies.

    Science.gov (United States)

    Cai, Dawei; Qin, Jian; Chen, Guangxia; Feng, Wan; Liu, Jun

    2017-10-01

    Studies evaluating the association between bisphosphonates exposure and gastric cancer (GC) risk have reached inconsistent conclusions. The purpose of this updated meta-analysis was to assess whether bisphosphonates exposure were associated with an increased risk of GC. We searched PubMed and Embase database and reviewed reference lists of retrieved articles to identify potential studies. Study selection and data abstraction were performed by two independent observers. We calculated pooled odds ratios and 95% CIs using the random effects models. The pooled relative risk showed no significant relationship between bisphosphonates exposure and GC risk (adjusted OR, 0.996, 95% CI, 0.860-1.152). The results were stable across stratified analysis on study design, sex, and duration of follow-up and geographic locations. We also investigated whether different types of bisphosphonates affected the pooled RR. Neither use of bisphosphonates, alendronate, nor etidronate was associated with GC risk. Our meta-analysis found no overall association between GC risk and bisphosphonates use. Further studies with large sample size and more covariate adjustments are needed.

  18. Oral Bisphosphonates and the Risk of Barrett's Esophagus: Case–Control Analysis of US Veterans

    Science.gov (United States)

    Lin, Derek; Kramer, Jennifer R.; Ramsey, David; Alsarraj, Abeer; Verstovsek, Gordana; Rugge, Massimo; Parente, Paola; Graham, David Y.; El-Serag, Hashem B.

    2014-01-01

    OBJECTIVES This study examined Barrett's esophagus (BE) risk factors in veterans to determine the association between risk of BE and use of oral bisphosphonates. METHODS We conducted a case – control study among eligible patients scheduled for an elective esophagogastroduodenoscopy (EGD) and a sample of patients eligible for screening colonoscopy recruited from primary care clinics from a single VA Medical Center. Cases with definitive BE were compared with controls; all underwent study EGD. Use of oral bisphosphonates was ascertained by reviewing filled prescriptions in electronic pharmacy records. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs), using multivariate logistic regression modeling while adjusting for sex, age, race, proton-pump inhibitor use, hiatal hernia, waist-to-hip ratio, Helicobacter pylori infection, and gastroesophageal reflux disorder (GERD) symptoms. RESULTS There were 285 BE cases, 1,122 endoscopy controls, and 496 primary care controls. Alendronate and risedronate were the only oral bisphosphonates prescribed. The proportion of BE cases with filled prescription of oral bisphosphonates (4.6%) was greater than in endoscopy controls (1.6%) or primary care controls (2.9%). In the adjusted analysis, oral bisphosphonate use was significantly associated with BE risk (OR = 2.33; 95% CI: 1.11 – 4.88) compared with the combined control groups. This association remained significant when BE cases were compared with endoscopy controls only (OR = 2.74; 95% CI: 1.28 – 5.87) but was attenuated when compared with primary care controls only (OR = 2.60; 95% CI: 0.99 – 6.84). The association was observed in patients with GERD symptoms (OR = 3.29; 95% CI: 1.36 – 7.97) but not in those without GERD symptoms. CONCLUSIONS Oral bisphosphonate use may increase the risk for BE, especially among patients with GERD. PMID:23857477

  19. Efficacy and Safety of Bisphosphonates for Low Bone Mineral Density After Kidney Transplantation

    Science.gov (United States)

    Kan, Shun-Li; Ning, Guang-Zhi; Chen, Ling-Xiao; Zhou, Yong; Sun, Jing-Cheng; Feng, Shi-Qing

    2016-01-01

    Abstract In patients with low bone mineral density (BMD) after kidney transplantation, the role of bisphosphonates remains unclear. We performed a systematic review and meta-analysis to investigate the efficacy and safety of bisphosphonates. We retrieved trials from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception through May 2015. Only randomized controlled trials that compared bisphosphonate-treated and control groups of patients with low bone mineral density after kidney transplantation were included. The primary outcomes were the percent change in BMD, the absolute change in BMD, and the BMD at the end of study at the lumbar spine. The results were expressed as the mean difference (MD) or relative risk (RR) with the 95% confidence interval (CI). We used a random-effects model to pool the outcomes. We included 17 randomized controlled trials with 1067 patients. Only 1 included trial was found to be at low risk of bias. The rest of the included studies were found to have high to uncertain risk of bias. Compared with the control group, those who received bisphosphonates had a significant increase in percent change in BMD (mean difference [MD] = 5.51, 95% confidence interval [CI] 3.22–7.79, P Bisphosphonates resulted in a significant improvement in percent change in BMD (MD = 4.95, 95% CI 2.57–7.33, P Bisphosphonates appear to have a beneficial effect on BMD at the lumbar spine and do not significantly decrease fracture events in recipients. However, the results should be interpreted cautiously due to the lack of robustness and the heterogeneity among studies. PMID:26844505

  20. Long-term use of bisphosphonates in osteoporosis

    Directory of Open Access Journals (Sweden)

    Basmah K. Alwahhabi

    2017-06-01

    Full Text Available Objectives: To report and describe the management and response to treatment of patients referred to the osteoporosis clinic after prolonged use of bisphosphonate BPs (4 years and more with and without new fracture (any site or any other new skeletal symptoms. Methods: This is a single center observational retrospective cohort study conducted from January 2009 to May 2016 in a tertiary center. We describe cause of referral, X-rays findings, management, and response to treatment. Results: Thirty-four patients, aged 46-89 years, were collected. Reason for referral included review of therapy (11 patients, recent low trauma fracture (21 patients, or chronic severe thigh pain (2 patients of unknown etiology. All patients with fracture or thigh pain (23/34 patients were treated with teriparatide 20 mcg daily. Sixteen of them (16/23 completed teriparatide course (18-24 months, 11 patients had complete healing of fracture at the end of the course, and 5 remained with nonunion of fracture, the remaining 5 patients were lost to follow up. Conclusion: Prolonged use of bisphosphonates can lead to atypical femoral fracture that may involve sites other than femoral shaft or rarely chronic thigh pain without fracture. Teriparatide may facilitates fracture healing and improve thigh pain.

  1. A Case Report of Bisphosphonate-induced Bilateral Osteoporotic Subtrochanteric Fracture Femurii: Review of Literature.

    Science.gov (United States)

    Uppin, Rajendra; Gupta, Srinath; Prakash, Shivank

    2016-01-01

    Osteoporosis is a significant health-care problem characterized by excessive skeletal fragility, susceptibility to low-trauma fractures in men as well as women. Any abnormality of the bone that reduces the strength of the bone predisposes it to mechanical failure during normal activity or with minimum trauma. The mechanical failure manifests itself as a fracture, and this fracture must be recognized as a pathological fracture if the patient is to be treated properly. Osteoporosis is one of the leading causes of such pathological fractures and accounts for 1.5 million fractures annually. In the following case report, we present a 56-year-old postmenopausal female patient with bilateral pathological subtrochanteric fracture femurii due to intake of bisphosponates for 4 years for osteoporosis. Bilateral pathological subtrochanteric femurii fractures are extremely uncommon injuries which occur in adults who sustain injuries due to trivial trauma. A variety of management modalities has been tried to treat this complex fracture pattern. Standard fixation treatment is intramedullary nailing. A postmenopausal female of rheumatoid arthritis aged 56 years, presented to our emergency department with a history of trivial fall at home. Following the fall, she was unable to bear weight on bilateral feet and complained of deformity. History revealed consumption of bisphosphonates (tablet alendronate 10 mg) for the last 4 years and glucocorticoids for rheumatiod arthritis. Radiographs were taken, which revealed bilateral pathological subtrochanteric fracture femurii. After obtaining necessary fitness, the patient was taken up for surgery. Closed reduction and Internal fixation with long proximal femoral nail were done. Bisphosphonate intake was stopped and teriparatide 20 µg/day subcutaneously given for 3 months. Fracture healed after 3 months and patient resumed her daily activities. In people taking long-term bisphoshponate therapy, symptomatic cortical stress reactions

  2. Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study.

    Science.gov (United States)

    Coloma, P M; de Ridder, M; Bezemer, I; Herings, R M C; Gini, R; Pecchioli, S; Scotti, L; Rijnbeek, P; Mosseveld, M; van der Lei, J; Trifirò, G; Sturkenboom, M

    2016-05-01

    Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy. A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data. This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates. A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6

  3. Bisphosphonate induced osteonecrosis of jaw in breast cancer patients: A systematic review.

    Science.gov (United States)

    Varun, Br; Sivakumar, Tt; Nair, Bindu J; Joseph, Anna P

    2012-05-01

    Bisphosphonate therapy is widely used for the treatment of bone metastasis in breast cancer patients. The aim of this study is to estimate the overall prevalence of bisphosphonate induced osteonecrosis of jaw (BONJ) in breast cancer patients with bone metastasis. A literature review was conducted to search and evaluate all the articles that contained original data on the prevalence of BONJ in breast cancer patients from the year 2003-2009. Pubmed search terms used were bisphosphonate, osteonecrosis, breast cancer and jaw. Eleven publications that fulfilled the inclusion criteria were chosen for the study. Case reports and reviews were excluded from the analysis based on assessing the title and abstract. Of the 2490 breast cancer patients, 69 developed BONJ with the overall prevalence rate of 2.8%. All the patients with BONJ had received zoledronate or pamidronate, either alone or in combinations. BONJ is a significant complication occurring in 2.8% of the breast cancer patients receiving bisphosphonates for metastatic bone disease. It is very important to identify the trigger factors associated with BONJ and also to establish guidelines for the prevention and effective treatment of this condition.

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

    Directory of Open Access Journals (Sweden)

    Candice Belchior Duplat

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Candice Belchior Duplat

    2012-08-01

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

  6. Switching of oral bisphosphonates to denosumab in chronic glucocorticoid users: a 12-month randomized controlled trial.

    Science.gov (United States)

    Mok, Chi Chiu; Ho, Ling Yin; Ma, Kwok Man

    2015-06-01

    To evaluate the effect of switching from oral bisphosphonates to denosumab on bone mineral density (BMD) in long-term glucocorticoid users. Adult patients who were receiving long-term prednisolone (≥2.5 mg/day for ≥1 year) and oral bisphosphonates (≥2 years) were recruited. Participants were randomized to either continue oral bisphosphonates or switch to denosumab (60 mg subcutaneously every 6 months) for 12 months. Serial BMD (lumbar spine, hip) and bone turnover markers (serum osteocalcin, P1NP, β-CTX) were measured. 42 women were recruited (age 54.7±12.9 years; 21 shifted to denosumab and 21 continued on bisphosphonates). The duration of prednisolone therapy was 101±66.3 months and the daily dose was 4.4±2.1 mg. Baseline demographic data, osteoporosis risk factors, and BMD at various sites were similar between the two groups of patients. At month 12, BMD of the spine and hip increased by +3.4±0.9% (p=0.002) and +1.4±0.6% (p=0.03), respectively, in the denosumab group; whereas the corresponding change was +1.5±0.4% (p=0.001) and +0.80±0.5% (p=0.12) in the bisphosphonate group. The spinal BMD at month 12 was significantly higher in the denosumab than bisphosphonate group after adjustment for baseline BMD and β-CTX values, and other confounding factors (p=0.01). Bone turnover markers (β-CTX and P1NP) were more strongly suppressed by denosumab than the bisphosphonates. Minor infections were more common in denosumab-treated patients while other adverse events occurred at similar frequencies between the two groups. In patients receiving long-term glucocorticoids, switching from oral bisphosphonates to denosumab resulted in greater gain of the spinal BMD and suppression of bone turnover markers after 12 months of therapy. The results have to be confirmed by a larger clinical trial with fracture as endpoint. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Interventions to increase adherence to acne treatment

    Directory of Open Access Journals (Sweden)

    Moradi Tuchayi S

    2016-10-01

    Full Text Available Sara Moradi Tuchayi,1 Tiffany M Alexander,2 Anish Nadkarni,1 Steven R Feldman1,3,4 1Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, 2Howard University College of Medicine, Washington, DC, 3Department of Public Health Sciences, 4Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA Background: Adherence to acne medication is poor and is a major reason why treatment plans are ineffective. Recognizing solutions to nonadherence is critical. Objective: The purpose of this study is to describe the hurdles associated with acne nonadherence and to provide mechanisms on how to ameliorate them. Methods: PubMed database was searched. Of the 419 search results, 29 articles were reviewed to identify hurdles to adherence and corresponding solutions. Results: Hurdles to primary nonadherence where the medication is not even started, include lack of knowledge, confusion about usage, weak physician–patient relationship, fear of adverse reactions, and cost. Secondary nonadherence hurdles where the medication is started but is not taken as directed include lack of results, complex regimens, side effects, busy lifestyle, forgetfulness, inconvenience, and psychiatric comorbidity. Solutions to these hurdles include treatment simplification, technology, and dynamic education. Limitations: Adherence is affected by numerous factors, but available literature analyzing acne adherence and interventions to improve adherence to treatment is limited. Conclusion: There are several hurdles in adhering to acne treatment. Recognition of these hurdles and finding appropriate solutions may be as important to treatment outcomes as choosing the right medication to prescribe. Keywords: acne vulgaris, adherence, pathogenesis, treatment, quality of life, prevalence, physician–patient relationship, lifestyle, clinic visit, disease severity

  8. Indirect comparison of bazedoxifene vs oral bisphosphonates for the prevention of vertebral fractures in postmenopausal osteoporotic women.

    Science.gov (United States)

    Ellis, Alexandra G; Reginster, Jean-Yves; Luo, Xuemei; Bushmakin, Andrew G; Williams, Robert; Sutradhar, Santosh; Mirkin, Sebastian; Jansen, Jeroen P

    2014-08-01

    Compare the efficacy of bazedoxifene with oral bisphosphonates for reduction of vertebral fracture risk in postmenopausal osteoporotic (PMO) women and in higher-risk patients based on evidence from randomized controlled trials (RCTs). Eight RCTs assessing vertebral fracture risk reduction with oral bisphosphonates (n = 7) or bazedoxifene (n = 1) were identified by a systematic literature review. Individual study results were pooled in a network meta-analysis (NMA) to indirectly compare treatment effects for overall PMO women and a higher-risk subgroup (FRAX ≥ 20%). Three sets of NMA analyses were conducted: aggregate data (AD) from the bisphosphonate RCTs and bazedoxifene RCT for the full population or the FRAX ≥20% subgroup (NMA AD); bisphosphonate AD and bazedoxifene AD from each FRAX subgroup adjusted for baseline risk (NMA AD meta-regression); and bisphosphonate AD and bazedoxifene individual patient data (IPD) adjusted for baseline risk/FRAX (NMA AD/IPD meta-regression). For the overall population, bisphosphonates had lower fracture risks versus bazedoxifene although there is considerable uncertainty in supporting one intervention over another. The relative risk reduction (RRR) for bazedoxifene was -0.23 (95% CrI: -1.11, 0.27) versus ibandronate, -0.17 (-0.76, 0.22) versus alendronate, and -0.06 (-0.62, 0.30) versus risedronate. RESULTS from the meta-regression analyses were similar. For the FRAX ≥20% population, estimated fracture rates with bazedoxifene were lower than with bisphosphonates, but again the uncertainty limits strong interpretation. The RRR for bazedoxifene was 0.51 (-0.31, 0.83) versus ibandronate, 0.53 (-0.18, 0.83) versus alendronate, and 0.57 (-0.07, 0.85) versus risedronate. The meta-regression analyses showed comparable findings. The analyses only considered vertebral fractures for oral bisphosphonates versus bazedoxifene, and IPD was available only for bazedoxifene. In light of this, bazedoxifene is comparable to

  9. 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.

  10. 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.

  11. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin

    Science.gov (United States)

    Xia, Yifeng; Liu, Yi-Liang; Xie, Yonghua; Zhu, Wei; Guerra, Francisco; Shen, Shen; Yeddula, Narayana; Fischer, Wolfgang; Low, William; Zhou, Xiaoying; Zhang, Yonghui; Oldfield, Eric; Verma, Inder M.

    2015-01-01

    Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not yet been successfully targeted. Here, we describe a combination therapy for treating these malignancies using two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of the KRAS and other small G-proteins critical for tumor growth and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant NF-κB activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mTOR pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations. PMID:25411474

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

    Directory of Open Access Journals (Sweden)

    J. Joshi Otero

    2011-03-01

    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.

  13. Bisphosphonate-related osteonecrosis of the jaws (Bronj).

    Science.gov (United States)

    Beninati, Francesco; Pruneti, Riccardo; Ficarra, Giuseppe

    2013-09-01

    Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is an extremely therapy resistant osteomyelitis-like disease exclusively involving the jaw bones of patients in treatment with bisphosphonates (BPs). The aim of this study was to evaluate the radiological and clinical findings and management of 51 patients with BRONJ diagnosed from 2004 to 2009 in our Reference Center. A prospective study was performed. The patients were examined every 2-6 months, depending on their clinical conditions. Positive outcome variables were the resolution of symptoms, persistence of bone exposure and /or fistula and the status of the lesional mucosa. The higher prevalence of the disease was noted in 2006 and 2007 and at the time of diagnosis 90% of patients had been treated with iv BPs. The main precipitating event leading to BRONJ was an invasive dental procedure in 61% of patients while no traumatic event could be identified in 16% of patients. The median time of follow-up was 19 months (range: 2-57), during which 31% of patients healed and 39% succumbed. In 78% of patients the therapy was medical, in 16% it consisted in surgical deep curettage and only in 6% it was necessary to perform an osteotomy to avoid a mandibular pathological fracture. All the patients in treatment with oral BPs healed from BRONJ with a median time of conservative treatment of 19 months. Prevention has lead to a progressive reduction in the prevalence of BRONJ. In our experience medical treatment is often sufficient to keep the disease under control and to lead to the healing of the lesions by spontaneous loss of the sequestrum. This approach seems to be very effective in patients who were in treatment with oral Bps preparations; BRONJ seems to have a more benign clinical behaviour in these patients.

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

    Directory of Open Access Journals (Sweden)

    Modi A

    2015-11-01

    interval 0.54–0.68. Conclusion: GI events after OP diagnosis were associated with a decreased likelihood of OP treatment initiation and an increased likelihood of treatment initiation with a non-bisphosphonate versus a bisphosphonate. Keywords: osteoporosis, postmenopausal, bisphosphonates, prescribing patterns

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

    DEFF Research Database (Denmark)

    Diez-Perez, Adolfo; Naylor, K E; Abrahamsen, B

    2017-01-01

    Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug....... INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified...... bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3...

  16. 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

  17. 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

  18. Impact of the U.S. Food and Drug Administration's Safety-Related Announcements on the Use of Bisphosphonates After Hip Fracture.

    Science.gov (United States)

    Kim, Seoyoung C; Kim, Dae Hyun; Mogun, Helen; Eddings, Wesley; Polinski, Jennifer M; Franklin, Jessica M; Solomon, Daniel H

    2016-08-01

    The U.S. Food and Drug Administration (FDA) issued several announcements related to potential risk of bisphosphonates including osteonecrosis of the jaw (2005), atrial fibrillation (2007), and atypical femur fracture (2010). We aimed to evaluate the impact of three FDA drug safety announcements on the use of bisphosphonates in patients with hip fracture using claims data from a U.S. commercial health plan (2004-2013). We calculated the proportion of patients in each quarter who received a bisphosphonate or other osteoporosis medication in the 6 months following hospitalization for hip fracture. Segmented logistic regression models examined the time trends. Among 22,598 patients with hip fracture, use of bisphosphonate decreased from 15% in 2004 to 3% in the last quarter of 2013. Prior to the 2007 announcement, there was a 4% increase in the odds of bisphosphonate use every quarter (OR 1.04; 95% CI, 1.02 to 1.07). After the 2007 announcement, there was a 4% decrease in the odds of bisphosphonate use (OR 0.96; 95% CI, 0.93 to 0.99) every quarter. The announcement in 2007 was associated with a significant decline in the rate of change of bisphosphonate uses over time (p bisphosphonate use continued to decrease by 4% (OR 0.96; 95% CI, 0.94 to 0.98) each quarter and the odds of other osteoporosis medication use remained stable over time (OR 0.99; 95% CI, 0.96 to 1.02). The FDA safety announcement related to atrial fibrillation in 2007 was significantly associated with a decrease in bisphosphonate use among patients with hip fracture. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

  19. Osteonecrosis of jaw associated with bisphosphonate use

    Directory of Open Access Journals (Sweden)

    Ashu Rastogi

    2012-01-01

    Full Text Available Bisphosphonates are associated with osteonecrosis of the jaw (ONJ that is defined as an area of exposed, nonvital bone in the maxilla or mandible persisting over 6-8 weeks. We describe a case of 55-year-old female who developed ONJ after tooth extraction and had been receiving oral ibandronate for osteoporosis. Diagnosis of ONJ was confirmed on CT scan. The patient was managed conservatively as she denied teriparatide therapy because of cost constraints.

