Years Of Bisphosphonate Therapy Research Articles

THU456 Beyond Guidelines: Treatment Of Concurrent Osteogenesis Imperfecta And Metastatic Bone Disease

Abstract Disclosure: M. Kanin: None. M. Lechner: None. Introduction: Osteogenesis imperfecta (OI) is a rare inherited skeletal dysplasia characterized by bone fragility and skeletal malformation predisposing patients to multiple, recurrent fractures. Treatment of OI is challenging and requires a multidisciplinary approach with emphasis on physical therapy and exercise in addition to medications. There is limited guidance on treatment in adults given truncated life expectancy. Furthermore, guidance on the treatment of OI in the setting of cancer bone metastases is lacking. We present the unique case of a woman with OI and new fracture in the setting of bone-metastatic endometrial cancer. Clinical Case: A 70 year old woman with Type I OI and endometrial adenocarcinoma initially presented to clinic with left hip and groin pain. Prior OI therapy included at least 10 years of bisphosphonate therapy and 3 years of intranasal calcitonin in her fifties. CT imaging revealed a lytic lesion in the L inferior pubic ramus with an associated pathologic fracture. She was treated with denosumab 120mg s.c. every 3 months for six total doses and palliative radiation to the pubic ramus. She developed osteonecrosis of the jaw and further treatment was terminated. She represented 2 years later with right hip pain and was found to have cancer involvement of her right iliac bone. Labs showed creatinine of 0.48 mg/dL, Calcium 9.8 mg/dl, bone specific alkaline phosphatase 17.9ug/L (7.0-22.4 ug/L), n-telopeptide 18.6 nM BCE (6.2-19.0 nM BCE), and vitamin D-25 48ng/ml. DEXA scan showed T scores at the AP spine of -3.2, LFN of -2.1, and RFN of -2.5. Our patient had a high functional status, minimal pain and acceptable quality of life. Given the presence of active bone metastases, we favored treatment with zolendronic acid 4mg i.v. monthly given her high fracture risk, combined with continued cancer therapy targeted to bone metastases. Clinical Lesson: To our knowledge, there are no guidelines or case reports for optimal treatment of patients with concurrent OI and bone metastases. While bisphosphonates are typically a first line treatment for OI, osteoporosis and metastatic bone disease, the duration and dosing of bisphosphonates varies for each condition. For example, zolendronic acid 4mg i.v. monthly is recommended for cancer patients with metastatic bone disease, while a dose of 5mg i.v. yearly is used for osteoporosis, depending on the severity. Additionally, no clear consensus exists for how often or how long bisphosphonates may be given in adults with OI and treatment durations vary markedly. Other agents that may be considered include denosumab, with indications across bone metastases, osteoporosis, and OI, though this was not available to our patient given her prior complication. Data for newer agents PTH analogs and romosuzumab are lacking. We present this case to highlight the need for an individualized treatment approach in these patients. Presentation: Thursday, June 15, 2023

Functional and Radiological Outcome in Atypical Subtrochanteric Femur Fracture After Surgical Fixation: A Retrospective Observational Study.

