Long-term Bisphosphonate Use Research Articles

Long-term bisphosphonate use increases risk of atypical hip fractures

Long-term bisphosphonate use increases risk of atypical hip fractures

Use of Bisphosphonates and Reduced Risk of Colorectal Cancer

Bisphosphonates are commonly used for the treatment of osteoporosis and bone metastases caused by breast cancer and were recently reported to be associated with a reduced risk of breast cancer, possibly acting through the mevalonate pathway, but their association with risk of other cancers is unknown. The Molecular Epidemiology of Colorectal Cancer study is a population-based, case-control study in northern Israel of patients with colorectal cancer and age-, sex-, clinic-, and ethnic group-matched controls. Long-term use of bisphosphonates before diagnosis was assessed in a subset of 933 pairs of postmenopausal female patients and controls, enrolled in Clalit Health Services, using computerized pharmacy records. The use of bisphosphonates for more than 1 year before diagnosis, but not for less than 1 year, was associated with a significantly reduced relative risk (RR) of colorectal cancer (RR, 0.50; 95% CI, 0.35 to 0.71). This association remained statistically significant after adjustment in a model for vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statins, vitamin D, and postmenopausal hormones (RR, 0.41; 95% CI, 0.25 to 0.67). Concomitant use of bisphosphonates and statins did not further reduce the risk. The use of oral bisphosphonates for more than 1 year was associated with a 59% relative reduction in the risk of colorectal cancer, similar to the recently reported association of this drug class with reduction in breast cancer risk.

Potential and Pitfalls of Using Large Administrative Claims Data to Study the Safety of Osteoporosis Therapies

Long-term bisphosphonate use may be associated with several rare adverse events. Such associations are not optimally evaluated in conventional randomized controlled trials due to the requirements of large numbers of patients and long-term follow-up. Alternatively, administrative claims data from various sources such as Medicare have been used. Because claims data are collected for billing and reimbursement purposes, they have limitations, including uncertain diagnostic validity and lack of detailed clinical information. Using such data for pharmacoepidemiologic research requires complex methodologies that may be less familiar to many researchers and clinicians. In this review, we discuss the strengths and limitations of using claims data for osteoporosis drug safety research, summarize recent advancements in methodologies that may be used to address the limitations, and present directions for future research using claims data.

Long-term use oral bisphosphonate-related osteonecrosis of the jaw without dental extraction in elderly: A case report

Bisphosphonate-associated osteonecrosis of the jaws (BRONJ) may have significant morbidities ranging from minimal discomfort to significant loss of function. We report a case of jaw osteonecrosis resulting from long-term use of bisphosphonate. An 83-year-old female, a long-term user of alendronate, developed jaw osteonecrosis without a history of recent dental extraction. Facial bone computed tomography of the patient showed a destructive osteolytic change of the whole right mandible bone with adjacent soft tissue swelling. After surgical debridement, antibiotic treatment, and discontinuation of alendronate, the patient recovered very well. Although uncommon, BRONJ has gained extensive attentions. Physicians should be aware of the possibility of BRONJ among long-term bisphosphonate users, and a collaboration of clinical pharmacist may be helpful in early detection.

Atraumatic Bilateral Femur Fracture in Long-Term Bisphosphonate Use

Atraumatic Bilateral Femur Fracture in Long-Term Bisphosphonate Use

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

SummaryThis 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.IntroductionA 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.MethodsA 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.ResultsSeveral 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.ConclusionsBisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is unproven and requires further research. Were the case to be proven, the risk–benefit ratio still remains favourable for use of bisphosphonates to prevent fractures.

Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort

Bisphosphonates are the primary therapy for postmenopausal and glucocorticoid-induced osteoporosis. Case series suggest a potential link between prolonged use of bisphosphonates and low-energy fracture of subtrochanteric or diaphyseal femur as a consequence of oversuppression of bone resorption. Using health care utilization data, we conducted a propensity score–matched cohort study to examine the incidence rates (IRs) and risk of subtrochanteric or diaphyseal femur fractures among oral bisphosphonate users compared with raloxifene or calcitonin users. A Cox proportional hazards model evaluated the risk of these fractures associated with duration of osteoporosis treatment. A total of 104 subtrochanteric or diaphyseal femur fractures were observed among 33,815 patients. The estimated IR of subtrochanteric or diaphyseal femur fractures per 1000 person-years was 1.46 [95% confidence interval (CI) 1.11–1.88] among the bisphosphonate users and 1.43 (95% CI 1.06–1.89) among raloxifene/calcitonin users. No significant association between bisphosphonate use and subtrochanteric or diaphyseal femur fractures was found [hazard ratio (HR) = 1.03, 95% CI 0.70–1.52] compared with raloxifene/calcitonin. Even with this large study size, we had little precision in estimating the risk of subtrochanteric or diaphyseal femur fractures in patients treated with bisphosphonates for longer than 5 years (HR = 2.02, 95% CI 0.41–10.00). The occurrence of subtrochanteric or diaphyseal femur fracture was rare. There was no evidence of an increased risk of subtrochanteric or diaphyseal femur fractures in bisphosphonate users compared with raloxifene/calcitonin users. However, this study cannot exclude the possibility that long-term bisphosphonate use may increase the risk of these fractures. © 2011 American Society for Bone and Mineral Research.