  20. Development of clinical utility of zoledronic acid and patient considerations in the treatment of osteoporosis

    Directory of Open Access Journals (Sweden)

    Johann D Ringe

    2010-06-01

    Full Text Available Johann D RingeDirektor der Med. Klinik 4, Allgemeine Innere, und Westdeutsches Osteoporose Zentrum (WOZ, Klinikum Leverkusen gGmbH, Leverkusen, GermanyAbstract: Osteoporosis is a major health concern, which results in the increased risk of fractures. There is a high risk for the first or consecutive fractures leading to considerable morbidity and debilitating consequences if osteoporosis is untreated. Currently, bisphosphonates are the mainstay of treatment for osteoporosis though long-term persistence and adherence to bisphosphonates, especially those taken orally, remain low. This medication noncompliance has serious consequences on osteoporotic patients as it is associated with a significantly higher fracture risk. Intravenous (IV zoledronic acid (ZOL, developed to increase compliance by overcoming the frequent and burdensome dosing requirements of oral bisphosphonates, is the first and the only once-yearly bisphosphonate globally approved for use in the treatment of up to 6 indications of osteoporosis. Several clinical studies have documented that a single infusion of IV ZOL resulted in decreased bone turnover and improved bone density for at least 12 months post infusion. This article traces the development of ZOL’s clinical utility and evaluates its patient preference by collating data from all major clinical trials, studying the efficacy and safety of ZOL in the treatment of osteoporosis and other benign bone disorders.Keywords: bisphosphonates, patient preference, efficacy, safety, Paget’s disease

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

    Directory of Open Access Journals (Sweden)

    Lih Anna

    2005-07-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusion 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.

  2. Frequency and Risk Factors Associated With Osteonecrosis of the Jaw in Cancer Patients Treated With Intravenous Bisphosphonates

    Science.gov (United States)

    O Hoff, Ana; Toth, Béla B; Altundag, Kadri; Johnson, Marcella M; Warneke, Carla L; Hu, Mimi; Nooka, Ajay; Sayegh, Gilbert; Guarneri, Valentina; Desrouleaux, Kimberly; Cui, Jeffrey; Adamus, Andrea; Gagel, Robert F; Hortobagyi, Gabriel N

    2008-01-01

    Introduction Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. The incidence and risk factors associated with this disorder have not been clearly defined. Materials and Methods We conducted a retrospective analysis of 4019 patients treated with intravenous bisphosphonates between 1996 and 2004. Our goals were to estimate the frequency, understand the clinical presentation, and identify risk factors associated with ONJ development. Results Sixteen of 1338 patients with breast cancer (1.2%) and 13 of 548 patients with multiple myeloma (2.4%) developed ONJ. The median dose and duration of treatment with pamidronate or zoledronic acid were significantly higher in patients with ONJ (p breast cancer. In multiple myeloma, dental extractions (HR, 9.78; 95% CI: 3.07–31.14; p = 0.0001) and osteoporosis (HR, 6.11; 95% CI: 1.56–23.98; p = 0.0095) were significant risk factors while controlling for bisphosphonate therapy. Thirteen of 29 patients were followed for a median of 17.1 mo (range, 7–67 mo); lesions healed in 3 patients during this period. Conclusions ONJ is an uncommon but long-lasting disorder that occurs mainly in breast cancer and multiple myeloma patients treated with intravenous bisphosphonates. High cumulative doses of bisphosphonates, poor oral health, and dental extractions may be significant risk factors for ONJ development. ONJ resolved in 23% of patients with conservative therapy. PMID:18558816

  3. Osteonecrosis of the jaw as a possible rare side effect of annual bisphosphonate administration for osteoporosis: A case report

    Directory of Open Access Journals (Sweden)

    Ehrenfeld Michael

    2011-09-01

    Full Text Available Abstract Introduction Osteonecrosis of the jaw is a serious side effect in patients receiving nitrogen-containing bisphosphonates intravenously due to malignant diseases. Albeit far less frequently, osteonecrosis of the jaw has also been reported to occur due to the oral administration of nitrogen-containing bisphosphonates due to osteoporosis. Annual infusions of zoledronic acid have been recommended in order to improve patient compliance, to optimize therapeutic effects and to minimize side effects. To date, osteonecrosis of the jaw has not been linked to the annual administration of bisphosphonates. Case presentation We report the case of a 65-year-old Caucasian woman suffering from osteoporosis who developed early stage osteonecrosis of the jaw in two locations, with chronic infections, after two months of oral bisphosphonate treatment and three annual administrations of zoledronic acid. Our patient was treated by fluorescence-guided resection of the necrotic jaw bone areas; local inflammation was treated by removal of a wisdom tooth and repeat root resections. Histopathology revealed typical hallmarks of osteonecrosis of the jaw. Conclusion Osteonecrosis of the jaw may occur as a consequence of annual administrations of zoledronic acid. It is conceivable that, due to the pharmacological properties of bisphosphonates, a jaw bone that encounters frequent local inflammations is more likely to develop osteonecrosis.

  4. Long-term treatment with alendronate increases the surgical difficulty during simple exodontias - an in vivo observation in Holtzman rats.

    Science.gov (United States)

    Conte-Neto, Nicolau; Bastos, Alliny de Souza; Spolidorio, Luis Carlos; Chierici Marcantonio, Rosemary Adriana; Marcantonio, Elcio

    2012-07-26

    Atraumatic teeth extractions protocols are highly encouraged in patients taking bisphosphonates (Bps) to reduce surgical trauma and, consequently, the risk of jaws osteonecrosis development. In this way, this paper aims to report the findings of increased surgical difficulty during simple exodontias in animals treated with bisphosphonates. Sixty male Holtzman rats were randomly distributed into three groups of 20 animals and received daily subcutaneous administration of 1 mg/kg (AL1) or 3 mg/kg (AL3) of alendronate or saline solution (CTL). After 60 days of drug therapy all animals were submitted to first lower molars extractions under general anesthesia. Operatory surgical time and the frequency of teeth fractures were measured as principal outcomes and indicators of surgical difficulty degree. Animals treated with alendronate (AL1 and AL3) were associated to higher operatory times and increased frequency of teeth fractures compared to match controls. The bisphosphonate therapy may be associated with an increased surgical difficulty and trauma following simple exodontias protocols, which is considered a critical issue when it comes to osteonecrosis development.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study

    Science.gov (United States)

    2011-01-01

    Background Bisphosphonates are common first line medications used for the management of benign bone disease. One of the most devastating complications associated with bisphosphonate use is osteonecrosis of the jaws which may be related to duration of exposure and hence cumulative dose, dental interventions, medical co-morbidities or in some circumstances with no identifiable aggravating factor. While jaw osteonecrosis is a devastating outcome which is currently difficult to manage, various forms of delayed dental healing may be a less dramatic and, therefore, poorly-recognised complications of bisphosphonate use for the treatment of osteoporosis. It is hypothesised that long-term (more than 1 year's duration) bisphosphonate use for the treatment of post-menopausal osteoporosis or other benign bone disease is associated with impaired dental healing. Methods/Design A case-control study has been chosen to test the hypothesis as the outcome event rate is likely to be very low. A total of 54 cases will be recruited into the study following review of all dental files from oral and maxillofacial surgeons and special needs dentists in Victoria where potential cases of delayed dental healing will be identified. Potential cases will be presented to an independent case adjudication panel to determine if they are definitive delayed dental healing cases. Two hundred and fifteen controls (1:4 cases:controls), matched for age and visit window period, will be selected from those who have attended local community based referring dental practices. The primary outcome will be the incidence of delayed dental healing that occurs either spontaneously or following dental treatment such as extractions, implant placement, or denture use. Discussion This study is the largest case-controlled study assessing the link between bisphosphonate use and delayed dental healing in Australia. It will provide invaluable data on the potential link between bisphosphonate use and osteonecrosis of the jaws

  7. Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study

    Directory of Open Access Journals (Sweden)

    Thomson Wendy

    2011-04-01

    Full Text Available Abstract Background Bisphosphonates are common first line medications used for the management of benign bone disease. One of the most devastating complications associated with bisphosphonate use is osteonecrosis of the jaws which may be related to duration of exposure and hence cumulative dose, dental interventions, medical co-morbidities or in some circumstances with no identifiable aggravating factor. While jaw osteonecrosis is a devastating outcome which is currently difficult to manage, various forms of delayed dental healing may be a less dramatic and, therefore, poorly-recognised complications of bisphosphonate use for the treatment of osteoporosis. It is hypothesised that long-term (more than 1 year's duration bisphosphonate use for the treatment of post-menopausal osteoporosis or other benign bone disease is associated with impaired dental healing. Methods/Design A case-control study has been chosen to test the hypothesis as the outcome event rate is likely to be very low. A total of 54 cases will be recruited into the study following review of all dental files from oral and maxillofacial surgeons and special needs dentists in Victoria where potential cases of delayed dental healing will be identified. Potential cases will be presented to an independent case adjudication panel to determine if they are definitive delayed dental healing cases. Two hundred and fifteen controls (1:4 cases:controls, matched for age and visit window period, will be selected from those who have attended local community based referring dental practices. The primary outcome will be the incidence of delayed dental healing that occurs either spontaneously or following dental treatment such as extractions, implant placement, or denture use. Discussion This study is the largest case-controlled study assessing the link between bisphosphonate use and delayed dental healing in Australia. It will provide invaluable data on the potential link between bisphosphonate use

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

    Science.gov (United States)

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

    2017-07-03

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

  9. Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss

    Science.gov (United States)

    LeBlanc, Adrian; Matsumoto, Toshio; Jones, Jeffrey A.; Shapiro, Jay; Lang, Thomas F.; Smith, Scott M.; Shackelford, Linda C.; Sibonga, Jean; Evans, Harlan; Spector, Elisabeth; hide

    2009-01-01

    Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss (Bisphosphonates) will determine whether antiresorptive agents, in conjunction with the routine inflight exercise program, will protect ISS crewmembers from the regional decreases in bone mineral density documented on previous ISS missions.

  10. Differential effects of bisphosphonates on breast cancer cell lines

    NARCIS (Netherlands)

    Verdijk, R.; Franke, H.R.; Wolbers, F.; Vermes, I.

    2007-01-01

    Bisphosphonates may induce direct anti-tumor effects in breast cancers cells in virtro. In this study, six bisphosphonates were administered to three breast caner cell lines. Cell proliferation was measured by quantification of th expressio of Cyclin D1 mRNA. Apoptosis was determined by flow

  11. Combining bisphosphonates with allograft bone for implant fixation

    NARCIS (Netherlands)

    Mathijssen, N.M.C.; Buma, P.; Hannink, G.J.

    2014-01-01

    The aim of this review was to discuss the current state of research of combining bisphosphonates with allograft bone for implant fixation. The allograft bone can only be reached by the bisphosphonate once it has been revascularized. However, this can be circumvented by local administration of

  12. 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

  13. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer.

    Science.gov (United States)

    Guarneri, Valentina; Miles, David; Robert, Nicholas; Diéras, Véronique; Glaspy, John; Smith, Ian; Thomssen, Christoph; Biganzoli, Laura; Taran, Tanya; Conte, PierFranco

    2010-07-01

    Long-term bisphosphonate therapy is associated with increased risk of osteonecrosis of the jaw (ONJ). In a retrospective analysis, a 16% ONJ incidence was reported in patients receiving bisphosphonates with anti-angiogenic therapy (bevacizumab or sunitinib) for bone metastases from breast, colon, or renal cell cancers. To assess ONJ incidence with bevacizumab, we analysed data from 3,560 patients receiving bevacizumab-containing therapy for locally recurrent or metastatic breast cancer (LR/MBC) in two double-blind, randomised trials (AVADO and RIBBON-1) and a large, non-randomised safety study (ATHENA). The overall incidence of ONJ with bevacizumab was 0.3% in the blinded phase of the two randomised trials and 0.4% in the single-arm study. There was a trend towards increased ONJ incidence in patients who received bisphosphonate therapy versus those with no bisphosphonate exposure (0.9 vs. 0.2%, respectively, in the pooled analysis of the randomised trials; 2.4 vs. 0%, respectively, in ATHENA). In conclusion, this is the largest analysis of ONJ in patients receiving bevacizumab for LR/MBC. The 0.3-0.4% incidence is considerably lower than previously suggested with anti-angiogenic therapy in a small retrospective analysis. The risk of ONJ appeared to be increased in patients exposed to bisphosphonates, a pattern consistent with observations before the introduction of anti-angiogenic therapy to breast cancer management. The 0.9-2.4% incidence seen in bisphosphonate-exposed patients receiving bevacizumab is within the 1-6% range reported for bisphosphonates alone. Good oral hygiene, dental examination, and avoidance of invasive dental procedures remain important in patients receiving bisphosphonates, irrespective of bevacizumab administration.

  14. 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....

  15. 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.

  16. Prevention of vascular calcification with bisphosphonates without affecting bone mineralization: a new challenge?

    Science.gov (United States)

    Neven, Ellen G; De Broe, Marc E; D'Haese, Patrick C

    2009-03-01

    Arterial calcification has been found to coexist with bone loss. Bisphosphonates, used as standard therapy for osteoporosis, inhibit experimentally induced vascular calcification, offering perspectives for the treatment of vascular calcification in renal failure patients. However, Lomashvili et al. report that the doses of etidronate and pamidronate that are effective in attenuating aortic calcification also decrease bone formation and mineralization in uremic rats, limiting their therapeutic use as anticalcifying agents.

  17. [Clinical features of osteonecrosis of jaws after bisphosphonates therapy for bone metastasis of breast cancer].

    Science.gov (United States)

    Guo, Yu-xing; Wang, Dian-can; Wang, Yang; Peng, Xin; Mao, Chi; Guo, Chuan-bin

    2016-02-18

    To understand the clinical features of osteonecrosis of the jaw after bisphosphonates use for therapy of breast cancer patients with bone metastasis. The cases diagnosed as bisphosphonates-related osteonecrosis of the jaws (BRONJ) were retrospectively analyzed from January 2011 to August 2015 in the Peking University School and Hospital of Stomatology, and those breast cancer patients with bone metastasis were selected. The clinical symptoms, imaging characteristics and treatment results were summarized. A total of 14 cases of breast cancer patients with bone metastasis were selected, with an average age of 60.21 years. The average time of suffering from breast cancer was 9.77 years, and the average time of bone metastasis and bisphosphonates drugs use was 5.67 and 3.29 years individually. There was no patient with systemic application history of hormone therapy, and no history of diabetes. There were 9 patients with tooth extractions history, and the mean time of bone necrosis symptoms was 8.58 months. There were 10 cases with bone necrosis occurring on mandible, 3 cases on maxilla, and one case with both upper and lower jaws involved. Among the 10 patients with surgical treatment, there were 3 cases cured, and 6 cases improved. However, the clinical symptoms of 2 cases with conservative treatment were significantly aggravated. The medication time between the bisphosphonates use beginning and the occurrence of BRONJ is relatively long. The history of diabetes and long-time hormone use did not exist in this group. Tooth extraction itself does not determine the severity of BRONJ. Mandible is the most common site involved by BRONJ. Surgical treatment can alleviate the clinical symptoms of BRONJ with breast cancer to some extent.

  18. 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.

  19. A survey of consultant members of the British Association of Oral and Maxillofacial Surgeons regarding bisphosphonate-induced osteonecrosis of the jaws.

    Science.gov (United States)

    Rogers, S N; Hung, J; Barber, A J; Lowe, D

    2009-12-01

    The aims of this survey of consultants in the British Association of Oral and Maxillofacial Surgeons were threefold. Firstly, to estimate the number of patients screened for oral health before starting intravenous bisphosphonate medication, secondly, to indicate the use of antibiotics in patients on bisphosphonates who need routine extraction of a lower first molar tooth, and finally to estimate the number of new and currently managed cases of bisphosphonate-induced osteonecrosis of the jaw (BONJ) in the last year, and approximately how many of those currently being managed had healed. A questionnaire was mailed to 322 consultants working at 154 hospitals in the summer of 2008. There were responses from 184 consultants (57%) and from 111 hospitals (72%). Screening patients before starting intravenous bisphosphonates was uncommon (15%). Almost all consultants would prescribe antibiotics for molar extraction and in about two-thirds this was both before and after extraction. Relatively few would stop bisphosphonates. Nearly two-thirds of consultants had seen new cases of BONJ from intravenous treatment in the last year, and a quarter had seen three or more. A similar proportion had patients on intravenous bisphosphonates under review for BONJ, and it was estimated that in a fifth of patients the lesion had healed. This survey indicates current practice among oral and maxillofacial surgeons in the UK. A national project for the registration of new patients will provide a stronger evidence base with respect to incidence, risk factors, and management of BONJ.

  20. 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

  1. Bisphosphonate-related osteonecrosis of jaws in advanced stage breast cancer was detected from bone scan: a case report

    Science.gov (United States)

    Chirappapha, Prakasit; Thongjood, Thanaporn; Aroonroch, Rangsima

    2017-01-01

    Bisphosphonates (BPs) are indicated to treat skeletal-related events (SREs) for cancer patients with bone metastasis. We report a 79-year-old woman with advanced stage breast cancer with bone metastasis who was prescribed BPs (zoledronate), then developed osteonecrosis of jaw. We provide a brief review of the pathogenesis, diagnosis and treatment of this complication. PMID:28210558

  2. Bisphosphonates and jaw osteonecrosis in patients with advanced breast cancer.

    Science.gov (United States)

    Sanna, G; Preda, L; Bruschini, R; Cossu Rocca, M; Ferretti, S; Adamoli, L; Verri, E; Franceschelli, L; Goldhirsch, A; Nolè, F

    2006-10-01

    In recent years, several cases of mandibular necrosis associated with long-term use of bisphosphonates have been reported. The estimated incidence varies from 1% to 4.6%. We conducted an observational study with the aim of determining the incidence of jaw osteonecrosis in advanced breast cancer patients with bone metastases under bisphosphonate treatment and to identify subjects at higher risk of developing this complication evaluating preclinical signs. We considered two groups of patients. All the patients complaining of odontostomatological symptoms underwent maxillary CT scan and maxillo-surgeon clinical examination. Asymptomatic patients were asked to perform a standard orthopantomography (OPT). From February 2005 to October 2005, we observed five patients with jaw bone necrosis (6%). Diagnosis was radiological and clinical. In two patients a confirmatory biopsy was performed. In the same time interval, OPTs were collected from 76 asymptomatic patients. Three OPTs revealed radiological features of suspicious mandibular necrosis. Maxillary CT scan confirmed the presence of an osteolityc area with signs of periosteal reaction. All the three patients were referred to maxillo-surgeon and two out of three patients underwent mandibular biopsy, but histopathological results were not conclusive. In our experience, the incidence of jaw bone necrosis in breast cancer patients seems to be higher than in other reports (6%). Radiological features of suspicious jaw necrosis were observed in three asymptomatic patients. We do not know how these findings should be considered. Anyway, standard OPT is a simple procedure, and may allow identification of periodontal conditions that in some way can predispose to the development of this uncommon event.