Background: Treatment for osteoporosis can have catastrophic side effects, including the uncommon fracture known as an atypical femur fracture (AFF), which is related to the long-term usage of antiresorptive agents. Bisphosphonate therapy may lead to significant and chronic suppression of bone turnover, impairing the bone's remodelling property and finally leading to incomplete or complete atypical femur fracture. AFF was defined by the American Society for Bone and Mineral Research (ASBMR) Task Force in 2010 and is far less prevalent than proximal femur (hip) fracture, with an incidence of 2 to 78 per 100,000 patients per year following two to eight years of bisphosphonate therapy, respectively. Due to the rarity of the fracture, it is still not clear what the functional and radiological outcome will be after surgery.Aim: To identify the functional and radiological outcomes of surgical fixation of atypical femur fractures.Methods: The study was conducted in a tertiary healthcare centre after scientific and ethical clearance from the competent authority. Between January 2018 and December 2021, individuals who were diagnosed with an atypical subtrochanteric femoral fracture associated with the use of bisphosphonates and treated surgically were retrospectively evaluated. The study's inclusion and exclusion criteria were used to include 20 patients. The features of an atypical subtrochanteric fracture were congruent with the radiographic findings. Most of the patients were treated with internal fixation with intramedullary osteosynthesis in standard with or without plate osteosynthesis. They were then followed up for a year to look at the functional and radiological outcomes.Results: All of the 20 patients who were included had an atypical subtrochanteric fracture, with 15 of them being female and 5 of them being male. The patients' mean age at surgery was 65.12 (range 49 to 82) years, and their average history of bisphosphonate use was 3 (range 2.5 to 5) years. All patients were treated surgically. We found that five months was the mean period for bone union (p = 0.990). Within six months, bone union was achieved in 11 patients (55 %) (p = 0.884). Five patients (about 25%) had implant failure and non-union, requiring two to three revision surgeries. At three, six, and nine months, the mean visual analogue score (VAS) was 4.14, 3.12, and 1.85, respectively. The modified Hip Harris Score had a mean of 72.66 and 15 patients (about 75% of them) could walk normally again after a fracture. The mean of the modified HHS was 72.66, and the VAS at three, six, and nine months was 4.14, 3.12, and 1.85, respectively.Conclusion: AFFs are rare fractures that must be treated effectively, and most of them require surgery. Successful treatment of AFF is possible by the use of intramedullary fixation, which enhances axial stability, serves as an internal splint, and lessens the likelihood of implant failure. A good functional and radiological prognosis can come from a stable fixation and a fracture that has been reduced anatomically.

P24 Ankylosing spondylitis & uveitis - challenges in management

Case report - IntroductionAnkylosing spondylitis is a chronic inflammatory condition involving spine, chest and sacroiliac joints. It can be associated with extra spinal manifestations which include uveitis and enthesitis, as well as other features of an inflammatory spondyloarthropathy including psoriasis and inflammatory bowel disease. It is characterised by the presence of inflammatory back pain, limited range of spinal movement, sacroiliitis on imaging, excess spinal bone formation and a high prevalence of HLA-B27. The main aims of treatment are to improve symptoms and retain function as well as to prevent disease complications.Case report - Case descriptionA 49-year-old male diagnosed with ankylosing spondylitis at the age of 23 (HLA-B27 positive, classical radiographic features on plain radiographs and MRI), with background of meningitis and subsequent epilepsy (not on treatment since the age of 13), severe hip osteoarthritis and osteoporosis. He has peripheral elbow and knee synovitis. At the age of 27 he developed sight-threatening bilateral recurrent anterior uveitis complicated by cystoid macular oedema (causing central vision loss). Initial management included anti-inflammatories and steroids. He progressed to biologics but developed a rash on adalimumab. He was switched to infliximab in 2010. In 2015 it was switched due to reduced response to golimumab which was non-beneficial. Subsequently he was switched to etanercept but after 3 months it was discontinued due to eye flare. The patient’s therapy was switched to certolizumab, which was non-beneficial for spine and discontinued. In 2016, infliximab was retried as the patient thought it worked best. Unfortunately, in 2018 patient developed Infliximab antibodies and treatment was changed to secukinumab. After 9 months this was stopped owing to ongoing active eye and spine disease. Adalimumab was re-tried; however, it was discontinued as it was showing no benefit. In 2020 Eeanercept (Benepali) was re-tried; however, only for 4 months because of severe flare of joint and eye disease. Tofacitinib was commenced but was non-beneficial and hence it was discontinued. Currently he continues on ixekizumab, oral prednisolone and also receives steroid eye and joint injections. On commencing biologics he was on methotrexate; however, the patient stopped. He was switched to mycophenolate mofetil which he remained on for 10 years. It was switched to methotrexate to try and control peripheral inflammatory joint disease better (re-tried for the second time) which the patient has recently discontinued as he felt it was non-beneficial.Case report - DiscussionThe case is very challenging. The patient’s disease continues to flare despite changing therapies. He continues to get flares in his back disease, eye disease and peripheral synovitis. His latest BASDI was 5.1 and VAS was 9/10. Measurements: intermalleolar distance 15cm, modified Schober’s 4cm, right lateral flexion 3.8cm and left lateral flexion 11cm. His latest MRI of whole spine and SI joints (in 2020) showed signs of previously active seronegative spondyloarthropathy with established cervical and thoracic ankyloses as well as bilateral sacroiliac joint ankylosis. There is a need for repeated steroid injections to the knees as well as the eyes. He continues on oral prednisolone which was first started in 2006. This is associated with multiple side effects, i.e., osteoporosis. The patient has already completed 8 years of bisphosphonate therapy. He is under regular review with the osteoporosis clinic. His bone density scan showed worsening bone mineral density and bisphosphonates had to be restarted. The patient adjusted medications depending on his symptoms. Recently he also discontinued methotrexate as he felt it was of no benefit to him at all. We are very limited at present to find combined medications to manage both the patient’s inflammatory back disease and inflammatory eye disease.Case report - Key learning pointsThis patient was diagnosed with ankylosing spondylitis 26 years ago. To date he has tried 5 different anti-TNF agents (two of which have also been re-tried at a different time point). This failed to control his disease as he continued to experience flares in either inflammatory back or eye disease. The biologic classes were also changed – he has tried one IL-17A agent as well as a JAK-I. Unfortunately, they both failed to control his disease. He currently continues on a second IL-17A; however, he still requires steroid eye and joint injections as well as systemic steroids. Throughout the years he has tried different DMARDs – most recently methotrexate. Unfortunately, the patient decided to discontinue it as he felt it was of no benefit to him. All of the above indicates that there is still a need to find a collaborative treatment option that will control the patient’s inflammatory back disease, inflammatory eye disease and peripheral synovitis. The aim would be, if possible, to decrease the steroid dose as well (currently on prednisolone 15mg daily) in order to prevent the steroid-associated side effects.