Prolonged Bisphosphonate Use Linked to Rare Fractures, Esophageal Cancer

TWO NEW REPORTS ADD TO CONcerns about the potential link between long-term use of bisphosphonates and serious adverse events. Bisphosphonates have become a mainstay of therapy for osteoporosis and have been demonstrated to substantially reduce hip fractures. However, a growing data set suggests that long-term use of these products is associated with an increased risk of a rare type of femoral fracture that occurs with little or no trauma. Additionally, there have been conflicting results on whether prolonged use might also be associated with an increased risk of esophageal cancer. The latest data appear to support an association.

Bisphosphonates' Use Could Be Limited by Fractures

Bisphosphonates' Use Could Be Limited by Fractures

Bilateral Simultaneous Femoral Diaphyseal Fractures in a Patient with Long-Term Ibandronate Use

Bisphosphonates are the most common medication used to treat patients with documented osteoporosis. Recently, reports have associated long-term bisphosphonate use with low-energy femur fractures. While no definitive mechanism has been associated, bisphosphonate use has been strongly implicated. This article presents the case of a 65-year-old woman with a 2-year history of ibandronate use presenting with simultaneous low-energy femoral shaft fractures. The patient reported prodromal bilateral thigh pain and was seen by a spine surgeon. A review of the literature implicates long-term ibandronate use in low-energy femur fractures. With most of the basic science studies demonstrating suppressed bone turnover after 5 years of treatment with alendronate, the significance of the present case also lies in the relatively short duration of time the patient was on ibandronate before suffering the bilateral femoral shaft fractures. Possible pathophysiology for the fractures includes suppressed bone turnover that may allow microcracks to propagate in cortical bone, which can weaken the bone and possibly predispose it to fractures. Patients who have been on bisphosphonates long term should be questioned about thigh pain and have radiographs of their femurs obtained if pain exists. Furthermore, if a patient presents with a single subtrochanteric or diaphyseal low-energy femur fracture after long-term bisphosphonate use, a radiograph of the contralateral femur should be obtained to assess for a cortical stress reaction.

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management.

FDA Statement on Relationship Between Bisphosphonate Use and Atypical Subtrochanteric and Femoral Shaft Fractures: A Considered Opinion

563 The location and description of the lowimpact fractures reported was consistent, and all patients had been undergoing longterm bisphosphonate therapy. To these authors, the fracture location and appearance was unique, unlike those seen in other conditions or causes. Specifically, insufficiency fractures of the lateral cortex of the femur with or without associated frank, complete fractures in patients with osteoporosis who do not take bisphosphonates are exceedingly rare, if indeed they occur at all. Schilcher and Aspenberg [6] calculated that when this pattern of femoral fracture was identified, the chance that the patient was undergoing longterm bisphosphonate therapy was 46 to 1. The association of this very specific pattern of femoral fracture and long-term bisphosphonate therapy seemed clear. These reports did not maintain that all fractures of the femur were related to long-term bisphosphonate use, only that this specific pattern of femoral fracture appeared to be so related. Furthermore, they did not claim that bisphosphonates have increased the number of femoral fractures. Many patients undergo bisphosphonate therapy. On the other hand, the related femoral fractures are quite rare. The signal-to-noise ratio is therefore quite low. Such fractures are difficult to identify in databases without specific information on the nature and specific imaging features of such fractures.