  3. Atypical femoral fracture due to chronic use of bisphosphonates: case report ☆

    Directory of Open Access Journals (Sweden)

    Eduardo Frois Temponi

    2015-08-01

    Full Text Available ABSTRACT The causal relationship between chronic use of bisphosphonates and occurrences of atypical femoral fractures has not yet been established. Nonetheless, it is known that their chronic use is more related to fractures with a pattern differing from that of classical osteoporotic fractures. Atypical fractures are still rare events and the benefit from using bisphosphonates remains greater for prevention and treatment of osteoporosis. There are few studies guiding the diagnosis and management of these fractures, thus making it difficult to achieve better results. In this report, we present the case of an elderly patient with an atypical femoral fracture that was managed in accordance with guidance from the American Society for Bone and Mineral Research.

  4. Extraction socket healing in rats treated with bisphosphonate: animal model for bisphosphonate related osteonecrosis of jaws in multiple myeloma patients.

    Science.gov (United States)

    Ali-Erdem, Mehmet; Burak-Cankaya, Abdulkadir; Cemil-Isler, Sabri; Demircan, Sabit; Soluk, Merva; Kasapoglu, Cetin; Korhan-Oral, Cuneyt

    2011-11-01

    The aim of this study is to replicate both clinical and histological presentation of bisphosphonate induced osteonecrosis of the jaws (BONJ) in an animal model of the disease state. Successful recapitulation of a BONJ-like indication in an animal model will be useful for studying pathogenesis, as well as prevention and treatment strategies for BONJ. Eighty (80) rats were prospectively and randomly divided into two groups; control group(40) and study group(40). All animals in study group, injected with a dose of 1 mg/kg dexamethasone (DX) subcutaneously on day 7, 14, or 21; and 1, 2, or 3 doses of 7.5 µg/kg zoledronic acid (ZA) subcutaneously administered to coincide with the last day of DX. Half of the animals from each group underwent extraction of the left mandibular molars and the remaining animals underwent extraction of the left maxillary molars under pentobarbital-induced general anesthesia. All animals were euthanized twenty-eight (28) days following tooth extractions. The amount of new bone trabecules as significantly decreased in bisphosphonate-dexamethasone (BP-DX) treated sockets. Difference between both groups was found statistically significant (p=0,0001). There's no foreign body reaction in sockets of both groups and no significance difference observed for fibrosis (p=0,306). The necrosis scores were significantly higher in BP-DX treated sockets (p=0,015). The inflamation scores were significantly higher for study group (p=0,0001). This study provides preliminary observations for the development of an animal model of BONJ. But we think that there is need for other studies have only BP treated group and larger study population.

  5. Bisphosphonates inactivate human EGFRs to exert antitumor actions.

    Science.gov (United States)

    Yuen, Tony; Stachnik, Agnes; 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; Bailey, Jack; Latif, Yathin; Mujtaba, Shiraz; Epstein, Solomon; Davies, Terry F; Bian, Zhuan; Zallone, Alberta; Aggarwal, Aneel K; Haider, Shozeb; New, Maria I; Sun, Li; Narla, Goutham; Zaidi, Mone

    2014-12-16

    Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free kinase assays, together with computational modeling, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause a global reduction in downstream signaling. By doing so, the drugs kill lung, breast, and colon cancer cells that are driven by activating mutations or overexpression of HER1. Knocking down HER isoforms thus abrogates cell killing by bisphosphonates, establishing complete HER dependence and ruling out a significant role for other receptor tyrosine kinases or the enzyme farnesyl pyrophosphate synthase. Consistent with this finding, colon cancer cells expressing low levels of HER do not respond to bisphosphonates. The results suggest that bisphosphonates can potentially be repurposed for the prevention and therapy of HER family-driven cancers.

  6. Osteonecrose dos maxilares associada ao uso de bisfosfonatos Bisphosphonate-related osteonecrosis of the jaws

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    Luis Augusto Passeri

    2011-08-01

    Full Text Available Os bisfosfonatos são potentes inibidores da reabsorção óssea e são utilizados no tratamento da osteoporose e de outras doenças que causam a perda de massa óssea, como doença de Paget, metástases ósseas e mieloma múltiplo, prevenindo fraturas patológicas. Desde 2003, estudos associam osteonecrose avascular dos ossos maxilares a seu uso, principalmente intravenoso. Na literatura, há relatos de ocorrência variando de 0,8% a 12%, dos pacientes, na sua maioria em uso prolongado. Médicos e dentistas devem estar cientes dessa potencial complicação no tratamento odontológico.Bisphosphonates are potent inhibitors of bone resorption, and are used in the treatment of osteoporosis and other diseases that cause bone mass loss, such as Paget's disease, bone metastases, and multiple myeloma, to prevent pathological fractures. Since 2003, avascular osteonecrosis of the jaw has been associated with the use of bisphosphonates, mainly intravenous. According to the literature, the occurrence of osteonecrosis of the jaw has ranged from 0.8% to 12% of the patients on bisphosphonates, most of them on prolonged use. Physicians and odontologists should be aware of that potential complication in dental treatment.

  7. Bisphosphonate-related osteonecrosis of the jaw in cancer patients: Implications for nurses.

    Science.gov (United States)

    Morris, Monica; Cruickshank, Susanne

    2010-07-01

    This paper reports a review of the literature with a specific focus on osteonecrosis of the jaw. Bisphosphonate drugs are commonly used in the treatment of bone disease secondary to myeloma and solid tumours, such as breast and prostate cancer. In the past few years, an uncommon but distressing condition known as osteonecrosis of the jaw (ONJ) has been detected in patients who are having bisphosphonate treatment, particularly the intravenous (IV) preparations. Osteonecrosis of the jaw results from bone exposure in the oral cavity with subsequent death of bone tissue (necrosis). The review searched key databases including Medline, British Nursing Index, Cochrane, and meeting abstracts to ascertain the extent of literature in this field. Fourty-two articles were reviewed which described the clinical manifestations of ONJ, the reported incidence and clinical cases. The results indicate there is an emerging body of evidence in this field and nurses delivering bisphosphonates need to familiarise themselves with the current guidance to ensure risks are minimised for patients.

  8. 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

  9. Efficacy and Safety of Bisphosphonates for Low Bone Mineral Density After Kidney Transplantation: A Meta-Analysis.

    Science.gov (United States)

    Kan, Shun-Li; Ning, Guang-Zhi; Chen, Ling-Xiao; Zhou, Yong; Sun, Jing-Cheng; Feng, Shi-Qing

    2016-02-01

    In patients with low bone mineral density (BMD) after kidney transplantation, the role of bisphosphonates remains unclear. We performed a systematic review and meta-analysis to investigate the efficacy and safety of bisphosphonates.We retrieved trials from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception through May 2015. Only randomized controlled trials that compared bisphosphonate-treated and control groups of patients with low bone mineral density after kidney transplantation were included. The primary outcomes were the percent change in BMD, the absolute change in BMD, and the BMD at the end of study at the lumbar spine. The results were expressed as the mean difference (MD) or relative risk (RR) with the 95% confidence interval (CI). We used a random-effects model to pool the outcomes.We included 17 randomized controlled trials with 1067 patients. Only 1 included trial was found to be at low risk of bias. The rest of the included studies were found to have high to uncertain risk of bias. Compared with the control group, those who received bisphosphonates had a significant increase in percent change in BMD (mean difference [MD] = 5.51, 95% confidence interval [CI] 3.22-7.79, P Bisphosphonates resulted in a significant improvement in percent change in BMD (MD = 4.95, 95% CI 2.57-7.33, P Bisphosphonates appear to have a beneficial effect on BMD at the lumbar spine and do not significantly decrease fracture events in recipients. However, the results should be interpreted cautiously due to the lack of robustness and the heterogeneity among studies.

  10. Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells.

    Science.gov (United States)

    Ebert, Regina; Meissner-Weigl, Jutta; Zeck, Sabine; Määttä, Jorma; Auriola, Seppo; Coimbra de Sousa, Sofia; Mentrup, Birgit; Graser, Stephanie; Rachner, Tilman D; Hofbauer, Lorenz C; Jakob, Franz

    2014-12-11

    Anti-resorptive bisphosphonates (BP) are used for the treatment of osteoporosis and bone metastases. Clinical studies indicated a benefit in survival and tumor relapse in subpopulations of breast cancer patients receiving zoledronic acid, thus stimulating the debate about its anti-tumor activity. Amino-bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase leading to accumulation of isopentenyl pyrophosphate (IPP) and the ATP/pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti-tumor effects μM concentrations are needed and a sensitizer for bisphosphonate effects would be beneficial in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation via inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy. MDA-MB-231, T47D and MCF-7 breast cancer cells were treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) and the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspase 3/7 activity (apoptosis), accumulation of IPP and ApppI, expression of ANKH, PANX1, ABCC1, SLC22A11, and the zoledronic acid target gene and tumor-suppressor KLF2. Treatment of MDA-MB-231 with BP induced caspase 3/7 activity, with zoledronic acid being the most effective. In MCF-7 and T47D either BP markedly suppressed cell viability with only minor effects on apoptosis. Co-treatment with probenecid enhanced BP effects on cell viability, IPP/ApppI accumulation as measurable in MCF-7 and T47D cells, caspase 3/7 activity and target gene expression. Novobiocin co-treatment of MDA-MB-231 yielded identical results on viability and apoptosis compared to probenecid, rendering SLC22A family members as candidate modulators of BP effects, whereas no such evidence was found for ANKH, ABCC1 and PANX1. In summary, we demonstrate effects of various bisphosphonates on caspase 3

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

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    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.

  12. Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study

    NARCIS (Netherlands)

    P.M. Coloma (Preciosa); M.A.J. de Ridder (Maria); I. Bezemer (Irene); R.M.C. Herings (Ron); R. Gini (Rosa); S. Pecchioli (Serena); L. Scotti (Lorenza); P.R. Rijnbeek (Peter); M. Mosseveld (Mees); J. van der Lei; G. Trifirò (Gianluca); M.C.J.M. Sturkenboom (Miriam)

    2016-01-01

    textabstractSummary: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely

  13. Prevalence of bisphosphonate associated osteonecrosis of the jaws in multiple myeloma patients

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    Blum Christina

    2010-07-01

    Full Text Available Abstract Background Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ is an adverse effect of bisphosphonate treatment with varying reported incidence rates. Methods In two neighboring German cities, prevalence and additional factors of the development of BP-ONJ in multiple myeloma patients with bisphosphonates therapy were recorded using a retrospective (RS and cross-sectional study (CSS design. For the RS, all patients treated from Jan. 2000 - Feb. 2006 were contacted by letter. In the CSS, all patients treated from Oct. 2006 - Mar. 2008 had a physical and dental examination. Additionally, a literature review was conducted to evaluate all articles reporting on BP-ONJ prevalence. PubMed search terms were: bisphosphonat, diphosphonate, osteonecrosis, prevalence and incidence. Results In the RS, data from 81 of 161 patients could be obtained; four patients (4.9% developed BP-ONJ. In the CSS, 16 of 78 patients (20.5% developed BP-ONJ. All patients with BP-ONJ had received zoledronate; 12 of these had had additional bisphosphonates. All except one had an additional trigger factor (tooth extraction [n = 14], dental surgical procedure [n = 2], sharp mylohyoid ridge [n = 3]. Conclusion The prevalence of BP-ONJ may have been underestimated to date. The oral examination of all patients in this CSS might explain the higher prevalence, since even early asymptomatic stages of BP-ONJ and previously unnoticed symptomatic BP-ONJ were recorded. Since nearly all patients with BP-ONJ had an additional trigger factor, oral hygiene and dental care might help to reduce BP-ONJ incidence.

  14. Syntheses and characterization of non-bisphosphonate quinoline derivatives as new FPPS inhibitors.

    Science.gov (United States)

    Liu, Jinggong; Liu, Weilin; Ge, Hu; Gao, Jinbo; He, Qingqing; Su, Lijuan; Xu, Jun; Gu, Lian-Quan; Huang, Zhi-shu; Li, Ding

    2014-03-01

    Farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in the biosynthesis of cholesterol and in the post-translational modification of signaling proteins. It has been reported that non-bisphosphonate FPPS inhibitors targeting its allosteric binding pocket are potentially important for the development of promising anti-cancer drugs. The following methods were used: organic syntheses of non-bisphosphonate quinoline derivatives, enzyme inhibition studies, fluorescence titration assays, synergistic effect studies of quinoline derivatives with zoledronate, ITC studies for the binding of FPPS with quinoline derivatives, NMR-based HAP binding assays, molecular modeling studies, fluorescence imaging assay and MTT assays. We report our syntheses of a series of quinoline derivatives as new FPPS inhibitors possibly targeting the allosteric site of the enzyme. Compound 6b showed potent inhibition to FPPS without significant hydroxyapatite binding affinity. The compound showed synergistic inhibitory effect with active-site inhibitor zoledronate. ITC experiment confirmed the good binding effect of compound 6b to FPPS, and further indicated the binding ratio of 1:1. Molecular modeling studies showed that 6b could possibly bind to the allosteric binding pocket of the enzyme. The fluorescence microscopy indicated that these compounds could get into cancer cells. Our results showed that quinoline derivative 6b could become a new lead compound for further optimization for cancer treatment. The traditional FPPS active-site inhibitors bisphosphonates show poor membrane permeability to tumor cells, due to their strong polarity. The development of new non-bisphosphonate FPPS inhibitors with good cell membrane permeability is potentially important. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. 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.

  16. Dual Effects of Bisphosphonates on Ectopic Skin and Vascular Soft Tissue Mineralization versus Bone Microarchitecture in a Mouse Model of Generalized Arterial Calcification of Infancy

    Science.gov (United States)

    Li, Qiaoli; Kingman, Joshua; Sundberg, John P.; Levine, Michael A.; Uitto, Jouni

    2015-01-01

    Generalized arterial calcification of infancy (GACI) is an intractable ectopic mineralization disorder caused by mutations in the ENPP1 gene resulting in reduced plasma inorganic pyrophosphate levels. We previously characterized the Enpp1asj mutant mouse as a model of GACI, and we have now explored the potential efficacy of bisphosphonates, non-hydrolyzable PPi analogs, in preventing ectopic mineralization in these mice. These mice were maintained on either basic diet (control) or diets containing etidronate or alendronate in three different concentrations (experimental). Considering low bioavailability of bisphosphonates when administered orally, subsequent studies tested the mice with subcutaneous injections of etidronate. The treatments were initiated at 4 weeks of age, and the degree of mineralization was assessed at 12 weeks of age by quantitation of calcium deposits in the muzzle skin containing dermal sheath of vibrissae and in aorta. We found that bisphosphonate treatments significantly reduced mineralization in skin and aorta. These changes in treated mice were accompanied with restoration of their bone microarchitecture, determined bymicrocomputed tomography. The inhibitory capacity of bisphosphonates, with mechanistic implications, was confirmed in a cell-based mineralization assay in vitro. Collectively, these results suggest that bisphosphonate treatment may be beneficial by a dual effect for preventing ectopic soft tissue mineralization while correcting decreased bone mineralization in GACI caused by ENPP1 mutations. PMID:26763447

  17. Antiresorptive drugs beyond bisphosphonates and selective oestrogen receptor modulators for the management of postmenopausal osteoporosis.

    Science.gov (United States)

    Reginster, J Y; Neuprez, A; Beaudart, C; Lecart, M P; Sarlet, N; Bernard, D; Disteche, S; Bruyere, O

    2014-06-01

    Osteoporotic fractures are a major cause of morbidity in the elderly population. Since postmenopausal osteoporosis is related to an increase in osteoclastic activity at the time of menopause, inhibitors of bone resorption have genuinely been considered an adequate strategy for prevention and treatment of osteoporosis. Bisphosphonates and selective oestrogen receptor modulators are widely prescribed to treat osteoporosis. However, other antiresorptive drugs have been developed for the management of osteoporosis, with the objective of providing a substantial reduction in osteoporotic fractures at all skeletal sites, combined with an acceptable long-term skeletal and systemic safety profile. Denosumab, a human monoclonal antibody to receptor activator for nuclear factor kappa B ligand, has shown efficacy against vertebral, nonvertebral and hip fractures. Its administration every 6 months as a subcutaneous formulation might significantly influence compliance and persistence to therapy. Additional results regarding long-term skeletal safety (i.e. osteonecrosis of the jaw and atypical diaphyseal femoral fracture) are needed. Odanacatib, a selective cathepsin K inhibitor, is a promising new approach to the inhibition of osteoclastic resorption, with the potential to uncouple bone formation from bone resorption. Results regarding its anti-fracture efficacy are expected in the coming months.

  18. Neridronic acid for the treatment of bone metabolic diseases.

    Science.gov (United States)

    Gatti, Davide; Viapiana, Ombretta; Idolazzi, Luca; Fracassi, Elena; Adami, Silvano

    2009-10-01

    Neridronic acid (6-amino-1-idroxyesilidene-1,1-bisphosphonate) is a nitrogen-containing bisphosphonate licensed in Italy for the treatment of osteogenesis imperfecta and Paget's disease of bone. The pharmacodynamic profile is similar to that of other nitrogen-containing bisphosphonates and is characterized by its high affinity for bone tissue particularly at sites undergoing a process of remodeling. In growing children affected by osteogenesis imperfect, neridronic acid rapidly increases bone mineral density as measured by dual X-ray absortiometry and this is associated with a significant decrease in fracture cumulative number. Similar results have been obtained also in newborns ( 75% of bone turnover markers) in 95% of the patients. Neridronic acid treatment has been reported to be effective also in other skeletal diseases such as osteoporosis, algodystrophy, hypercalcemia of malignancy and bone metastasis. Neridronic acid has been developed only for parenteral use, and it is the only one used as intramuscular injection. This avoids all the limitations of oral bisphosphonates and may be offered for a home treatment with simple nursing assistance.

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

    Directory of Open Access Journals (Sweden)

    Flodin L

    2014-07-01

    Full Text Available Lena Flodin,1,2 Maria Sääf,3 Tommy Cederholm,4 Amer N Al-Ani,2,5 Paul W Ackermann,5,6 Eva Samnegård,7 Nils Dalen,7 Margareta Hedström2,51Department of Geriatric Medicine, Karolinska University Hospital Stockholm, Sweden; 2Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden; 3Department of Endocrinology, Metabolism, and Diabetes, Karolinska University Hospital, Stockholm, Sweden; 4Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden; 5Department of Orthopedics, Karolinska University Hospital, Stockholm, Sweden; 6Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 7Department of Clinical Science, Division of Orthopedics, Karolinska Institutet, Danderyd Hospital, Stockholm, SwedenBackground: After a hip fracture, a catabolic state develops, with increased bone loss during the first year. The aim of this study was to evaluate the effects of postoperative treatment with calcium, vitamin D, and bisphosphonates (alone or together with nutritional supplementation on total hip and total body bone mineral density (BMD.Methods: Seventy-nine patients (56 women, with a mean age of 79 years (range, 61–96 years and with a recent hip fracture, who were ambulatory before fracture and without severe cognitive impairment, were included. Patients were randomized to treatment with bisphosphonates (risedronate 35 mg weekly for 12 months (B; n=28, treatment with bisphosphonates along with nutritional supplementation (40 g protein, 600 kcal daily for the first 6 months (BN; n=26, or to controls (C; n=25. All participants received calcium (1,000 mg and vitamin D3 (800 IU daily. Total hip and total body BMD were assessed with dual-energy X-ray absorptiometry at baseline, 6, and 12 months. Marker of bone resorption C-terminal telopeptide of collagen I and 25-hydroxy vitamin D were analyzed in serum

  20. Use of intravenous bisphosphonates in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems.

    Science.gov (United States)

    Oster, Gerry; Lamerato, Lois; Glass, Andrew G; Richert-Boe, Kathryn E; Lopez, Andrea; Chung, Karen; Richhariya, Akshara; Dodge, Tracy; Wolff, Greg G; Balakumaran, Arun; Edelsberg, John

    2014-05-01

    The purpose of this paper is to document the use of intravenous (IV) bisphosphonates for prevention of skeletal-related events (SREs) in patients with bone metastases (BM) due to breast cancer (BC), lung cancer (LC), or prostate cancer (PC). Using data from two large US health systems, we identified all patients aged ≥ 18 years with primary BC, LC, or PC and newly diagnosed BM between 1/1/1995 and 12/31/2009. Starting with the diagnosis of BM, we reviewed medical and administrative records for evidence of receipt of IV bisphosphonates (zoledronic acid or pamidronate) and occurrence of SREs. Initiation of IV bisphosphonates prior to occurrence of an SRE was designated "primary prophylaxis"; use following an SRE was designated "secondary prophylaxis". We identified a total of 1,193 patients with newly diagnosed BM, including 400 with BC, 332 with LC, and 461 with PC. Use of IV bisphosphonates was substantially higher in BC (55.8 % of all patients) than in LC (14.8 %) or PC (20.2 %). Use of IV bisphosphonates was fairly evenly split between primary and secondary prophylaxis in BC (26.3 vs. 29.5 %, respectively) and PC (10.6 vs 9.5 %); in LC, however, primary prophylaxis was much less common than secondary prophylaxis (4.8 vs 9.9 %). Almost one half of all patients with BM due to BC, and substantially more with LC and PC, do not receive IV bisphosphonates. Among patients receiving such therapy, treatment often is not initiated until after the occurrence of an SRE. Our study suggests that IV bisphosphonates may be substantially underutilized in patients with BM due to these common cancers.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-03-15

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

  2. Denosumab: A Unique Perspective on Adherence and Cost-effectiveness Compared With Oral Bisphosphonates in Osteoporosis Patients.