Determinants of Oral Bisphosphonate Use Beyond 5 Years.

Few studies have examined factors that determine bisphosphonate (BP) continuation beyond 5 years in clinical practice. To investigate factors associated with BP continuation among women who completed 5 years of BP therapy. Women who received 5 consecutive years of oral BP treatment entered the cohort during 2002-2014 and were followed up to 5 additional years. Multivariable logistic regression was used to evaluate the association of demographic and clinical factors with adherent treatment continuation. The cohort included 19,091 women with a median age of 72 years. Baseline and time-varying factors associated with increased odds of BP continuation after 5 years were (a) most recent bone mineral density (BMD) T-score -2 to -2.4 (OR = 1.31, 95% CI = 1.25-1.38), T-score -2.5 to -2.9 (OR = 1.48, 95% CI = 1.39-1.57), and T-score ≤ -3.0 (OR = 1.57, 95% CI = 1.47-1.68) versus T-scores above -2.0; (b) index date before 2008 (OR =1.35, 95% CI = 1.29-1.41); and (c) diabetes mellitus (OR = 1.08, 95% CI = 1.01-1.16). In contrast, factors associated with decreased odds of BP continuation were (a) recent hip (OR = 0.61, 95% CI = 0.52-0.71) or humerus (OR = 0.79, 95% CI = 0.66-0.94) fracture or fracture other than hip, wrist, spine, or humerus (OR = 0.90, 95% CI = 0.84-0.97); (b) Charlson Comorbidity Index score > 2 (OR = 0.91, 95% CI = 0.84-0.98); (c) history of rheumatoid arthritis (OR = 0.89, 95% CI = 0.80-0.99); (d) Hispanic (OR = 0.89, 95% CI=0.85-0.94) or Asian (OR = 0.90, 95% CI = 0.85-0.94) race/ethnicity; and (e) use of proton pump inhibitors (OR = 0.65, 95% CI = 0.59-0.71). Patient age and fracture before BP initiation were not associated with treatment continuation. Clinical factors predicting continued BP treatment beyond 5 years include low BMD T-score, absence of recent fracture, and earlier era of treatment. Use of proton pump inhibitors was associated with lower likelihood of BP continuation. Other clinical and demographic factors were also noted to have variable effects on BP treatment continuation. This study was supported by a grant from the National Institute on Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH; R01AG047230, S1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Kaiser Permanente. Lo has received previous research funding from Amgen and Sanofi, unrelated to the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, unrelated to the current study. Ettinger has served as an expert witness for Teva Pharmaceuticals, unrelated to the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. The other authors have nothing to disclose. These data were presented at the 2018 Annual Meeting of the American Society of Bone and Mineral Research (ASBMR), September 28-October 1, 2018, Montreal, Quebec, Canada.