Femoral Insufficiency Fractures Associated with Prolonged Bisphosphonate Therapy

Emerging evidence has linked the long-term use of bisphosphonates with femoral insufficiency fractures. It has been suggested that the prolonged effect on bone remodeling leads to the accumulation of microfractures and weakening of bone. We investigated the association between bisphosphonate use and femoral insufficiency fractures. We evaluated 100 patients with low-energy femoral shaft fractures before and after bisphosphonates became available for use. Twenty-one consecutive patients who presented between January 1995 and February 1997 were compared with 79 consecutive patients who presented between January 2007 and February 2009. The radiographs of all 100 patients were examined for evidence of preexisting insufficiency fractures. We identified insufficiency fractures by a transverse fracture line on the tension side of the femur with lateral cortical thickening immediately adjacent to the fracture. Relevant details from the history were recorded. Forty-one patients had an underlying femoral insufficiency fracture, all of whom had been receiving bisphosphonate therapy. Among the 21 patients with low-energy femoral fractures before the availability of bisphosphonates, none had insufficiency fractures. Of the 41 patients with insufficiency fractures, 29 (71%) had prodromal pain and 18 (44%) had bilateral insufficiency fractures. Bisphosphonate use was associated (odds ratio greater than 1000) with insufficiency fracture. The mean duration of bisphosphonate use in patients with insufficiency fractures was longer than in patients without fractures (7.1 versus 3.2 years). Long-term bisphosphonate use is associated with insufficiency fractures of the femoral shaft, which commonly present with prodromal thigh pain and may be bilateral. These fractures were not seen before bisphosphonates became available for use.

Insufficient bilateral femoral subtrochanteric fractures in a patient receiving imatinib mesylate

We present a case of insufficient bilateral femoral subtrochanteric fractures in a patient who was treated with imatinib mesylate, an anticancer drug, for 1year after a diagnosis of chronic myelogenous leukemia (CML). A 60-year-old woman presented with bilateral thigh pain for 6months. A plain radiograph revealed bilateral progressive insufficient fractures on the subtrochanteric areas of the femurs. MRI of the femurs revealed incomplete stress fractures and no evidence of bone metastasis on either femur. Bone densitometry showed normal T-scores around the hip joint and spine. The patient had normal serum levels of calcium, vitamin D derivatives, and thyroid hormones. Serum phosphate levels were decreased, and parathyroid hormone levels were increased. Serum osteocalcin and urinary N-telopeptide of collagen cross-links (NTx) were both decreased. A bone biopsy demonstrated normocellular marrow without leukemic cells. A histomorphometric evaluation of her bones revealed reduced bone turnover despite secondary hyperparathyroidism. The serum markers for bone metabolism and histomorphometric evaluations in this patient suggest that the drug may have an effect on bone metabolism. These effects could be seen for both bone formation and resorption: this could result in impaired bone mineralization, a severely suppressed bone turnover rate, insufficient fractures, and bone necrosis, which are sometimes seen with long-term use of bisphosphonates. To our knowledge, this is the first case of an insufficient bilateral femoral shaft fracture that is potentially related to the use of imatinib mesylate in a patient with CML. Careful examination of bone metabolism should be performed in patients with CML because imatinib mesylate treatment is a lifelong process.

Atraumatic Bilateral Femur Fracture in Long-Term Bisphosphonate Use

Atraumatic Bilateral Femur Fracture in Long-Term Bisphosphonate Use

Bisphosphonates Cause Osteonecrosis of the Jaw-Like Disease in Mice

Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a morbid bone disease linked to long-term bisphosphonate use. Despite its broad health impact, mechanistic study is lacking. In this study, we have established a mouse model of BONJ-like disease based on the equivalent clinical regimen in myeloma patients, a group associated with high risk of BONJ. We demonstrate that the murine BONJ-like disease recapitulates major clinical and radiographical manifestations of the human disease, including characteristic features of osseous sclerosis, sequestra, avascular, and radiopaque alveolar bone in the jaw that persists beyond a normal course of wound healing following tooth extraction. We find that long-term administration of bisphosphonates results in an increase in the size and number of osteoclasts and the formation of giant osteoclast-like cells within the alveolar bone. We show that the development of necrotic bone and impaired soft tissue healing in our mouse model is dependent on long-term use of high-dose bisphosphonates, immunosuppressive and chemotherapy drugs, as well as mechanical trauma. Most importantly, we demonstrate that bisphosphonate is the major cause of BONJ-like disease in mice, mediated in part by its ability to suppress osseous angiogenesis and bone remodeling. The availability of this novel mouse model of BONJ-like disease will help elucidate the pathophysiology of BONJ and ultimately develop novel approaches for prevention and treatment of human BONJ.