    Science.gov (United States)

    Morizio, Paige; Burkhart, Jena I; Ozawa, Sachiko

    2018-04-01

    To assess the cost-effectiveness as well as adherence and patient preference for denosumab compared with oral bisphosphonates for the treatment of osteoporosis. Two comprehensive PubMed literature searches (from data inception to December 2017) were performed. The first search included the terms osteoporosis, denosumab, bisphosphonate, and adherence or persistence or compliance or preference. The search terms osteoporosis, denosumab, cost, and effectiveness were used in the second literature search. Additional references were included from reviewing literature citations. All English-language clinical trials on adherence (as compliance and persistence) or patient preference for denosumab compared with oral bisphosphonates were evaluated. In addition, articles analyzing the cost-effectiveness of denosumab compared with generic alendronate were evaluated. Four studies that assessed patient preference showed positive outcomes for preference and satisfaction for subcutaneous use of denosumab every 6 months versus oral alendronate weekly, oral ibandronate monthly, or oral risedronate monthly. Three studies evaluated persistence and compliance and/or adherence and showed improved persistence and compliance rates with denosumab compared with bisphosphonate therapy. Twelve articles and 3 abstracts assessed cost-effectiveness of denosumab compared with generic alendronate. The majority of articles showed that denosumab was cost-effective, and even cost-saving in patients older than 75 years of age and those who have a history of previous fractures, lower bone mineral density T-scores, and more risk factors. Denosumab compared with oral bisphosphonates may improve patient preference and adherence as well as provide a cost-effective treatment strategy, especially among higher-risk and older adults with osteoporosis.

  3. Renal transport of bisphosphonates: accumulation by renal cortical slices enhanced by calcium phosphate ions

    Energy Technology Data Exchange (ETDEWEB)

    Troehler, U.; Bonjour, J.P.; Fleisch, H.

    1985-07-01

    Bisphosphonates have been recognized as useful therapeutic agents in metabolic bone disease. Earlier studies showed a net renal secretion of 1-hydroxy-ethylidene-1,1-bisphosphonate (HEBP). They suggested a renal cellular uptake of this compound. The authors further studied this concept by investigating the uptake in vitro of /sup 14/C-HEBP by rat renal cortex slices. HEBP was accumulated against a concentration gradient, a process that was dependent on time, temperature, and substrate concentration. Unlike that of /sup 3/H-p-aminohippurate, the uptake was not affected by change in medium Na+ or glucose and acetate concentration, or by anoxia and various metabolic inhibitors. It was, however, markedly increased by raising the medium calcium and inorganic phosphate concentration. Equilibrium dialysis with renal cortex homogenates suggests that HEBP binds to a cytosolic macromolecule through a process that exhibits saturability and calcium dependency. In conclusion, the results suggest that the bisphosphonate HEBP can penetrate kidney cells by a process that does not appear to be energy dependent, but is markedly influenced by the extracellular calcium-phosphate concentration.

  4. Comparative risks for cancer associated with use of calcitonin, bisphosphonates or selective estrogen receptor modulators among osteoporosis patients: a population-based cohort study.

    Science.gov (United States)

    Hsiao, Fei-Yuan; Hsu, William Wei-Yuan

    2017-10-01

    This population-based cohort study was to compare the risks of incident cancer in osteoporosis patients who used bisphosphonates, calcitonin or selective estrogen receptor modulators (SERMs). We identified 9995 patients who were diagnosed with osteoporosis and prescribed osteoporosis drugs (bisphosphonate (n = 4675), calcitonin (n = 3993) and SERMs (n = 1327)) between 1 January 2000 and 31 December 2006 in Taiwan's National Health Insurance Research Database. Date of first prescription of osteoporosis drugs was assigned as the index date. The outcome measurement was incident cancer, defined by a first-ever inpatient visit with a primary diagnosis of cancer. All patients were followed until the occurrence of cancer. For those who did not develop cancer, we censored them at 1 year after their last prescription of osteoporosis drugs. Cox proportional hazard models were used to examine the association between risk of cancer and use of calcitonin, bisphosphonates or SERMs. The incidence rate of cancer was 68.8, 34.0 and 29.6 per 1000 person years in the calcitonin, SERMs and bisphosphonate cohorts, respectively. Compared with bisphosphonate users, calcitonin users were associated with an increased risk of cancer (adjusted hazard ratio (HR) 2.11, 95% confidence interval (CI) 2.01-2.21, P bisphosphonate, supporting the recent warning issued by the European Medicines Agency and US Food and Drug Administration. SERMs is found to be associated with an increased risk of cancer than bisphosphonate. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. Optimal treatment increased the seed germination of Salvia verticillata L.

    Directory of Open Access Journals (Sweden)

    ALALEH KHAKPOOR

    2015-12-01

    Full Text Available Most seeds of the medicinal species are variable regarding their ecological compatibility with environmental conditions. Therefore, identifying the ecophysiological factors that affect dormancy and create optimal conditions for seed germination of medicinal plants is necessary for their culture and production. To evaluate the effect of different treatments on seed germination of medicinal species of Salvia verticillata, collected in the summer of 2010 in Eastern Azarbaijan, we have performed completely randomized experimental tests with 4 replications. The experimental design of treatment prior to growth included: scrape the skin with sandpaper, treatment with 500 ppm gibberellic acid for 24 and 48 h, treatment with citric acid for 10, 20 and 30 minutes, chilling for 2 and 4 weeks, treatment with warm water at 70°C and control treatment. Results showed that the effect of different treatments was significant on seed germination percent of the medicinal plant Salvia verticillata. Scrape the skin with sandpaper, citric acid treatment for 10, 20 and 30 minutes, and gibberellic acid treatment for 24 hours, increased the germination percentage compared to the control treatment. The most positive impact was observed on the dormancy breaking and germination of medicinal species Salvia verticillata.

  6. Neurobehavioral response to increased treatment dosage in chronic, severe aphasia

    Directory of Open Access Journals (Sweden)

    Jennifer L Mozeiko

    2014-04-01

    •\tIncreased activation in S2’s bilateral inferior frontal gyrus following the second treatment session indicates that a second Treatment Period can influence continued neuroplastic change in severe, chronic aphasia. •\tS1 appears to show the most activation following Treatment Period I. It is possible that his greater lesion volume or site did not allow for benefit from a second dose to the same degree as S2. •\tActivation changes (or lack thereof in both cases corresponded with performance on the naming task in the scanner, reflecting the effect of treatment. •\tFor S2, neuroimaging supported the behavioral results which favor a second dose of ILAT. For S1, behavioral results, particularly in his consistent increases on the BNT, are not supported by either the behavioral results in the scanner or the BOLD response.

  7. Vitamin K nutritional status and undercarboxylated osteocalcin in postmenopausal osteoporotic women treated with bisphosphonates.

    Science.gov (United States)

    Iwamoto, Jun; Takada, Tetsuya; Sato, Yoshihiro

    2014-01-01

    Serum undercarboxylated osteocalcin (ucOC) is an index of vitamin K nutritional status in treatment-naive postmenopausal osteoporotic women. The purpose of the present study was to reveal the association between vitamin K nutritional status and serum ucOC concentrations in postmenopausal osteoporotic women taking bisphosphonates. Eighty-six postmenopausal women with osteoporosis (age range: 47-90 years) initiated bisphosphonate treatment. Vitamin K nutritional status was evaluated using a simple vitamin K-intake questionnaire and serum ucOC concentrations were measured after 6 months of treatment. The patients were divided into two groups according to the simple vitamin K-intake questionnaire score: a low vitamin K-intake (score =40) group (n=19). There were no significant differences between the groups in baseline parameters including age, height, body weight, body mass index, serum alkaline phosphatase (ALP), urinary cross-linked N-terminal telopeptides of type I collagen (NTX), and changes in serum ALP and urinary NTX concentrations during the 6-month treatment period. However, the mean serum ucOC concentration after 6 months of treatment was significantly higher in the low vitamin K-intake group (2.79 ng/mL) than in the normal vitamin K-intake group (2.20 ng/mL). These results suggest that 78% of postmenopausal osteoporotic women treated with bisphosphonates may have vitamin K deficiency as indicated by low vitamin K-intake and high serum ucOC concentrations, despite having a similar reduction in bone turnover to women who have normal vitamin K-intake.

  8. Waiting Time Increases Risk of Attrition in Gambling Disorder Treatment

    DEFF Research Database (Denmark)

    Linnet, Jakob; Pedersen, Anders Sune

    2014-01-01

    Attrition is a well known problem in psychotherapeutic treatment. Patients with addiction have high attrition rates, and it is therefore important to identify factors that can improve completion rates in addiction. Here, we investigated the influence of waiting time as a predictor of treatment...... completion in gambling disorder. We compared 48 gambling disorder sufferers with a 56% completion rate (21 non-completers and 27 completers). Binomial logistic regression analysis showed that waiting time from initial contact to the first session with a therapist was a significant predictor of risk...... of attrition: longer waiting times were associated with increased risk of attrition. Age, gender, or comorbidity was not associated with an increased risk of attrition. These data suggest that gambling disorder sufferers benefit from fast access to treatment, and that longer waiting time increases the risk...

  9. 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

  10. Increases in body mass index following initiation of methadone treatment.

    Science.gov (United States)

    Fenn, Jennifer M; Laurent, Jennifer S; Sigmon, Stacey C

    2015-04-01

    Despite the clear efficacy of methadone for opioid dependence, one less desirable phenomenon associated with methadone may be weight gain. We examined changes in body mass index (BMI) among patients entering methadone treatment. A retrospective chart review was conducted for 96 patients enrolled in an outpatient methadone clinic for ≥ 6 months. The primary outcome of BMI was assessed at intake and a subsequent physical examination approximately 1.8 ± 0.95 years later. Demographic, drug use and treatment characteristics were also examined. There was a significant increase in BMI following intake (pmethadone treatment enrollment was associated with clinically significant weight gain, particularly among female patients. This study highlights the importance of efforts to help patients mitigate weight gain during treatment, particularly considering the significant health and economic consequences of obesity for individuals and society more generally. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Risperidone treatment increases CB1 receptor binding in rat brain

    DEFF Research Database (Denmark)

    Secher, Anna; Husum, Henriette; Holst, Birgitte

    2010-01-01

    , the ghrelin receptor, neuropeptide Y, adiponectin and proopiomelanocortin. We investigated whether the expression of these factors was affected in rats chronically treated with the antipsychotic risperidone. METHODS: Male Sprague-Dawley rats were treated with risperidone (1.0 mg/kg/day) or vehicle (20......% hydroxypropyl beta-cyclodextrin) for 28 days. Expression of the aforementioned factors were examined together with plasma prolactin and ghrelin levels. RESULTS: No difference in body weight gained during treatment was observed between risperidone and vehicle treated rats, but plasma risperidone levels...... positively correlated with visceral fat mass. Risperidone treatment increased CB(1) receptor binding in the arcuate nucleus (40%), hippocampus (25-30%) and amygdala (35%) without concurrent alterations in the CB(1) receptor mRNA. Risperidone treatment increased adiponectin mRNA. CONCLUSION: The present study...

  12. Increasing trend of metronidazole resistance in the treatment of ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-02-22

    Feb 22, 2010 ... implemented in a given area or population. This increasing emergence of antimicrobial resistance in H. pylori treatment posses serious public health problems and is therefore necessary that new drug regimens be examined. Key words: Helicobacter pylori, drug resistance, metronidazole, gene mutations, ...

  13. Increasing trend of metronidazole resistance in the treatment of ...

    African Journals Online (AJOL)

    Helicobacter pylori are gram negative spiral bacteria that colonize the human stomach. Infection with H. pylori is associated with chronic gastritis, peptic ulcer, gastric adenocarcinoma and gastric mucosaassociated lymphoid tissue (MALT) lymphoma. Antibiotic resistance is an ever increasing problem with the treatment of ...

  14. A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates.

    Science.gov (United States)

    Cosman, F; Gilchrist, N; McClung, M; Foldes, J; de Villiers, T; Santora, A; Leung, A; Samanta, S; Heyden, N; McGinnis, J P; Rosenberg, E; Denker, A E

    2016-01-01

    In women with osteoporosis treated with alendronate for >12 months and oral bisphosphonates for >3 of the last 4 years, switching to MK-5442, a calcium receptor antagonist, stimulated endogenous parathyroid hormone (PTH) secretion and increased bone turnover marker levels, but produced a decline in bone mineral density (BMD) at all sites. This study assessed the effects of switching from long-term oral bisphosphonate therapy to the calcium-sensing receptor antagonist MK-5442 on BMD and bone turnover markers (BTMs) in post-menopausal women with osteoporosis. This randomized, active and placebo-controlled, dose-ranging study enrolled 526 postmenopausal women, who had taken alendronate (ALN) for ≥12 months preceding the trial and any oral bisphosphonate for ≥3 of the preceding 4 years and had spine or hip BMD T-scores ≤-2.5 or ≤-1.5 with ≥1 prior fragility fracture. Women were randomized to continue ALN 70 mg weekly or switch to MK-5442 (5, 7.5, 10, or 15 mg daily) or placebo. Switching from ALN to MK-5442 produced a dose-dependent parathyroid hormone (PTH) pulse of threefold to sixfold above baseline at 1 h, with PTH levels that remained twofold to threefold above baseline at 4 h and returned to baseline by 24 h. Switching to MK-5442 or placebo increased BTM levels compared to baseline within 3 months and MK-5442 10 mg increased BTM levels compared to placebo by 6 months. With all MK-5442 doses and placebo, spine and hip BMD declined from baseline, and at 12 months, BMD levels were below those who continued ALN (all groups P < 0.05 vs ALN). There was also a dose-dependent increase in the incidence of hypercalcemia with MK-5442. Switching from ALN to MK-5442 resulted in a pulsatile increase in PTH and increases in BTMs, but a decline in BMD compared with continued ALN. MK-5442 is not a viable option for the treatment of osteoporosis.

  15. "Phoenix jaw"-bone regeneration of the necrotic mandible between pathological fractures: an unusual but evocative course of bisphosphonate-related osteonecrosis.

    Science.gov (United States)

    Imai, Tomoaki; Michizawa, Masahiro

    2014-07-01

    Management of advanced bisphosphonate-related osteonecrosis of the jaw, particularly in cases of pathological fractures with extraoral fistulas, is a challenging responsibility for craniomaxillofacial specialists. Although a periosteal reaction is occasionally observed in cases with extensive sequestra, few reports have documented circumferential periosteal osseous formation resulting in bone repair. We present the case of a 78-year-old woman who was treated for breast cancer and received intravenous bisphosphonates. She had bisphosphonate-related osteonecrosis of the jaw with bilateral pathological fractures of the mandible. During the course of minimally invasive treatment, the necrotic segment was separated with circumferential exposure, and new bone spontaneously formed with osseous union to the unilateral fractured stump. The present case typically highlights the potential of periosteal osteogenesis to regain an acceptable state even for patients with severe "bis-phossy jaw," particularly those with pathological fractures, although we do not advocate the universality of the phenomenon presented as "phoenix jaw."

  16. Increased libido associated with donepezil treatment: a case report.

    Science.gov (United States)

    Segrec, Nusa; Zaman, Rashid; Pregelj, Peter

    2016-01-01

    Inappropriate verbal and physical sexual behaviour is not common among individuals with dementia, but when it does occur, it can have profound consequences. We report a case of 79-year-old woman with dementia of the Alzheimer's type who complained of increased libido after an increased dose of donepezil, which was being used along with tianeptine. Donepezil withdrawal led to the resolution of increased libido, but when it was reintroduced, increased libido reappeared once again (Naranjo score: 7). Increased libido was not reported by the patient during the 6-year follow-up period after donepezil withdrawal. A potential mechanism of acetylcholinesterase inhibitor-induced increased libido and the current literature on hypersexuality as a side-effect of donepezil treatment are discussed. © 2015 The Authors. Psychogeriatrics © 2015 Japanese Psychogeriatric Society.

  17. The relationship between bisphosphonate use and demographic characteristics of male osteoporosis patients

    Directory of Open Access Journals (Sweden)

    Alev Cevikoi

    2011-01-01

    Full Text Available INTRODUCTION: This study aimed to investigate a number of demographic characteristics in males with osteoporosis (OP treated with bisphosphonate and determine whether any of these measures could act as an effective indicator of medication persistence and compliance. MATERIAL AND METHOD: Among the patients with OP who applied to our clinic and were prescribed weekly oral bisphosphonate treatment, 89 patients over 50 years of age were included in this study. The demographic characteristics of these patients were evaluated. The number of medications used by the patients over the past 1 and 3 years were counted, and the persistence and compliance with bisphosphonate treatment was estimated. The patients were divided into two groups: fully compliant and noncompliant subjects. The two groups of patients were compared separately for 1 and 3 years while considering their demographic characteristics. RESULTS: The mean age of the 89 patients included in the study was 62.43 + 9.41 years. Comparisons among the studied demographic characteristics during the 1-year period of medication use indicated that the educational status of the fully compliant patients was higher. During the 3-year period of medication use, educational status was the only demographic characteristic that was determined to be significantly lower in the noncompliant patients than in the fully compliant group. CONCLUSION: Although deficiencies in medication persistence and compliance during osteoporosis treatment can lead to serious health and social problems in both genders, the causes of these deficiencies have not been thoroughly clarified. We suggest that the educational status of the patient may contribute to these deficiencies.

  18. In vivo distribution of zoledronic acid in a bisphosphonate-metal complex-based nanoparticle formulation synthesized by a reverse microemulsion method.