A Case Presentation

Case Presentation: A 24-year-old woman with a history of recurrent fractures and multiple bony pains was diagnosed with polyostotic fibrous dysplasia (FD) 3 years previously. There were no associated cutaneous or endocrine manifestations (hypophosphatemia, hormone excess state). She received optimal calcium and vitamin D supplementation. As the patient had persistent pain, she was treated with pamidronate intravenously 1 mg/kg/day for 3 days every 4 months, with serial monitoring of serum N-terminal telopeptide. After 2 years of bisphosphonate therapy, the patient presented with complaint of pain in the left leg, spontaneous in onset, and she underwent an X-ray. X-ray of the left tibia-fibula (Fig. 1) displayed a spiral, noncomminuted fracture of the tibial diaphysis, with beaking of the adjacent cortex and increased cortical bone density. Serum calcium, phosphorus, and vitamin D levels were normal. What is the diagnosis?

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

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.

Delayed healing of lower limb fractures with bisphosphonate therapy.

Bisphosphonate therapy (BT) is used commonly in the management of osteoporosis. A systematic review was conducted investigating delayed union of lower limb, long bone fractures in patients on BT. We specifically assessed whether BT increases the risk of delayed union or non-union in lower limb, long bone fractures. A literature search was conducted in the PubMed and Embase™ on 4 November 2014. Articles that investigated lower limb fractures, history of BT and fracture union were included in the review. A total of 9,809 papers were retrieved and 14 were deemed suitable for this review. The mean time to union in patients on BT was 8.5 months. A longer time to union was reported in a study investigating BT users versus controls (6.5 vs 4.8 months respectively). The mean rate of delayed or non-union for BT associated atypical fractures was 20% per fracture. Specifically in one study, delayed union was more common in the cohort with more than three years of BT (67%) than in the group with less than three years of BT (26%). Surgical fixation was associated with improved outcomes compared with non-operative management. BT has been described to be associated with multiple adverse outcomes related to atypical fractures. Current evidence recommends operative management for this patient group. Further investigation is required to evaluate the exact effects of BT on lower limb fractures, in particular typical femoral fractures.

A large amount of microdamages in the cortical bone around fracture site in a patient of atypical femoral fracture after long-term bisphosphonate therapy

A breast cancer patient developed an atypical femoral fracture after 9years of bisphosphonate therapy for the treatment of multiple bone metastases. We histopathologically analyzed the femoral cortical bone at the fracture site and the iliac cancellous bone. Four months prior to the fracture, the patient had experienced pain in the right femur and underwent plain radiography and bone scintigraphy which revealed cortical thickening and radioisotope accumulation at each site, respectively. The patient had also experienced a non-traumatic fracture at the same site on the contralateral side 2years earlier. Based on these findings, atypical femoral fracture was diagnosed and intramedullary nailing performed. A cortical bone specimen taken from near the fracture site during surgery showed marked microdamages, and analysis of the iliac cancellous bone specimen revealed severely suppressed bone turnover. These findings suggest that microdamage and severely suppressed bone turnover are associated with atypical femoral fracture reported in this patient with long-term bisphosphonate therapy.

Controversies in Osteoporosis Management

Bisphosphonates are effective treatments for osteoporosis. The pharmacology and observance of atypical femoral fractures in patients on long-term therapy raise questions about the need for intermittent discontinuation of treatment, a "drug holiday." Fracture protection benefits of bisphosphonate therapy far outweigh the risk of atypical fractures for the first 10 years of therapy. However, because the fracture probability of therapy abates slowly after stopping the treatment while the risk of atypical fracture appears to decrease quickly, a "drug holiday" of 1 to 2 years should be considered after 3 to 5 years of bisphosphonate therapy except in those patients who remain at very high fracture risk.

Bilateral ulna fractures associated with bisphosphonate therapy

We report a case of bilateral ulna stress fractures following bilateral femoral fractures associated with long-term bisphosphonate use. The patient is an 84-year-old woman receiving 15 years of bisphosphonate therapy. She did not have any preexisting medical conditions which are known secondary causes of bone loss. She was mostly housebound and used a walking frame for ambulation. She presented with atraumatic right ulna pain and subsequent atraumatic left ulna pain a month later. She was treated conservatively in backslabs and her bisphosphonate was stopped. Investigations did not reveal any secondary causes of osteoporosis or metabolic bone disorders.