Risks and benefits of long-term bisphosphonate therapy

The risks and benefits of long-term bisphosphonate therapy were reviewed. Bisphosphonates are used first line in the treatment of osteoporosis due to their demonstrated ability to reduce the risk of fracture. Benefits on bone mineral density (BMD) and fracture prevention appear to be sustained for 7-10 years; however, the lack of clinical trials extending beyond this treatment period has raised the question of how long therapy should be continued. Furthermore, some reports have suggested the potential for an increased risk of fragility fractures due to oversuppression of bone turnover with long-term bisphosphonate use. Though rare, these fragility fractures appear to have a specific fracture pattern and tend to occur after 3-8 years of bisphosphonate therapy. The use of a drug holiday has been considered as an option to avoid this risk. Data suggest that bisphosphonates have a residual therapeutic effect after being stopped and that fracture benefit appears to be sustained 2-5 years after discontinuation. This sustained benefit, however, was observed only in women with good adherence who were treated with bisphosphonate therapy for at least 2 years and whose BMD was not in the osteoporotic range before discontinuation. The benefits of long-term bisphosphonate therapy in patients at high risk of fracture likely outweigh the risks. In lower risk patients, such as those with a BMD in the osteopenic or normal range after two to five years of treatment and no history of fracture, consideration could be given to stopping therapy for two to five years.

Unusual case of a conservatively treated pathological fracture after sequestrectomy in a patient with long-term oral bisphosphonate use

Bisphosphonates are used in the management of metastatic bone disease, Paget’s disease of bone and osteoporosis. A long-term complication of these drugs is bisphosphonate-related osteonecrosis of the jaws (BRONJ). Treatment of BRONJ can be quite challenging, and remains a topic of debate. We report the case of a 74-year-old woman who had used Fosamax ® (alendronate sodium) orally for four years. After 3½ years she developed pain, swelling, and a fistula in the left mandible. After exploration and sequestrectomy in combination with antibiotic treatment, osteolysis with a pathological fracture developed. Given the extent of the disorder and a decrease in complaints after the surgery, a non-surgical approach was chosen with continuation of the antibiotic treatment for 10 weeks, a soft diet and not wearing of dentures. During follow-up complaints subsided, the intra-oral fistula disappeared and the fracture healed. This is the first report of healing of a BRONJ patient stage III with pathological fracture. It illustrates the remaining healing potential of the bisphosphonate-treated bone.

Bisphosphonate-Related Osteonecrosis of the Jaw Associated With Dental Implants

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented devastating side effect of long-term bisphosphonate (BP) use. There is scarce information in the literature on BRONJ associated with dental implants (DIs). The purpose of this study was to present a large series of cases of this association. The files of all patients with BRONJ associated with DIs who were treated in the department of oral and maxillofacial surgery from 2003 to 2009 were reviewed. Data on demographics, medical background, type, and duration of BP treatment before the development of BRONJ, mode of therapy, and therapeutic outcome were retrieved. Of the 27 patients enrolled into the study, 11 (41%) developed BRONJ while taking oral BPs and 16 (59%) developed BRONJ associated with intravenous BPs. BRONJ developed after mean periods of 68 months (median, 60), 16.4 months (median, 13), and 50.2 months (median, 35) in patients on alendronate, zoledronic acid, and pamidronate, respectively. Only 6 patients developed BRONJ during the first 6 months after DI placement. When BP treatment had been started before DI placement, there was a mean duration of 16.2 months (median, 11) until the appearance of BRONJ development. Long-term antibiotics and only essential surgical procedures comprised the treatment of choice, and the response rate was considerably better for patients taking the oral type of BPs. There was no significant association between BRONJ and diabetes, steroid intake, or smoking habits. Patients undergoing BP treatment and who receive DIs require a prolonged follow-up period to detect any development of BRONJ associated with DIs.

Atypical Insufficiency Fracture of the Tibia Associated With Long-Term Bisphosphonate Therapy

Osteoporosis is a major public health threat affecting millions of individuals in the United States. Bisphosphonate therapy is currently recognized as a first-line treatment of osteoporosis through the inhibition of osteoclast activity. Concerns have been raised about potential oversuppression of bone turnover and the development of atypical skeletal fragility associated with long-term use of bisphosphonates. A number of case reports in the literature have documented atypical insufficiency fractures in patients on long-term bisphosphonate therapy. This case outlines what we believe is the second documented atypical tibial insufficiency fracture in a patient on long-term bisphosphonate therapy, and highlights the need for increased awareness of atypical insufficiency fractures as well as the need for more data concerning the long-term effects of bisphosphonate therapy.