    Science.gov (United States)

    Li, Xu; Naguib, Youssef W; Cui, Zhengrong

    2017-06-30

    Bisphosphonates are used to treat bone diseases such as osteoporosis and cancer-induced bone pain and fractures. It is thought that modifying the pharmacokinetics and biodistribution profiles of bisphosphonates (i.e. rapid renal clearance and extensive bone absorption) will not only reduce their side effects, but also expand their clinical applications to extraskeletal tissues. In the present work, using zoledronic acid (Zol) and calcium as model bisphosphonate and metal molecules, respectively, we prepared DOPA (an anionic lipid)-coated spherical Zol-Ca nanocomposites (Zol-Ca@DOPA) and developed Zol-nanoparticle formulations (i.e. Zol-Ca@bi-lipid NPs) based on the nanocomposites. The influence of the inputted weight ratio of Zol-Ca@DOPA to DSPE-PEG 2k on the properties (e.g. size, size distribution, loading efficiency, encapsulation efficiency, zeta potential, and polydispersity) of Zol-Ca@bi-lipid NPs was investigated, and a type of Zol-Ca@bi-lipid NPs with size around 25nm was selected for further studies. In a mouse model, the Zol-Ca@bi-lipid NPs significantly reduced the bone distribution of Zol, increased the blood circulating time of Zol, and altered the distribution of Zol in major organs, as compared to free Zol. It is expected that similar nanoparticles prepared with bisphosphonate-metal complexes can be explored to expand the applications to bisphosphonates in extraskeletal tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Bisphosphonate-related osteonecrosis of the jaw in metastatic breast cancer patients: a review of 25 cases.

    Science.gov (United States)

    Kim, Hong-Joon; Park, Tae-Jun; Ahn, Kang-Min

    2016-12-01

    Intravenous bisphosphonates have been used in metastatic breast cancer patients to reduce pathologic bone fracture and bone pain. However, necrosis of the jaw has been reported in those who received intravenous bisphosphonates. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is caused by dental extraction, dental implant surgery, and denture wearing; however, it occurs spontaneously. The purpose of this study was to report BRONJ in metastatic breast cancer patients. Consecutive 25 female patients were referred from the Department of Oncology from 2008 to 2014 for jaw bone discomfort. Staging of breast cancer, history of bisphosphonate infusion, etiology of BRONJ, and treatment results were reviewed. Average age of the patients was 55.4 years old (38-74). Twelve maxillae and 16 mandibles were involved. Conservative treatments such as irrigation, antibiotic medication, analgesics, and oral gargle were applied for all patients for the initial treatment. Patients who had sequestrum underwent debridement and primary closure. The etiologies of BRONJ were dental extraction (19 cases), dental implant (2 cases), and endodontic treatment (1 case). However, three patients did not have any risk factors to cause BRONJ. Three patients died of progression of metastasis during follow-up periods. Surgical debridement was performed in 21 patients with success in 18 patients. Three patients showed recurred bone exposure and infection after operation. Prevention of the BRONJ is critical in metastatic breast cancer patients. Conservative treatment to reduce pain, discomfort, and infection is recommended for the initial therapy. However, if there is a sequestrum, surgical debridement and primary closure is the key to treat the BRONJ.

  20. Effects of bisphosphonate on oxidative stress levels in patients with different types of cancer.

    Science.gov (United States)

    Koçer, Murat; Nazıroğlu, Mustafa; Koçer, Gülperi; Sönmez, Tolga Taha

    2014-02-01

    We investigated the effects of bisphosphonate (BP) on oxidative stress levels in blood of patients with cancer. In total, 19 patients with cancer and 21 healthy subjects were included in the study. BP was intravenously administrated to the participants for 6 weeks. The patients had higher lipid peroxidation (LP) levels in the plasma and erythrocyte samples but lower glutathione peroxidase (GSH-Px) and plasma vitamin E values. In patients treated with BP, calcium and LP levels decreased, but GSH-Px and vitamin E values improved. In conclusion, we observed that treatment with BP alleviated oxidative stress induced by cancer.

  1. Antiresorptive and anti-angiogenetic octacalcium phosphate functionalized with bisphosphonates: An in vitro tri-culture study.

    Science.gov (United States)

    Forte, Lucia; Torricelli, Paola; Boanini, Elisa; Gazzano, Massimo; Fini, Milena; Bigi, Adriana

    2017-05-01

    Development of new materials for the local administration of bisphosphonates (BPs) is aimed to avoid the negative side effects of prolonged systemic use of these potent drugs. In this work, we synthesized octacalcium phosphate (OCP) in the presence of two potent BPs and obtained a single crystalline phase up to a zoledronate and alendronate content of 3.5wt% and 5.2wt%, respectively. Both BPs provoke minor structural modifications and a reduction of the crystal dimensions of OCP, which suggests a preferential interaction of the BPs with the structure of the calcium phosphate. Alendronate containing samples display increased values of zeta potential with respect to that of OCP, and an initial burst release of the BP in solution. At variance, the zeta potential of zoledronate functionalized samples decreases on increasing the content of zoledronate, which is not appreciably released in solution. Bone microenvironment response to the composite materials was investigated in vitro using a triculture model. BP functionalized samples downregulate the viability of the cells, sustain osteoblast differentiation and accelerate the production of collagen type I and osteocalcin. At variance, they inhibit monocyte differentiation into osteoclast and provoke a dose dependent reduction of VEGF production, exhibiting antiresorptive and anti-angiogenetic properties that can be usefully exploited for the local treatment of abnormal bone losses. Bisphosphonates (BPs) are powerful drugs for the treatment of bone diseases. However, BPs systemic administration suffers several undesirable side effects, which stimulate the development of suitable systems for their local administration. In this study we functionalized octacalcium phosphate (OCP) with alendronate and zoledronate in order to get biomaterials able to couple the good biological performance of OCP with the therapeutic properties of the BPs. The results provide novel information on the interaction between these two potent BPs and

  2. Nanocrystalline carbonate-apatites: role of Ca/P ratio on the upload and release of anticancer platinum bisphosphonates

    Science.gov (United States)

    Iafisco, Michele; Palazzo, Barbara; Martra, Gianmario; Margiotta, Nicola; Piccinonna, Sara; Natile, Giovanni; Gandin, Valentina; Marzano, Cristina; Roveri, Norberto

    2011-12-01

    In the present study two nanocrystalline apatites have been investigated as bone-specific drug delivery devices to be used for treatment of bone tumors either by local implantation or by injection. In order to assess how the Ca/P ratio can influence the adsorption and release of anticancer platinum-bisphosphonate complexes, two kinds of apatite nanocrystals having different Ca/P ratios but similar morphologies, degree of crystallinity, and surface areas have been synthesized and characterized. The two platinum-bisphosphonate complexes considered were the bis-{ethylenediamineplatinum(ii)}-2-amino-1-hydroxyethane-1,1-diyl-bisphosphonate and the bis-{ethylenediamineplatinum(ii)}medronate. The Ca/P ratio plays an important role in the adsorption as well as in the release of the two drugs. In fact, the apatite with a higher Ca/P ratio showed greater affinity for both platinum complexes. Also the chemical structure of the two Pt complexes appreciably affects their affinity towards as well as their release from the two kinds of apatites. In particular, the platinum complex whose bisphosphonate contains a free aminic group showed greater upload and smaller release. The cytotoxicity of the Pt complexes released from the apatite was tested against human cervical, colon, and lung cancer cells as well as against osteosarcoma cells. In agreement with previous work, the Pt complexes released were found to be more cytotoxic than the unmodified complexes.In the present study two nanocrystalline apatites have been investigated as bone-specific drug delivery devices to be used for treatment of bone tumors either by local implantation or by injection. In order to assess how the Ca/P ratio can influence the adsorption and release of anticancer platinum-bisphosphonate complexes, two kinds of apatite nanocrystals having different Ca/P ratios but similar morphologies, degree of crystallinity, and surface areas have been synthesized and characterized. The two platinum-bisphosphonate

  3. Bisphosphonate-related osteonecrosis of the jaw: An insight

    Directory of Open Access Journals (Sweden)

    Shalini Kapoor

    2013-01-01

    Full Text Available Bisphosphonates are potent inhibitors of osteoclast activity that reduce bone turnover and re-establish the balance between bone resorption and formation. They are effective in multiple clinical settings including postmenopausal osteoporosis, low bone mass in men, and drug-induced bone loss. Bisphosphonate-associated osteonecrosis of jaws (BRONJ may result in serious oral complications, such as osteomyelitis and chronic exposure of necrotic bone. Dentists must be familiar with this disorder and pay special attention to all patients on bisphosphonate therapy due to their defective osteoclast function and reduced osseous tissue vascularity, leading to impaired wound healing and progressive necrosis of jaw bones. The purpose of this article is to review the history and pathogenesis of BRONJ, provide guidance to dentists on possible measures to prevent and manage patients with BRONJ.

  4. Country report: United Kingdom. Bifunctional bisphosphonate complexes with 99mTc and 188Re for the diagnosis and therapy of bone metastases

    International Nuclear Information System (INIS)

    Torres Martin de Rosales, Rafael; Blower, P.J.

    2010-01-01

    1,1-Bisphosphonates (BPs) are a family of compounds extensively used in the management of disorders of bone metabolism. 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. 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. 3 In particular, the rhenium compounds 186/188 Re-hydroxyethylidene-1,1-diphosphonate ( 186/188 Re-HEDP) have shown promise as palliative agents for bone metastases in recent clinical trials. 4 The radiochemicals consist of a complex of a BP (e.g. methylene diphosphonate, MDP) with gamma- ( 99m Tc) or beta- ( 186/186 Re) emitters

  5. Long-term treatment with alendronate increases the surgical difficulty during simple exodontias – an in vivo observation in Holtzman rats

    Directory of Open Access Journals (Sweden)

    Conte-Neto Nicolau

    2012-07-01

    Full Text Available Abstract Background Atraumatic teeth extractions protocols are highly encouraged in patients taking bisphosphonates (Bps to reduce surgical trauma and, consequently, the risk of jaws osteonecrosis development. In this way, this paper aims to report the findings of increased surgical difficulty during simple exodontias in animals treated with bisphosphonates. Methods Sixty male Holtzman rats were randomly distributed into three groups of 20 animals and received daily subcutaneous administration of 1 mg/kg (AL1 or 3 mg/kg (AL3 of alendronate or saline solution (CTL. After 60 days of drug therapy all animals were submitted to first lower molars extractions under general anesthesia. Operatory surgical time and the frequency of teeth fractures were measured as principal outcomes and indicators of surgical difficulty degree. Results Animals treated with alendronate (AL1 and AL3 were associated to higher operatory times and increased frequency of teeth fractures compared to match controls. Conclusions The bisphosphonate therapy may be associated with an increased surgical difficulty and trauma following simple exodontias protocols, which is considered a critical issue when it comes to osteonecrosis development.

  6. 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

  7. Increased Trichotillomania Symptoms in a Child With Fluoxetine Treatment.

    Science.gov (United States)

    Yektaş, Çiğdem; Tufan, Ali Evren

    Trichotillomania (TTM) is a mental disorder characterized by uncontrolled and impulsive hair pulling leading to hair loss, distress, and disordered functioning. Treatment choices include behavioral therapy (especially habit reversal training) and selective serotonin reuptake inhibitors. However, randomized controlled trials conducted with selective serotonin reuptake inhibitors have led to controversial results of effectiveness for TTM. Here, we report a female patient whose TTM symptoms increased after fluoxetine use.

  8. Osteonecrosis de los maxilares asociada al empleo de bifosfonatos Bisphosphonate-associated osteonecrosis of the jaw

    Directory of Open Access Journals (Sweden)

    J.L. del Castillo Pardo de Vera

    2007-10-01

    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.

  9. Bisphosphonate related osteonecrosis of the jaws: report of two cases

    Energy Technology Data Exchange (ETDEWEB)

    Han, Jin Woo [College of Dentistry, Gangneung Wonju National University, Gangneung (Korea, Republic of)

    2011-09-15

    Bisphosphonates are compounds used to treat osteoporosis and malignant bone metastasis. Despite the benefits related to the use of these medications, osteonecrosis of the jaws is a significant complication in a subset of patients receiving these drugs. This complication occurs either spontaneously or after a simple dento-alveolar surgery. Recently there were two patients who showed the features of bisphosphonate related osteonecrosis of the jaws (BRONJ) in Gangneung Wonju National University Dental Hospital. The patients revealed the clinical and radiological features of classical osteomyelitis. This report presents two cases of BRONJ which were examined by plain radiography and computed tomography.

  10. The cumulative incidence of and risk factors for latent beaking in patients with autoimmune diseases taking long-term glucocorticoids and bisphosphonates.

    Science.gov (United States)

    Sato, H; Kondo, N; Wada, Y; Nakatsue, T; Iguchi, S; Fujisawa, J; Kazama, J J; Kuroda, T; Nakano, M; Endo, N; Narita, I

    2016-03-01

    The incidence of beaking, which has been reported to precede atypical femoral fracture, was high and increased over 2 years in patients with autoimmune diseases who were taking bisphosphonates and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking, and bisphosphonate drug holidays should be considered. Atypical femoral fractures (AFFs) have been recently recognized as complications associated with bisphosphonate (BP) use. AFFs are considered to be stress fractures; localized periosteal thickening of the lateral cortex is often present at the fracture site; this thickening is termed "beaking." Beaking has been reported to precede AFF. The aims of the present study were to evaluate the incidence of latent beaking in patients with autoimmune diseases taking BPs and glucocorticoids and to identify risk factors for beaking. A total of 125 patients with autoimmune diseases who were taking BPs and glucocorticoids was included; 116 patients underwent X-rays and analysis of serum and urine bone metabolic markers annually for 2 years. Mean patient age was 54.5 years; there were 105 (90.5%) females and the mean duration of disease was 13.2 years. Focal lateral cortical thickening in femoral X-rays was defined as beaking. Beaking was detected in 15 femora of 10 patients (8.0%) at the time of recruitment. Over the 2-year observation period, the incidence of beaking increased to 21 femora of 12 patients (10.3%), and a complete AFF at the location of beaking occurred in one patient. Beaking was associated with a longer duration of BP treatment (6.1 ± 1.0 years vs. 5.0 ± 2.9 years, p = 0.01). Age 40-60 years, BP therapy ≥4 years, and diabetes mellitus were significantly associated with beaking. The incidence of beaking was high, and increased over 2 years, in patients with autoimmune diseases who were taking BPs and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking. Long-term BP

  11. Dynamic contrast enhanced magnetic resonance imaging in monitoring bone metastases in breast cancer patients receiving bisphosphonates and endocrine therapy

    Energy Technology Data Exchange (ETDEWEB)

    Montemurro, F.; Russo, F.; Martincich, L.; Cirillo, S.; Gatti, M.; Aglietta, M.; Regge, D. [Inst. for Cancer Research and Treatment, Torino (Italy)

    2004-02-01

    To study the role of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in monitoring the response of bone metastases to endocrine therapy combined with bisphosphonates in patients with breast cancer. Ten breast cancer patients with bone metastases who were to receive endocrine therapy and bisphosphonates were investigated prospectively by DCE-MRI. We chose a reference lesion for each patient who was studied at baseline, within 3 weeks from the second administration of bisphosphonates, and after 4 and 8 months from the initiation of medical treatment. Time/intensity curves, representing temporal changes of signal intensity in areas of interest in the context of the target lesions (ROI), were obtained for each DCE-MRI. Changes in the shape of the T/I curves suggesting tumor regression were seen shortly after the initiation of medical treatment in the three patients who had the most durable responses. DCE-MRI has the potential to detect early changes related to medical treatment in bone metastases from breast cancer. If confirmed in larger series, these data identify DCE-MRI as a diagnostic tool for evaluating new bone targeting antineoplastic agents.

  12. Activation of Src kinase by protein-tyrosine phosphatase-PEST in osteoclasts: comparative analysis of the effects of bisphosphonate and protein-tyrosine phosphatase inhibitor on Src activation in vitro.

    Science.gov (United States)

    Chellaiah, Meenakshi A; Schaller, Michael D

    2009-08-01

    PTP-PEST is involved in the regulation of sealing ring formation in osteoclasts. In this article, we have shown a regulatory role for PTP-PEST on dephosphorylation of c-Src at Y527 and phosphorylation at Y418 in the catalytic site. Activation of Src in osteoclasts by over-expression of PTP-PEST resulted in the phosphorylation of cortactin at Y421 and WASP at Y294. Also enhanced as a result, is the interaction of Src, cortactin, and Arp2 with WASP. Moreover, the number of osteoclasts displaying sealing ring and bone resorbing activity was increased in response to PTP-PEST over-expression as compared with control osteoclasts. Cells expressing constitutively active-Src (527YDeltaF) simulate the effects mediated by PTP-PEST. Treatment of osteoclasts with a bisphosphonate alendronate or a potent PTP inhibitor PAO decreased the activity and phosphorylation of Src at Y418 due to reduced dephosphorylation state at Y527. Therefore, Src-mediated phosphorylation of cortactin and WASP as well as the formation of WASP.cortactin.Arp2 complex and sealing ring were reduced in these osteoclasts. Similar effects were observed in osteoclasts treated with an Src inhibitor PP2. We have shown that bisphosphonates could modulate the function of osteoclasts by inhibiting downstream signaling mediated by PTP-PEST/Src, in addition to its effect on the inhibition of the post-translational modification of small GTP-binding proteins such as Rab, Rho, and Rac as shown by others. The promising effects of the inhibitors PP2 and PAO on osteoclast function suggest a therapeutic approach for patients with bone metastases and osteoporosis as an alternative to bisphosphonates.

  13. Circulating sclerostin and estradiol levels are associated with inadequate response to bisphosphonates in postmenopausal women with osteoporosis.

    Science.gov (United States)

    Morales-Santana, Sonia; Díez-Pérez, Adolfo; Olmos, José M; Nogués, Xavier; Sosa, Manuel; Díaz-Curiel, Manuel; Pérez-Castrillón, José L; Pérez-Cano, Ramón; Torrijos, Antonio; Jodar, Esteban; Rio, Luis Del; Caeiro-Rey, José R; Reyes-García, Rebeca; García-Fontana, Beatriz; González-Macías, Jesús; Muñoz-Torres, Manuel

    2015-12-01

    The biological mechanisms associated with an inadequate response to treatment with bisphosphonates are not well known. This study investigates the association between circulating levels of sclerostin and estradiol with an inadequate clinical outcome to bisphosphonate therapy in women with postmenopausal osteoporosis. This case-control study is based on 120 Spanish women with postmenopausal osteoporosis being treated with oral bisphosphonates. Patients were classified as adequate responders (ARs, n=66, mean age 68.2±8 years) without incident fractures during 5 years of treatment, or inadequate responders (IRs, n=54, mean age 67±9 years), with incident fractures between 1 and 5 years of treatment. Bone mineral density (DXA), structural analysis of the proximal femur and structural/fractal analysis of the distal radius were assessed. Sclerostin concentrations were measured by ELISA and 17β-estradiol levels by radioimmunoassay based on ultrasensitive methods. In the ARs group, sclerostin serum levels were significantly lower (p=0.02) and estradiol concentrations significantly higher (p=0.023) than in the IRs group. A logistic regression analysis was performed, including as independent variables in the original model femoral fracture load, 25 hydroxyvitamin D, previus history of fragility fracture, sclerostin and estradiol. Only previous history of fragility fracture (OR 14.04, 95% CI 2.38-82.79, p=0.004) and sclerostin levels (OR 1.11, 95% CI 1.02-1.20, p=0.011), both adjusted by estradiol levels remained associated with IRs. Also, sclerostin concentrations were associated with the index of resistance to compression (IRC) in the fractal analysis of the distal radius, a parameter on bone microstructure. Sclerostin and estradiol levels are associated with the response to bisphosphonate therapy in women with postmenopausal osteoporosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Intravenous aminohydroxypropylidene bisphosphonate does not modify {sup 99m}Tc-hydroxymethylene bisphosphonate bone scintigraphy. A prospective study; L`aminohydroxypropylidene bisphosphonate (APD) intraveineux ne modifie pas la scintigraphie osseuse au Tc{sup 99m}-hydroxymethylene bisphosphonate (Tc{sup 99m}-HMDP). Une etude prospective

    Energy Technology Data Exchange (ETDEWEB)

    Macro, M.; Bouvard, G.; Le Gangneux, E.; Colin, T.; Loyau, G. [Caen Univ., 14 (France)

    1995-02-01

    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 {sup 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.

  15. Does oral prednisolone treatment increase the incidence of acute laminitis?

    Science.gov (United States)

    Jordan, V J; Ireland, J L; Rendle, D I

    2017-01-01

    It is accepted among equine practitioners that glucocorticoid treatment is a risk factor for the development of laminitis. However, there is little published evidence of a link between glucocorticoids and laminitis. To determine whether horses receiving oral prednisolone are at increased risk of laminitis. Retrospective case-control study. Clinical records of horses registered with the ambulatory service at Liphook Equine Hospital between January 2001 and November 2014 were reviewed retrospectively to identify horses that had received treatment with oral prednisolone. For each treated horse, 2 time-matched controls that received veterinary attention but were not treated with prednisolone were selected. Incidence of laminitis was compared between the 2 groups and factors associated with laminitis were assessed using Cox regression analysis. Of the 416 horses treated with prednisolone, 16 (3.8%) were diagnosed with laminitis subsequent to the initiation of prednisolone treatment with an overall incidence of 2.60 (95% CI 1.49-4.22) cases per 100 horse-years at risk. A total of 7 horses (1.7%) developed laminitis during the course of their treatment and 3 (0.7%) of the horses treated with prednisolone were ultimately subjected to euthanasia as a result of laminitis. A total of 46 (5.7%), of the 814 time-matched control horses were diagnosed with laminitis during the study period with an overall incidence of 3.46 (95% CI 2.54-4.62) cases per 100 horse-years at risk. Of these, 12 (1.5%) were subjected to euthanasia as a result of laminitis. There were no significant differences in the overall laminitis incidence rate (P = 0.8), incidence rate during prednisolone treatment (P = 0.09), or probability of laminitis (P = 0.3) between the 2 groups. Mean survival time was greater in the prednisolone than the control group. Equine metabolic syndrome and increasing age were associated with increased risk of laminitis. Administration of oral prednisolone did not increase the risk

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

    Science.gov (United States)

    Brunetti, G; Papadia, F; Tummolo, A; Fischetto, R; Nicastro, F; Piacente, L; Ventura, A; Mori, G; Oranger, A; Gigante, I; Colucci, S; Ciccarelli, M; Grano, M; Cavallo, L; Delvecchio, M; Faienza, M F

    2016-07-01

    In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI. Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate. Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls. DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients. Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects

  17. 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.

  18. Models for anti-tumor activity of bisphosphonates using refined topochemical descriptors

    Science.gov (United States)

    Goyal, Rakesh K.; Singh, G.; Madan, A. K.

    2011-10-01

    An in silico approach comprising of decision tree (DT), random forest (RF) and moving average analysis (MAA) was successfully employed for development of models for prediction of anti-tumor activity of bisphosphonates. A dataset consisting of 65 analogues of both nitrogen-containing and non-nitrogen-containing bisphosphonates was selected for the present study. Four refinements of eccentric distance sum topochemical index termed as augmented eccentric distance sum topochemical indices 1-4 ( {ξ_{{1c}}^{{ADS}},ξ_{{2c}}^{{ADS}},ξ_{{3c}}^{{ADS}},ξ_{{4c}}^{{ADS}}} ) have been proposed so as to significantly augment discriminating power. Proposed topological indices (TIs) along with the exiting TIs (>1,400) were subsequently utilized for development of models for prediction of anti-tumor activity of bisphosphonates. A total of 43 descriptors of diverse nature, from a large pool of molecular descriptors, calculated through E-Dragon software (version 1.0) and an in-house computer program were selected for development of suitable models by employing DT, RF and MAA. DT identified two TIs as most important and classified the analogues of the dataset with an accuracy of 97% in training set and 90.7% in tenfold cross-validated set. Random forest correctly classified the analogues with an accuracy of 89.2%. Four independent models developed through MAA predicted the activity of analogues of the dataset with an accuracy of 87.6% to 89%. The statistical significance of proposed models was assessed through intercorrelation analysis, specificity, sensitivity and Matthew's correlation coefficient. The proposed models offer a vast potential for providing lead structures for development of potent anti-tumor agents for treatment of cancer that has spread to the bone.

  19. Niacin treatment increases plasma homocyst(e)ine levels.

    Science.gov (United States)

    Garg, R; Malinow, M; Pettinger, M; Upson, B; Hunninghake, D

    1999-12-01

    Studies have reported high levels of plasma homocyst(e)ine as an independent risk factor for arterial occlusive disease. The Cholesterol Lowering Atherosclerosis Study reported an increase in plasma homocyst(e)ine levels in patients receiving both colestipol and niacin compared with placebo. Thus the objective of this study was to examine the effect of niacin treatment on plasma homocyst(e)ine levels. The Arterial Disease Multiple Intervention Trial, a multicenter randomized, placebo-controlled trial, examined the effect of niacin compared with placebo on homocyst(e)ine in a subset of 52 participants with peripheral arterial disease. During the screening phase, titration of niacin dose from 100 mg to 1000 mg daily resulted in a 17% increase in mean plasma homocyst(e)ine level from 13.1 +/- 4.4 micromol/L to 15.3 +/- 5.6 micromol/L (P ine levels in the niacin group and a 7% decrease in the placebo group (P =.0001). This difference remained statistically significant at the end of follow-up at 48 weeks. Niacin substantially increased plasma homocyst(e)ine levels, which could potentially reduce the expected benefits of niacin associated with lipoprotein modification. However, plasma homocyst(e)ine levels can be decreased by folic acid supplementation. Thus further studies are needed to determine whether B vitamin supplementation to patients undergoing long-term niacin treatment would be beneficial.

  20. Relevance of bisphosphonate long-term therapy in radiation therapy of endosteal jaw metastases; Zur Relevanz einer Bisphosphonat-Langzeittherapie bei der Strahlentherapie enossaler Kiefermetastasen

    Energy Technology Data Exchange (ETDEWEB)

    Groetz, K.A. [HSK Dr. Horst-Schmidt-Kliniken, Wiesbaden (Germany). Akademisches Lehrkrankenhaus, Klinik fuer Mund-Kiefer-Gesichtschirurgie; Mainz Univ. (Germany). Klinik und Poliklinik fuer Mund-, Kiefer- und Gesichtschirurgie; Walter, C.; Al-Nawas, B. [Mainz Univ. (Germany). Klinik und Poliklinik fuer Mund-, Kiefer- und Gesichtschirurgie; Kuettner, C. [HSK Dr. Horst-Schmidt-Kliniken, Wiesbaden (Germany). Akademisches Lehrkrankenhaus, Klinik fuer Mund-Kiefer-Gesichtschirurgie

    2007-04-15

    Background and Purpose: Bisphosphonates are used in the treatment of bone metastasis and malignant myeloma. They have been associated with osteonecrosis of the jaw (ONJ) since the year 2003. Etiology and pathogenesis of this clinical problem are not clear. The high rate of newly diagnosed cases is alarming. Based on the collective of two departments of oral and maxillofacial surgery, the results of therapy in the coincidence of systemic bisphosphonate treatment and local radiotherapy (RT) are analyzed. Patients and Methods: In the course of 33 months (01/2003-09/2005), 63 synchronic or metachronic ONJs were seen in 42 patients as newly diagnosed episodes. Three of the 42 patients had an RT of jaw metastasis. Results: Only one patient was followed over the whole treatment period. Under RT she developed a therapy-refractory ONJ similar to osteoradionecrosis at a dose of 40 Gy. She required a wide segmental osteotomy of the mandible resulting in a total loss of masticatory function. In 39 patients with 60 ONJs without RT not a single segmental resection of the mandible was necessary. Conclusion: Local RT in bisphosphonate long-term therapy seems to be a high risk constellation. As long as the pathogenesis of bisphosphonate-associated ONJ is unclear, patients subjected to RT of the head-and-neck area should be treated.

  1. Adverse cardiovascular effects of nitrogen-containing bisphosphonates in patients with osteoporosis: A nationwide population-based retrospective study.

    Science.gov (United States)

    Wang, Jen-Chun; Chien, Wu-Chien; Chung, Chi-Hsiang; Liao, Wen-I; Tsai, Shih-Hung

    2016-07-15

    Bisphosphonates (BPs) are a class of medications used for the treatment of osteoporosis. Nitrogen-containing BPs (N-BPs) are more potent than non-nitrogenous BPs in terms of their effects on osteoporosis. We examined the effects of N-BPs on osteoporosis in patients included in a large population-based cohort study. Based on the National Health Insurance Research Database of Taiwan, we identified 1258 patients with osteoporosis who had received N-BP treatment from 2005 through 2010. During the retrospective observation period, N-BP users had significantly higher incidence rates of hypertension, acute ischemic stroke, atrial fibrillation (Af), and congestive heart failure (CHF), and lower rates of hyperlipidemia than patients who did not use N-BPs. Overall, N-BP users had a higher incidence of cardiovascular events at the end of the follow-up period. After adjustment for age, sex, and comorbidities, the risk of developing cardiovascular events was significantly high for patients using N-BPs. Patients who received N-BP therapy also had a higher risk of Af and CHF than those who did not during the five-year follow-up period. We provide evidence that patients with osteoporosis using N-BP therapy have an increased risk of CHF and Af. This potential risk should be weighed against the reduction in the risk of osteoporotic fractures. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

    Science.gov (United States)

    Yu, Tingsheng; Witten, Paul Eckhard; Huysseune, Ann; Buettner, Anita; To, Thuy Thanh; Winkler, Christoph

    2016-02-01

    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. © 2016. Published by The Company of Biologists Ltd.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Bisphosphonate-functionalized poly(β-amino ester) network polymers.

    Science.gov (United States)

    Guven, Melek Naz; Seckin Altuncu, Merve; Demir Duman, Fatma; Eren, Tugce Nur; Yagci Acar, Havva; Avci, Duygu

    2017-05-01

    Three novel bisphosphonate-functionalized secondary diamines are synthesized and incorporated into poly(β-amino ester)s (PBAEs) to investigate the effects of bisphosphonates on biodegradation and toxicity of PBAE polymer networks. These three novel amines, BPA1, BPA2, and BPA3, were prepared from the reactions of 1,4-butanediamine, 1,6-hexanediamine, or 4,9-dioxa-1,12-dodecanediamine with tetraethyl vinylidene bisphosphonate, respectively. The PBAE macromers were obtained from the aza-Michael addition reaction of these amines to 1,6-hexane diol diacrylate (HDDA) and poly(ethylene glycol) diacrylate (PEGDA, M n  = 575) and photopolymerized to produce biodegradable gels. These gels with different chemistries exhibited similar degradation behavior with mass loss of 53-73% within 24 h, indicating that degradation is mostly governed by the bisphosphonate group. Based on the in vitro cytotoxicity evaluation against NIH 3T3 mouse embryonic fibroblast cells, the degradation products do not exhibit significant toxicity in most cases. It was also shown that PBAE macromers can be used as cross-linkers for the synthesis of 2-hydroxyethyl methacrylate hydrogels, conferring small and customizable degradation rates upon them. The materials reported have potential to be used as nontoxic degradable biomaterials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1412-1421, 2017. © 2017 Wiley Periodicals, Inc.

  5. 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 ...

  6. 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 ...

  7. Increasing nerve agent treatment efficacy by P-glycoprotein inhibition.

    Science.gov (United States)

    Joosen, Marloes J A; Vester, Stefanie M; Hamelink, Jouk; Klaassen, Steven D; van den Berg, Roland M

    2016-11-25

    One of the shortcomings of current treatment of nerve agent poisoning is that not all drugs effectively penetrate the blood-brain barrier (BBB), whereas most nerve agents easily do. P-glycoprotein (Pgp) efflux transporters at the BBB may contribute to this aspect. It was previously shown that Pgp inhibition by tariquidar enhanced the efficacy of nerve agent treatment when administered as a pretreatment. In the present study soman-induced seizures were also substantially prevented when the animals were intravenously treated with tariquidar post-poisoning, in addition to HI-6 and atropine. In these animals, approximately twice as much AChE activity was present in their brain as compared to control rats. The finding that tariquidar did not affect distribution of soman to the brain indicates that the potentiating effects were a result of interactions of Pgp inhibition with drug distribution. In line with this, atropine appeared to be a substrate for Pgp in in vitro studies in a MDR1/MDCK cell model. This indicates that tariquidar might induce brain region specific effects on atropine distribution, which could contribute to the therapeutic efficacy increase found. Furthermore, the therapeutic enhancement by tariquidar was compared to that of the less specific and less potent Pgp inhibitor cyclosporine A. This compound appeared to induce a protective effect similar to tariquidar. In conclusion, treatment with a Pgp inhibitor resulted in enhanced therapeutic efficacy of HI-6 and atropine in a soman-induced seizure model in the rat. The mechanism underlying these effects should be further investigated. To that end, the potentiating effect of nerve agent treatment should be addressed against a broader range of nerve agents, for oximes and atropine separately, and for those at lower doses. In particular when efficacy against more nerve agents is shown, a Pgp inhibitor such as tariquidar might be a valid addition to nerve agent antidotes. Copyright © 2016 Elsevier Ireland

  8. 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.

  9. Bisphosphonate-related atypical femoral fracture with bone metastasis of breast cancer: case report and review.

    Science.gov (United States)

    Hayashi, Kazunori; Aono, Masanari; Shintani, Kousuke; Kazuki, Kenichi

    2014-03-01

    Intravenous bisphosphonates (BPs) have been used to reduce the frequency of skeletal-related events due to bone metastases of several kinds of cancers. Although many studies on BP-related atypical fractures (BRAFs) due to the use of BP for osteoporosis treatment have been reported, few reports on BRAFs arising as a complication of long-term BP use for bone metastasis of cancer are available. A 62-year-old woman with a history of breast cancer presented with right thigh pain after she had a fall. Radiographs indicated a transverse fracture in the shaft of the right femur. She had been on zoledronate treatment for six years. Based on radiographic and histopathological findings, we concluded that the fracture was not a pathological fracture associated with metastasis but was a complication of long-term BP treatment. Clinical oncologists should consider the possibility of BRAFs in patients on long-term zoledronate treatment for bone metastases.

  10. Safety of I.V. Nonnitrogen bisphosphonates on the occurrence of osteonecrosis of the jaw: long-term follow-up on prostate cancer patients.

    Science.gov (United States)

    Rodrigues, Paulo; Hering, Flávio; Imperio, Marcio

    2015-06-01

    The aim of the study was to disclose information about the recently incorporated bisphosphonates therapies used to treat prostate cancer patients and their potential risks because the chemical nature and nitrogen content varies among the available drugs on the market. Three hundred twenty-four consecutive prostate cancer patients were submitted to bisphosphonates therapy after antiandrogen treatment was started. Zoledronic acid was administered monthly (n = 45), bimonthly (n = 15), trimonthly (n = 19), and semestrally (n = 15), and monthly intravenous clodronate was administered in an additional 156 cases. Fourteen additional cases switched the drugs during the course of the treatment. After a median follow-up of 54 ± 24 (control), 63 ± 7 (clodronate), and 54 ± 6 months (zoledronic acid), the only 2 patients (0.6%) who developed osteonecrosis of the jaw (ONJ) occurred in those who switched the drug. This study is the longest and the largest ever reported on bisphosphonates usage in prostate cancer patients. ONJ seems to be exclusively related to nitrogen content bisphosphonates. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Solid-State NMR, Crystallographic, and Computational Investigation of Bisphosphonates and Farnesyl Diphosphate Synthase-Bisphosphonate Complexes

    Energy Technology Data Exchange (ETDEWEB)

    Mao,J.; Mukherjee, S.; Zhang, Y.; Cao, R.; Sanders, J.; Song, Y.; Zhang, Y.; Meints, G.; Gao, Y.; et al.

    2006-01-01

    Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseases and are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), but the details of how these molecules bind are not fully understood. Here, we report the results of a solid-state {sup 13}C, {sup 15}N, and {sup 31}P magic-angle sample spinning (MAS) NMR and quantum chemical investigation of several bisphosphonates, both as pure compounds and when bound to FPPS, to provide information about side-chain and phosphonate backbone protonation states when bound to the enzyme. We then used computational docking methods (with the charges assigned by NMR) to predict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determine the structures of two potent bisphosphonate inhibitors, finding good agreement with the computational results, opening up the possibility of using the combination of NMR, quantum chemistry and molecular docking to facilitate the design of other, novel prenytransferase inhibitors.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Pharmacologically Inactive Bisphosphonates as an Alternative Strategy for Targeting Osteoclasts: In Vivo Assessment of 5-Fluorodeoxyuridine-Alendronate in a Preclinical Model of Breast Cancer Bone Metastases.

    Science.gov (United States)

    Schem, Christian; Tower, Robert J; Kneissl, Philipp; Rambow, Anna-Christina; Campbell, Graeme M; Desel, Christine; Damm, Timo; Heilmann, Thorsten; Fuchs, Sabine; Zuhayra, Maaz; Trauzold, Anna; Glüer, Claus C; Schott, Sarah; Tiwari, Sanjay

    2017-03-01

    Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

  14. Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium ranelate and teriparatide.

    Science.gov (United States)

    Carvalho, N N C; Voss, L A; Almeida, M O P; Salgado, C L; Bandeira, F

    2011-09-01

    Atypical femoral fractures have rarely been reported in women taking bisphosphonates, but this is still a controversial issue. Data are derived mainly from observation studies because a post hoc analysis from a randomized clinical trial did not find any such association. The aim of this study was to report three cases of what are considered atypical femoral fractures and their responses to the use of strontium ranelate and teriparatide. We studied three postmenopausal women with a diagnosis of osteoporosis who suffered fractures of the subtrochanteric region and femoral diaphysis with no major trauma while on long-term use of bisphosphonates. All the major features of atypical femoral fractures highlighted in the Task Force Report of the American Society for Bone and Mineral Research were present in the three cases. They had had unconsolidated fractures for approximately 1 yr before being referred to our center. After 3 months on strontium ranelate 2 g/d, serum osteocalcin and serum β-carboxyterminal telopeptide had increased in case 1 by 125 and 100%, respectively, and in case 2 by 50 and 22%, respectively, with total closure of the fracture. In case 3, after 1 month on teriparatide 20 μg/d, a radiographic closure of the fracture was achieved, and 3 months later serum osteocalcin and serum β-carboxyterminal telopeptide had increased by 300 and 22%, respectively. Our finding showed that both teriparatide and strontium ranelate had a rapid bone anabolic effect on unhealed atypical fractures associated with chronic bisphosphonate use.

  15. Bisphosphonates and Risk of Subtrochanteric, Femoral Shaft, and Atypical Femur Fracture: Sensitivity and Trim and Fill Studies

    Science.gov (United States)

    Liu, Jie; Zhang, Hong-xin; Lu, Xiong-xiong; Hu, Jia-jia

    2014-01-01

    Objective: This study carried out sensitivity analysis and trim-fill analysis between bisphosphonates and subtrochanteric, femoral shaft, and atypical femur fracture. Methods: A random-effects model was used finally. Sensitivity, trim and fill, and publication bias analyses were done. Results: Under a random-effects model (I2=87.535), the Z-value=5.672, p-value of test of nullBisphosphonate exposure was associated with an increased risk of atypical femur fracture (3.243 [95% CI 2.160–4.870]). When any study is removed, the remaining sensitivity analysis results are still significant. Trim and fill results show that two studies were missed. After filling them, a funnel plot of precision by log risk ratio was more symmetrical. Conclusion: This study suggests that (1) there is an increased risk of subtrochanteric, femoral shaft, and atypical femur fracture in bisphosphonate users; (2) any single study does not influence the total sensitivity; (3) two studies have been lost, theoretically. PMID:24205872

  16. The risk of second hip fracture is decreased with compliant and persistent use of bisphosphonates

    DEFF Research Database (Denmark)

    Hansen, Louise; Vestergaard, Peter; Petersen, Karin Dam

    , previously employed by the same authors in a cost of illness study, was modified to estimate the cost-effectiveness of bisphosphonate treatment is Danish fracture patients above 50 years. The model applied an incidence-based, bottom-up approach from a societal perspective and, thus, included direct...... discounted at 3% rate. This model includes all Danish citizens above 50 years of age with a fracture during the study period. The model inputs have been estimated from Danish registries and published peer-reviewed literature. The applied effectiveness measure was the number of hip fractures, based...... the average cost was EUR 13,395 and 0.17 hip fractures per woman. The incremental cost-effectiveness ratio (ICER) resulted in a cost saving of EUR 18,623 per prevented hip fracture. In the alendronate treatment arm, the average cost and effect was EUR 5,631 and 0.16 hip fractures per man. The no treatment arm...

  17. Smoking increases the likelihood of Helicobacter pylori treatment failure.

    Science.gov (United States)

    Itskoviz, David; Boltin, Doron; Leibovitzh, Haim; Tsadok Perets, Tsachi; Comaneshter, Doron; Cohen, Arnon; Niv, Yaron; Levi, Zohar

    2017-07-01

    Data regarding the impact of smoking on the success of Helicobacter pylori (H. pylori) eradication are conflicting, partially due to the fact that sociodemographic status is associated with both smoking and H. pylori treatment success. We aimed to assess the effect of smoking on H. pylori eradication rates after controlling for sociodemographic confounders. Included were subjects aged 15 years or older, with a first time positive C 13 -urea breath test (C 13 -UBT) between 2007 to 2014, who underwent a second C 13 -UBT after receiving clarithromycin-based triple therapy. Data regarding age, gender, socioeconomic status (SES), smoking (current smokers or "never smoked"), and drug use were extracted from the Clalit health maintenance organization database. Out of 120,914 subjects with a positive first time C 13 -UBT, 50,836 (42.0%) underwent a second C 13 -UBT test. After excluding former smokers, 48,130 remained who were eligible for analysis. The mean age was 44.3±18.2years, 69.2% were females, 87.8% were Jewish and 12.2% Arabs, 25.5% were current smokers. The overall eradication failure rates were 33.3%: 34.8% in current smokers and 32.8% in subjects who never smoked. In a multivariate analysis, eradication failure was positively associated with current smoking (Odds Ratio {OR} 1.15, 95% CI 1.10-1.20, psmoking was found to significantly increase the likelihood of unsuccessful first-line treatment for H. pylori infection. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  18. A collagen-hydroxyapatite scaffold allows for binding and co-delivery of recombinant bone morphogenetic proteins and bisphosphonates.

    Science.gov (United States)

    Murphy, Ciara M; Schindeler, Aaron; Gleeson, John P; Yu, Nicole Y C; Cantrill, Laurence C; Mikulec, Kathy; Peacock, Lauren; O'Brien, Fergal J; Little, David G

    2014-05-01

    An emerging paradigm in orthopedics is that a bone-healing outcome is the product of the anabolic (bone-forming) and catabolic (bone-resorbing) outcomes. Recently, surgical and tissue engineering strategies have emerged that combine recombinant human bone morphogenetic proteins (rhBMPs) and bisphosphonates (BPs) in order to maximize anabolism and minimize catabolism. Collagen-based scaffolds that are the current surgical standard can bind rhBMPs, but not BPs. We hypothesized that a biomimetic collagen-hydroxyapatite (CHA) scaffold would bind both agents and produce superior in vivo outcomes. Consistent with this concept, in vitro elution studies utilizing rhBMP-2 ELISA assays and scintillation counting of (14)C-radiolabeled zoledronic acid (ZA) confirmed delayed release of both agents from the CHA scaffold. Next, scaffolds were tested for their capacity to form ectopic bone after surgical implantation into the rat hind limb. Using CHA, a significant 6-fold increase in bone volume was seen in rhBMP-2/ZA groups compared to rhBMP-2 alone, confirming the ability of ZA to enhance rhBMP-2 bone formation. CHA scaffolds were found to be capable of generating mineralized tissue in the absence of rhBMP-2. This study has implications for future clinical treatments of critical bone defects. It demonstrates the relative advantages of co-delivering anabolic and anti-catabolic agents using a multicomponent scaffold system. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  19. The effect of osteoporosis treatments on fatigue properties of cortical bone tissue

    Directory of Open Access Journals (Sweden)

    Garry R. Brock

    2015-06-01

    Full Text Available Bisphosphonates are commonly prescribed for treatment of osteoporosis. Long-term use of bisphosphonates has been correlated to atypical femoral fractures (AFFs. AFFs arise from fatigue damage to bone tissue that cannot be repaired due to pharmacologic treatments. Despite fatigue being the primary damage mechanism of AFFs, the effects of osteoporosis treatments on fatigue properties of cortical bone are unknown. To examine if fatigue-life differences occur in bone tissue after different pharmacologic treatments for osteoporosis, we tested bone tissue from the femurs of sheep given a metabolic acidosis diet to induce osteoporosis, followed by treatment with a selective estrogen reception modulator (raloxifene, a bisphosphonate (alendronate or zoledronate, or parathyroid hormone (teriparatide, PTH. Beams of cortical bone tissue were created and tested in four-point bending fatigue to failure. Tissue treated with alendronate had reduced fatigue life and less modulus loss at failure compared with other treatments, while tissue treated with PTH had a prolonged fatigue life. No loss of fatigue life occurred with zoledronate treatment despite its greater binding affinity and potency compared with alendronate. Tissue mineralization measured by microCT did not explain the differences seen in fatigue behavior. Increased fatigue life with PTH suggests that current treatment methods for AFF could have beneficial effects for restoring fatigue life. These results indicate that fatigue life differs with each type of osteoporosis treatment.

  20. Effects of bisphosphonates on tooth eruption in children with osteogenesis imperfecta.

    Science.gov (United States)

    Kamoun-Goldrat, Agnès; Ginisty, Danielle; Le Merrer, Martine

    2008-06-01

    Bisphosphonates are currently used in the therapy of osteogenesis imperfecta (OI) to decrease the bone fragility observed in OI patients. Bisphosphonate therapy delays tooth eruption in rats. The aim of this study was to determine whether or not bisphosphonate therapy delays tooth eruption in children. The clinical emergence of teeth was observed and the calculated dental age and the number of delayed teeth were determined for 33 OI patients treated with bisphosphonates and for strictly gender- and age-matched controls. There were significant differences between bisphosphonate-treated patients and controls for calculated dental age and number of delayed teeth. Bisphosphonate therapy was associated with a mean delay of 1.67 yr in tooth eruption in children with OI.

  1. 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...

  2. Osteoporosis in the aging male: Treatment options

    Directory of Open Access Journals (Sweden)

    Stephen P Tuck

    2008-01-01

    Full Text Available Stephen P Tuck1, Harish K Datta21Departments of Rheumatology, James Cook University Hospital, Marton Road, Middlesbrough, Cleveland, UK; 2School of Clinical and Laboratory Sciences, The Medical School, University of Newcastle, Newcastle upon Tyne, UKAbstract: In elderly women, loss in bone mass and micro-architectural changes are generally attributed to the onset of menopause. Men do not experience menopause, they do, however, experience age-related acceleration in bone loss and micro-architecture deterioration. The incidence of osteoporotic fractures in elderly men, just as in aged women, increases exponentially with age; the rise in men, however, is some 5–10 years later than in women. Up to 50% of male osteoporotics have no identifiable etiology; however elderly males have much higher likelihood of having an identifiable secondary cause than younger men. Therefore, clinical and laboratory evaluation of aged male osteoporotics must be thorough and should be aimed at identifying lifestyle or conditions contributing to bone loss and fragility. It is essential to identify and treat secondary causes and ensure adequate vitamin D and calcium intake before embarking upon treatment with pharmacological agents. The evidence from a limited number of trials suggests that bisphosphonates, especially alendronate and risedronate, are effective in improving BMD, and seem to be the treatments of choice in aged men with osteoporosis. In cases where bisphosphonates are contra-indicated or ineffective, teriparatide or alternatives such as strontium should be considered.Keywords: male osteoporosis, bone mineral density, fracture risk, bisphosphonates, PTH

  3. A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ?

    Science.gov (United States)

    Hasegawa, T; Kawakita, A; Ueda, N; Funahara, R; Tachibana, A; Kobayashi, M; Kondou, E; Takeda, D; Kojima, Y; Sato, S; Yanamoto, S; Komatsubara, H; Umeda, M; Kirita, T; Kurita, H; Shibuya, Y; Komori, T

    2017-08-01

    Root amputation, extraction of a single tooth, bone loss or severe tooth mobility, and an unclosed wound were significantly associated with increased risk of developing medication-related osteonecrosis of the jaw (MRONJ). We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. Osteonecrosis of the jaws can occur following tooth extraction in patients receiving bisphosphonate drugs. Various strategies for minimizing the risk of MRONJ have been advanced, but no studies have comprehensively analyzed the efficacy of factors such as primary wound closure, demographics, and drug holidays in reducing its incidence. The purpose of this study was to retrospectively investigate the relationships between these various risk factors after tooth extraction in patients receiving oral bisphosphonate therapy. Risk factors for MRONJ after tooth extraction were evaluated using univariate and multivariate analysis. All patients were investigated with regard to demographics; type and duration of oral bisphosphonate use; whether they underwent a discontinuation of oral bisphosphonates before tooth extraction (drug holiday), and the duration of such discontinuation; and whether any additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. We found that root amputation (OR = 6.64), extraction of a single tooth (OR = 3.70), bone loss or severe tooth mobility (OR = 3.60), and an unclosed wound (OR = 2.51) were significantly associated with increased risk of developing MRONJ. We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. We find no evidence supporting the efficacy of a pre-extraction short-term drug holiday from oral bisphosphonates in reducing the risk of MRONJ.

  4. Genetic investigation of bisphosphonate-related osteonecrosis of jaw (BRONJ via whole exome sequencing and bioinformatics.

    Directory of Open Access Journals (Sweden)

    Jee-Hwan Kim

    Full Text Available Complications associated with the use of bisphosphonate (BP have risen over the years due to an increase in the prescription of BP. BP-related osteonecrosis of jaw (BRONJ, one of the complications linked to the consumption of BP, greatly affects patients with minor dental trauma, incurring a long healing period. While BRONJ afflicts only a minority of patients prescribed with BP, BRONJ is a multigenic disease affected both by environmental and genetic factors having a distinctive phenotype. This study aims to discover genetic biomarkers associated with BRONJ via whole exome sequencing (WES followed by statistical analysis. Sixteen individuals who had been prescribed with bisphosphonate medication and diagnosed as BRONJ were chosen and each individual's saliva sample was collected for WES. 126 randomized subsamples from the GSK project representing 109 male and 17 female Koreans were used as a control data set. Fisher's exact test was carried out to assess the significance of genetic variants in BRONJ patients. Gene set enrichment analysis (GSEA (DAVID Bioinformatics Resource 6.7 was used to perform a cluster analysis of variants found from Fisher's exact test. The results from this study suggest that BRONJ-inducing factors are genetically associated and BRONJ occurs due to the malfunctioning of post-translational modification in osteoclast leading to the impairment of cell morphology and adhesion.

  5. Synthesis, characterization and biodistribution of bisphosphonates Sm-153 complexes: correlation with molecular modeling interaction studies

    Energy Technology Data Exchange (ETDEWEB)

    Neves, M. E-mail: mneves@itn.pt; Gano, L.; Pereira, N.; Costa, M.C.; Costa, M.R.; Chandia, M.; Rosado, M.; Fausto, R

    2002-04-01

    Bisphosphonates (BPs) are characterized by a P-C-P backbone structure and two phosphonic acid groups bonded to the same carbon, and are established as osteoclast-mediated bone resorption inhibitors. The nature of the groups attached to the central carbon atom are responsible in determining the potency of bisphosphonates as anti-resorption drugs. However, it is not yet clear the exact relationship between their molecular structure and pharmacologic activities. In this study, molecular geometries of pamidronate, alendronate and neridronate, differing only in the length of the aliphatic chains, were predicted by molecular mechanics and their interactions with hydroxyapatite, the main bone mineral component, were examined. We report the synthesis and radiochemical characterization of {sup 153}Sm complexes with pamidronate, alendronate and neridronate. Hydroxyapatite binding and biodistribution studies of these complexes have shown a good correlation with the theoretical molecular modeling interaction studies. So, it is possible to conclude that computational chemistry techniques are a good approach to evaluate specific interactions and may play a relevant role in determining the relative ability of BPs to mineral bone, and open new perspectives to the design of new BPs with increased pharmacological activity. These techniques could be extended to BPs as ligands to carrier radioactive metals, aiming for new bone therapeutic radiopharmaceuticals.

  6. Bisphosphonate-Based Strategies for Bone Tissue Engineering and Orthopedic Implants

    Science.gov (United States)

    Cattalini, Juan Pablo; Boccaccini, Aldo R.; Lucangioli, Silvia

    2012-01-01

    Bisphosphonates (BPs) are a group of well-established drugs that are applied in the development of metabolic bone disorder-related therapies. There is increasing interest also in the application of BPs in the context of bone tissue engineering, which is the topic of this review, in which an extensive overview of published studies on the development and applications of BPs-based strategies for bone regeneration is provided with special focus on the rationale for the use of different BPs in three-dimensional (3D) bone tissue scaffolds. The different alternatives that are investigated to address the delivery and sustained release of these therapeutic drugs in the nearby tissues are comprehensively discussed, and the most significant published approaches on bisphosphonate-conjugated drugs in multifunctional 3D scaffolds as well as the role of BPs within coatings for the improved fixation of orthopedic implants are presented and critically evaluated. Finally, the authors' views regarding the remaining challenges in the fields and directions for future research efforts are highlighted. PMID:22440082

  7. α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.

    Science.gov (United States)

    Matthiesen, Robert A; Varney, Michelle L; Xu, Pauline C; Rier, Alex S; Wiemer, David F; Holstein, Sarah A

    2018-01-15

    Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation of an α-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel α-methyl triazole bisphosphonates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Efficacy of systemic bisphosphonate delivery on osseointegration of implants under osteoporotic conditions: lessons from animal studies.

    Science.gov (United States)

    Vohra, Fahim; Al-Rifaiy, Mohammad Qasim; Almas, Khalid; Javed, Fawad

    2014-09-01

    The aim was to systematically review the role of systemic bisphosphonate (BP) delivery on osseointegration of implants under osteoporotic conditions. The addressed focused question was "Does systemic BP delivery enhance osseointegration of implants under osteoporotic conditions?" PubMed/MEDLINE and Google-Scholar databases were searched from 1994 up to and including December 2013 using different combinations of the following keywords: "bone to implant contact", "implant", "bisphosphonate", "osseointegration" and "osteoporosis". Review articles, case-reports, commentaries, letters to the Editor, unpublished articles and articles published in languages other than English were excluded. Fifteen animal studies fulfilled our eligibility criteria. Osteoporotic conditions were induced via bilateral ovariectomy (OVX). BPs used in the studies were ibandronate, zoledronic acid and alendronate. Results from 12 studies showed that systemic BP delivery significantly increased bone volume and bone-to-implant contact under osteoporotic conditions. Two studies reported no significant difference in osseointegration among OVX animals with and without systemic BP delivery. In one study, systemic BP delivery negatively influenced implant osseointegration. Rough-surfaced and polished implants were used in 11 and one study respectively. In 3 studies implant surface characteristics remained unclear. Within the limits of the present study, it is concluded that systemic BP delivery enhances implant osseointegration in animals with induced osteoporotic conditions. However, in a clinical scenario, the potential risk of BP related ONJ in osteoporotic patients undergoing dental implant therapy cannot be disregarded. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Bisphosphonate Use Is Associated With Reduced Risk of Myocardial Infarction in Patients With Rheumatoid Arthritis

    Science.gov (United States)

    Wolfe, Frederick; Bolster, Marcy B; O’Connor, Christopher M; Michaud, Kaleb; Lyles, Kenneth W; Colón-Emeric, Cathleen S

    2013-01-01

    Bisphosphonates have been shown to reduce mortality in patients with osteoporotic fractures, but the mechanism is unclear. Bisphosphonates have immunomodulatory effects that may influence the development of vascular disease. We sought to determine if bisphosphonate use is associated with a reduced risk of myocardial infarction (MI) in a rheumatoid arthritis (RA) population with high prevalence of bisphosphonate use and vascular disease. Adult patients with RA enrolled in the National Data Bank for Rheumatic Diseases, a longitudinal study of RA patients enrolled continuously from U.S. rheumatology practices between 2003 and 2011, were included in the analysis (n = 19,281). Patients completed questionnaires every 6 months. including questions on medication use, demographic information, clinical information, and health status. MIs were confirmed by a central adjudicator. Among the 5689 patients who were treated with bisphosphonates at some time during the study period, the risk of MI while on bisphosphonate compared to when not on bisphosphonate was 0.56 (95% confidence interval [CI], 0.37–0.86; p bisphosphonate users compared to nonusers. This finding suggests a potential mechanism for the mortality reduction observed with bisphosphonate medications. PMID:23074131

  10. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity.

    Science.gov (United States)

    Cornell, R F; Kassim, A A

    2016-04-01

    The use of modern therapies such as thalidomide, bortezomib and lenalidomide coupled with upfront high-dose therapy and autologous stem cell transplant (ASCT) has resulted in improved survival in patients with newly diagnosed multiple myeloma (MM). However, patients with relapsed/refractory multiple myeloma (RRMM) often have poorer clinical outcomes and might benefit from novel therapeutic strategies. Emerging therapies, such as deacetylase inhibitors, monoclonal antibodies and new proteasome inhibitors, appear promising and may change the therapeutic landscape in RRMM. A limited number of studies has shown a benefit with salvage ASCT in patients with RRMM, although there remains ongoing debate about its timing and effectiveness. Improvement in transplant outcomes has re-ignited a debate on the timing and possible role for salvage ASCT and allogeneic stem cell transplant in RRMM. As the treatment options for management of patients with RRMM become increasingly complex, physicians must consider both disease- and patient-related factors in choosing the appropriate therapeutic approach, with the goal of improving efficacy while minimizing toxicity.

  11. Prevalence of evaluation and treatment of glucocorticoid-induced osteoporosis in men.

    Science.gov (United States)

    Cruse, Laura M; Valeriano, Joanne; Vasey, Frank B; Carter, John D

    2006-10-01

    Screening and treatment of glucocorticoid- induced osteoporosis in male patients is less than recommended despite available screening and therapies. We determined if men treated with long-term oral glucocorticoid therapy for any reason receive assessment and therapy for the prevention and treatment of glucocorticoid-induced osteoporosis. A retrospective computer-generated chart review was performed involving all men given prednisone from January 2002 through July 2002. There were 370 patients evaluated from the James A. Haley Veterans Affairs Hospital, Tampa, Florida, a large teaching hospital for the University of South Florida College of Medicine. Charts were reviewed for bone mineral density testing; dose, duration, and indication of glucocorticoid therapy; age of the patients as of January 2002;continuous or intermittent dosing; history of fracture; bone loss prevention medication use, including bisphosphonate, calcitonin, testosterone replacement therapy, calcium, and vitamin D; and the steroid-prescribing and screening practitioner's specialty and sex. Of the 370 men, 258 used 7.5 mg prednisone or more daily and 295 used glucocorticoids for more than 3 months. Of the 370 men, 163 had a bone mineral density test; 87 were treated with a bisphosphonate. Calcium and vitamin D were given to half of the patients. Of the patients with a normal T-score, 13 of 55 were treated with a bisphosphonate (24%) compared with 24 of 40 (60%) with an osteopenic score and 14 of 21 (67%) with osteoporosis. Of the 46 patients with no score available but indication that it had been ordered or otherwise addressed, 23 patients were treated empirically with a bisphosphonate. Rheumatology screened 75% of their patients, whereas primary care screened 30% of their patients. Bone mineral density testing was performed or ordered for less than half of the glucocorticoid-treated patients and less than one third were taking bisphosphonate therapy. Further intervention is needed to increase

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

    Science.gov (United States)

    Ang, Celina; Doyle, Erin; Branch, Andrea

    2016-01-21

    Best known for their anti-resorptive activity in bone, bisphosphonates (BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor (HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.

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

    Science.gov (United States)

    Ang, Celina; Doyle, Erin; Branch, Andrea

    2016-01-01

    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. PMID:26811636

  14. Treatment Option Overview (Prostate Cancer)

    Science.gov (United States)

    ... of bisphosphonate drugs to prevent or slow the growth of bone metastases is being studied in clinical trials. There are treatments for bone pain caused by bone metastases or hormone therapy. Prostate cancer that has spread to the ...

  15. Clinical effects of sirolimus treatment in patients with increased ...

    African Journals Online (AJOL)

    In addition, liver function, blood glucose, blood lipid levels, rejection reaction incidence, and mortality were recorded to evaluate the effects of SRL. Results: Scr .... and after treatment (p > 0.05). Blood glucose levels were normalized after treatment, and this difference was significant (p < 0.05) (Table 1). Adverse reactions.

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

    OpenAIRE

    S. V. Komisarenko; S. O. Kosterin; E. V. Lugovskoy; V. I. Kalchenko

    2013-01-01

    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[...

  17. Intermittent bisphosphonate therapy in postmenopausal osteoporosis - Progress to date

    OpenAIRE

    Reginster, Jean-Yves; Malaise, Olivier; Neuprez, A.; Jouret, V. E.; Close, Pierre

    2007-01-01

    Bisphosphonates are the most widely prescribed drugs in osteoporosis today. They have unequivocally shown their ability to reduce fracture rate at the spine (alendronic acid, risedronic acid, ibandronic acid) and at the hip (alendronic acid and risedronic acid). However, their dosage and administration procedures and the adverse reactions induced by their oral intake are responsible for low adherence. Therefore, intermittent regimens have been developed. Weekly alendronic acid and risedronic ...

  18. Bisphosphonates and dental implants: A meta-analysis.

    Science.gov (United States)

    Chrcanovic, Bruno Ramos; Albrektsson, Tomas; Wennerberg, Ann

    2016-04-01

    To test the null hypothesis of no difference in the implant failure rates, marginal bone loss, and postoperative infection for patients receiving or not receiving bisphosphonates, against the alternative hypothesis of a difference. An electronic search was undertaken in October 2015 in PubMed/Medline, Web of Science, and Embase, plus hand-searching and databases of clinical trials. Eligibility criteria included clinical human studies, either randomized or not. A total of 18 publications were included in the review. Concerning implant failure, the meta-analysis found a risk ratio of 1.73 (95% confidence interval [CI] 1.21-2.48, P = .003) for patients taking bisphosphonates, when compared to patients not taking the medicament. The probability of an implant failure in patients taking bisphosphonates was estimated to be 1.5% (0.015, 95% CI 0.006- 0.023, standard error [SE] 0.004, P bisphosphonates may affect the marginal bone loss of dental implants, due to a limited number of studies reporting this outcome. Due to a lack of sufficient information, meta-analysis for the outcome "postoperative infection" was not performed. The results of the present study cannot suggest that the insertion of dental implants in patients taking BPs affects the implant failure rates, due to a limited number of published studies, all characterized by a low level of specificity, and most of them dealing with a limited number of cases without a proper control group. Therefore, the real effect of BPs on the osseointegration and survival of dental implants is still not well established.

  19. Exposure to bisphosphonates and risk of gastrointestinal cancers: series of nested case-control studies with QResearch and CPRD data

    Science.gov (United States)

    Coupland, Carol; Hippisley-Cox, Julia

    2013-01-01

    Objective To investigate the association between use of bisphosphonates estimated from prescription information and risk of gastrointestinal cancers. Design Series of nested case-control studies. Setting General practices in the United Kingdom contributing to the QResearch primary care database (660) and the Clinical Practice Research Datalink (CPRD) (643). Participants Patients aged ≥50 with a diagnosis of a primary gastrointestinal cancer in 1997-2011, each matched with up to five controls by age, sex, practice, and calendar year. Main outcome measures Odds ratios for incident gastrointestinal cancers (colorectal, oesophageal, gastric) and use of bisphosphonates, adjusted for smoking status, ethnicity, comorbidities, and use of other drugs. Results 20 106 and 19 035 cases of colorectal cancer cases, 5364 and 5135 cases of oesophageal cancer cases, and 3155 and 3157 cases of gastric cancer were identified from QResearch and CPRD, respectively. Overall bisphosphonate use (at least one prescription) was not associated with risk of colorectal, oesophageal, or gastric cancers in either database. Adjusted odds ratios (95% confidence interval) for QResearch and CPRD were 0.97 (0.79 to 1.18) and 1.18 (0.97 to 1.43) for oesophageal cancer; 1.12 (0.87 to 1.44) and 0.79 (0.62 to 1.01) for gastric cancer; and 1.03 (0.94 to 1.14) and 1.10 (1.00 to 1.22) for colorectal cancer. Additional analyses showed no difference between types of bisphosphonate for risk of oesophageal and colorectal cancers. For gastric cancer, alendronate use was associated with an increased risk (1.47, 1.11 to 1.95; P=0.008), but only in data from the QResearch database and without any association with duration and with no definitive confirmation from sensitivity analysis. Conclusions In this series of population based case-control studies in two large primary care databases, exposure to bisphosphonates was not associated with an increased risk of common gastrointestinal cancers. PMID:23325866

  20. Intrinsic mechanical behavior of femoral cortical bone in young, osteoporotic and bisphosphonate-treated individuals in low- and high energy fracture conditions

    Science.gov (United States)

    Zimmermann, Elizabeth A.; Schaible, Eric; Gludovatz, Bernd; Schmidt, Felix N.; Riedel, Christoph; Krause, Matthias; Vettorazzi, Eik; Acevedo, Claire; Hahn, Michael; Püschel, Klaus; Tang, Simon; Amling, Michael; Ritchie, Robert O.; Busse, Björn

    2016-02-01

    Bisphosphonates are a common treatment to reduce osteoporotic fractures. This treatment induces osseous structural and compositional changes accompanied by positive effects on osteoblasts and osteocytes. Here, we test the hypothesis that restored osseous cell behavior, which resembles characteristics of younger, healthy cortical bone, leads to improved bone quality. Microarchitecture and mechanical properties of young, treatment-naïve osteoporosis, and bisphosphonate-treated cases were investigated in femoral cortices. Tissue strength was measured using three-point bending. Collagen fibril-level deformation was assessed in non-traumatic and traumatic fracture states using synchrotron small-angle x-ray scattering (SAXS) at low and high strain rates. The lower modulus, strength and fibril deformation measured at low strain rates reflects susceptibility for osteoporotic low-energy fragility fractures. Independent of age, disease and treatment status, SAXS revealed reduced fibril plasticity at high strain rates, characteristic of traumatic fracture. The significantly reduced mechanical integrity in osteoporosis may originate from porosity and alterations to the intra/extrafibrillar structure, while the fibril deformation under treatment indicates improved nano-scale characteristics. In conclusion, losses in strength and fibril deformation at low strain rates correlate with the occurrence of fragility fractures in osteoporosis, while improvements in structural and mechanical properties following bisphosphonate treatment may foster resistance to fracture during physiological strain rates.

  1. Effects of medication reviews performed by a physician on treatment with fracture-preventing and fall-risk-increasing drugs in older adults with hip fracture-a randomized controlled study.

    Science.gov (United States)

    Sjöberg, Christina; Wallerstedt, Susanna M

    2013-09-01

    To investigate whether medication reviews increase treatment with fracture-preventing drugs and decrease treatment with fall-risk-increasing drugs. Randomized controlled trial (1:1). Departments of orthopedics, geriatrics, and medicine at Sahlgrenska University Hospital, Gothenburg, Sweden. One hundred ninety-nine consecutive individuals with hip fracture aged 65 and older. Medication reviews, based on assessments of risks of falls and fractures, regarding fracture-preventing and fall-risk-increasing drugs, performed by a physician, conveyed orally and in written form to hospital physicians during the hospital stay, and to general practitioners after discharge. Primary outcomes were changes in treatment with fracture-preventing and fall-risk-increasing drugs 12 months after discharge. Secondary outcomes were falls, fractures, deaths, and physicians' attitudes toward the intervention. At admission, 26% of intervention and 29% of control participants were taking fracture-preventing drugs, and 12% and 11%, respectively, were taking bone-active drugs, predominantly bisphosphonates. After 12 months, 77% of intervention and 58% of control participants were taking fracture-preventing drugs (P = .01), and 29% and 15%, respectively, were taking bone-active drugs (P = .04). Mean number of fall-risk-increasing drugs per participants was 3.1 (intervention) and 3.1 (control) at admission and 2.9 (intervention) and 3.1 (control) at 12 months (P = .62). No significant differences in hard endpoints were found. The responding physicians (n = 65) appreciated the intervention; on a scale from 1 (very bad) to 6 (very good), the median rating was 5 (interquartile range (IQR) 4-6) for the oral part and 5 (IQR 4-5.5) for the text part. Medication reviews performed and conveyed by a physician increased treatment with fracture-preventing drugs but did not significantly decrease treatment with fall-risk-increasing drugs in older adults with hip fracture. Prescribing physicians appreciated

  2. Studies of the Effectiveness of Bisphosphonate and Vanadium-Bisphosphonate Compounds In Vitro against Axenic Leishmania tarentolae

    Directory of Open Access Journals (Sweden)

    Amy T. Christensen

    2016-01-01

    Full Text Available Leishmaniasis is a disease that is a significant problem for people, especially in tropical regions of the world. Current drug therapies to treat the disease are expensive, not very effective, and/or of significant side effects. A series of alkyl bisphosphonate compounds and one amino bisphosphonate compound, as well as alendronate and zoledronate, were tested as potential agents against Leishmania tarentolae. Also, two polyoxometalates (POMs with nitrogen-containing bisphosphonate ligands, vanadium/alendronate (V5(Ale2 and vanadium/zoledronate (V3(Zol3, were tested against L. tarentolae and compared to the results of the alendronate and zoledronate ligands alone. Of the compounds evaluated in this study, the V5(Ale2 and V3(Zol3 complexes were most effective in inhibiting the growth of L. tarentolae. The V5(Ale2 complex had a larger impact on cell growth than either alendronate or orthovanadate alone, whereas zoledronate itself has a significant effect on cell growth, which may contribute to the activity of the V3(Zol3 complex.

  3. Increased hope following successful treatment for hepatitis C infection.

    Science.gov (United States)

    Bjøro, Benedikte; Dalgard, Olav; Midgard, Håvard; Verbaan, Hans; Småstuen, Milada Cvancarova; Rustøen, Tone

    2018-03-01

    To evaluate hope in hepatitis C patients 9 years after curative treatment with pegylated interferon and ribavirin. Successful treatment of hepatitis C leads to improved quality of life in responders compared with non-responders. The long-term effect of successful treatment on hope in these patients is not known. Cross-sectional follow-up study of patients who displayed a sustained virological response to previous hepatitis C treatment. Patients infected with hepatitis C genotype 2 or 3 from a randomized controlled study during 2004-2006 were included. A representative subgroup of those who achieved a sustained virological response was re-evaluated in 2012-2014. The patients were examined, had a blood test and completed a questionnaire (Herth Hope Index and demographic and clinical characteristics). The hope level was compared between patients and an age-matched sample from the general population (N = 1,481). The data were analysed using multiple regression. A total of 104 Norwegian and Swedish hepatitis C patients were included in this follow-up study; their mean age was 48 years, and 61% were men. Patients treated for hepatitis C scored higher than the general population on the total Herth Hope Index and for 11 of the 12 individual items. Age, gender, educational level, employment status and civil status were associated with a higher Herth Hope Index in those who had received hepatitis C treatment. Patients achieving a sustained viral response had a higher hope level than the general population 9 years after successful treatment of hepatitis C virus infection. © 2017 John Wiley & Sons Ltd.

  4. A retrospective study evaluating frequency and risk factors of osteonecrosis of the jaw in 576 cancer patients receiving intravenous bisphosphonates.

    Science.gov (United States)

    Thumbigere-Math, Vivek; Tu, Lam; Huckabay, Sabrina; Dudek, Arkadiusz Z; Lunos, Scott; Basi, David L; Hughes, Pamela J; Leach, Joseph W; Swenson, Karen K; Gopalakrishnan, Rajaram

    2012-08-01

    To evaluate the frequency, risk factors, and clinical presentation of bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ). We performed a retrospective analysis of 576 patients with cancer treated with intravenous pamidronate and/or zoledronate between January, 2003 and December, 2007 at the University of Minnesota Masonic Cancer Center and Park Nicollet Institute. Eighteen of 576 identified patients (3.1%) developed BRONJ including 8 of 190 patients (4.2%) with breast cancer, 6 of 83 patients (7.2%) with multiple myeloma, 2 of 84 patients (2.4%) with prostate cancer, 1 of 76 patients (1.3%) with lung cancer, 1 of 52 patients (1.9%) with renal cell carcinoma, and in none of the 73 patients with other malignancies. Ten patients (59%) developed BRONJ after tooth extraction, whereas 7 (41%) developed it spontaneously (missing data for 1 patient). The mean number of BP infusions (38.1 ± 19.06 infusions vs. 10.5 ± 12.81 infusions; P<0.001) and duration of BP treatment (44.3 ± 24.34 mo vs. 14.6 ± 18.09 mo; P<0.001) were significantly higher in patients with BRONJ compared with patients without BRONJ. Multivariate Cox proportional hazards regression analysis showed that diabetes [hazard ratio (HR)=3.40; 95% confidence interval (CI), 1.14-10.11; P=0.028], hypothyroidism (HR=3.59; 95% CI, 1.31-9.83; P=0.013), smoking (HR=3.44; 95% CI, 1.28-9.26; P=0.015), and higher number of zoledronate infusions (HR=1.07; 95% CI, 1.03-1.11; P=0.001) significantly increased the risk of developing BRONJ. Increased cumulative doses and long-term BP treatment are the most important risk factors for BRONJ development. Type of BP, diabetes, hypothyroidism, smoking, and prior dental extractions may play a role in BRONJ development.

  5. Treatment increases stress-corrosion resistance of aluminum alloys

    Science.gov (United States)

    Jacobs, A. J.

    1966-01-01

    Overaging during heat treatment of the aluminum alloys immediately followed by moderate plastic deformation, preferably by shock loading achieves near optimum values of both yield strength and resistance to stress corrosion. Similar results may be obtained by substituting a conventional deformation process for the shock loading step.

  6. Foraging at wastewater treatment works increases the potential for ...

    African Journals Online (AJOL)

    Wastewater treatment works (WWTWs) are known to provide profitable foraging areas for insectivorous bats in Europe and the New World because of their association with high abundance of pollution-tolerant midges (Diptera). However, bats that feed on these insects may also accumulate metal pollutants such as cadmium ...

  7. Increasing nerve agent treatment efficacy by P-glycoprotein inhibition

    NARCIS (Netherlands)

    Joosen, M.J.A.; Vester, S.M.; Hamelink, J.; Klaassen, S.D.; Berg, R.M. van den

    2016-01-01

    One of the shortcomings of current treatment of nerve agent poisoning is that not all drugs effectively penetrate the blood-brain barrier (BBB), whereas most nerve agents easily do. P-glycoprotein (Pgp) efflux transporters at the BBB may contribute to this aspect. It was previously shown that Pgp

  8. Electrokinetic Treatment for Model Caissons with Increasing Dimensions

    Directory of Open Access Journals (Sweden)

    Eltayeb Mohamedelhassan

    2012-01-01

    Full Text Available Electrokinetic treatment has been known in geotechnical engineering for over six decades, yet, the technique is rarely used. This stems from the absence of design guidelines and specifications for electrokinetic treatment systems. An important issue that need to be investigated and understood in order to devise guidelines from experimental results is the effect of the foundation element size on the outcome of the treatment. Also important is determining the optimum distance between the electrodes and estimating the energy consumption prior to treatment. This experimental study is a preliminary step in understanding some of the issues critical for the guidelines and specifications. Four model caissons with surface areas between 16000 and 128000 mm2 were embedded in soft clayey soil under water and treated for 168 hr with a dc voltage of 6 V. From the results, a distance between the anode (model caisson and the cathode equal 0.25 times the outside diameter of the model caisson was identified as optimum. Relationships between the surface area and axial capacity of the model caisson and the surface area and energy consumption were presented. The equations can be used to preliminary estimate the load capacity and the energy consumption for full-scale applications.

  9. Potential significance of antiestrogen therapy in the development of bisphosphonate related osteonecrosis of the jaw.

    Science.gov (United States)

    Vaszilko, Mihaly; Kovacs, Evelin; Restar, Laszlo; Balla, Bernadett; Cseplo, Krisztina; Kosa, Janos; Lakatos, Peter

    2014-12-01

    There are known risk factors and established treatment protocols for bisphosphonate-related osteonecrosis of the jaw (BRONJ), but it remains a difficult disease to treat, with the risk of relapses. This study investigates whether or not there is a relationship between antiestrogen therapy and BRONJ. In our prospective study, we followed up 93 patients with BRONJ who were seen at our clinic between 2006 and 2011. We found that breast cancer patients had a significantly worse prognosis than patients with other underlying illnesses (p breast cancer raise the possibility that estrogen deficiency might be a newly discovered risk factor for BRONJ. Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  10. Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?

    Science.gov (United States)

    Vasanwala, Rashida F; Sanghrajka, Anish; Bishop, Nicholas J; Högler, Wolfgang

    2016-07-01

    Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment

  11. Effects of Bisphosphonates and Calcium plus Vitamin-D Supplements on Cognitive Function in Postmenopausal Osteoporosis§.

    Science.gov (United States)

    Safer, Umut; Safer, Vildan Binay; Demir, Sibel Ozbudak; Yanikoglu, Inci

    2016-01-01

    Postmenopausal osteoporosis has been linked to accelerated cognitive decline; however, little is known about the effects of medical treatment on cognitive functions. In this prospective study, we evaluated the effects of bisphosphonate treatment and calcium plus vitamin D supplementation on cognitive functions in 45 women with postmenopausal osteoporosis who were started on medical treatment. The medications included alendronate, zoledronic acid, risedronate, or ibandronic acid along with a low or high dose of calcium plus vitamin D supplements. The cognitive function was assessed by the mini-mental state examination (MMSE) test. All subjects underwent bone mineral density (BMD) measurement via dual-energy X-ray absorptiometry at baseline and at study completion. The mean T-score improved significantly at 1 year, except for neck of the femur area. The mean MMSE score did not change significantly at 12 months (26.40 ± 2.07 vs. 26.48 ± 2.07; p = 0.513), with no difference among bisphosphonates combined with calcium plus vitamin D. Higher dose (1200 mg/800 U/day) of calcium plus vitamin D supplementation tended to have a greater improvement as compared with lower dose (600 mg/400 U/day) (Δ MMSE: 0.11 ± 0.72 vs. -0.14 ± 0.69). Cognitive functions in the women remained unaltered, whereas bone BMD T-scores were significantly improved at the 12(th) month after the administration of bisphosphonates and calcium plus vitamin D supplements. Higher doses of calcium plus vitamin D supplements were likely to have better cognitive effects as compared with lower doses.

  12. Bisphosphonate-related osteonecrosis of jaw (BRONJ) in Japanese population: a case series of 13 patients at our clinic.

    Science.gov (United States)

    Nomura, Takeshi; Shibahara, Takahiko; Uchiyama, Takeshi; Yamamoto, Nobuharu; Shibui, Takeo; Yakushiji, Takashi; Watanabe, Akira; Muramatsu, Kyotaro; Ogane, Satoshi; Murayama, Masato; Sekine, Riyo; Nakata, Erika; Fujimoto, Yuko

    2013-01-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) affects quality of life and is an important problem for dentists. A Japanese position paper on BRONJ was published in 2010. The purpose of this study was to review clinical data on the treatment of BRONJ obtained at the Clinic of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba Hospital to further our understanding of this disease. A total of 13 patients (6 men and 7 women) were included. All the patients included in this study had received Bisphosphonate (BP) therapy and had BRONJ. Five of them (38.5%) had received oral BP therapy for os