Risks for Jaw Osteonecrosis Drastically Increases After 2 Years of Bisphosphonate Therapy

Article Title and Bibliographic Information Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN. Barasch A, Cunha-Cruz J, Curro FA, Hujoel P, Sung AH, Vena D, Voinea-Griffin AE; CONDOR Collaborative Group, Beadnell S, et al. J Dent Res 2011;90(4):439-44. Reviewers Sunday O. Akintoye, BDS, DDS, MS, Elliot V. Hersh, DMD, MS, PhD Purpose/Question To determine risks associated with bisphosphonate therapy and identify other risk factors for osteonecrosis of the jaw (ONJ) Source of Funding National Institute of Dental and Craniofacial Research grants U01DE016747, U01DE016755, U01DE016750, U01DE016746, U01DE016754, and U01DE016752 Type of Study/Design Multicenter case-control study Level of Evidence Level 2: Limited-quality, patient-oriented evidence Strength of Recommendation Grade Not applicable

The Clinical Use of Denosumab for the Management of Low Bone Mineral Density in Postmenopausal Women

Osteoporosis is a leading cause of debility and declining quality of life in postmenopausal women worldwide. Treatment of osteoporosis has been ubiquitous throughout the developed world since the mid-1990s, most notably with the introduction of bisphosphonates in 1995. Nonetheless, the incidence of hip fractures increased by 25% between 1990 and 2000, despite advances in osteoporosis therapy. Studies indicate that bone density increases over the first 3 years of bisphosphonate therapy and then plateaus or perhaps even declines, placing these patients at greater risk of fracture. Since hip fractures are associated with increased morbidity, mortality, and increased cost of health care, improvements in treating osteoporosis are critical. Denosumab is a novel monoclonal antibody targeted against the receptor activator of nuclear factor-κB ligand (RANKL) that inhibits osteoclast activity. Initial data suggest that denosumab increases bone mineral density for greater than 3 years. Of greater importance, denosumab has been shown to decrease vertebral fractures by 68%, nonvertebral fractures by 19%, and hip fractures by 42% for at least 36 months. Data also indicate that the safety profile of denosumab is equivalent to other drugs used in osteoporosis management, but potential risks of immunosuppression and cancer have been hypothesized.

The use of intravenous bisphosphonate therapy to treat vertebral fractures due to osteoporosis among boys with Duchenne muscular dystrophy

The impact of intravenous bisphosphonate treatment to treat painful vertebral fractures in boys with DMD has not been documented. In this retrospective observational study of seven boys, 2 years of intravenous bisphosphonate therapy was associated with back pain improvement and stabilization or increases in the height ratios of fractured vertebrae. Boys with Duchenne muscular dystrophy (DMD) are at risk for vertebral fractures. We studied the impact of intravenous bisphosphonate therapy for the treatment of painful vertebral fractures in DMD. This was a retrospective observational study in seven boys with DMD (median 11.6 years, range 8.5 to 14.3) treated with intravenous pamidronate (9 mg/kg/year) or zoledronic acid (0.1 mg/kg/year) for painful vertebral fractures. At baseline, 27 vertebral fractures were evident in the seven boys. After 2 years of bisphosphonate therapy, 17 of the fractures had an increase in the most severely affected vertebral height ratio, 10 vertebrae stabilized, and none showed a decrease in height ratio. Back pain resolved completely (N = 3) or improved (N = 4). The median change in lumbar spine volumetric bone mineral density Z-score was 0.5 standard deviations (interquartile range, -0.3 to 1.7). Two boys had three incident vertebral fractures in previously normal vertebral bodies that developed over the observation period. There was a decline in the trabecular bone formation rate on trans-iliac bone biopsy but no evidence of osteomalacia. First-dose side effects included fever and malaise (N = 4), hypocalcemia (N = 2), and vomiting (N = 1); there were no side effects with subsequent infusions. Intravenous bisphosphonate therapy was associated with improvements in back pain and stabilization to improvement in vertebral height ratios of previously fractured vertebral bodies. At the same time, such therapy does not appear to completely prevent the development of new vertebral fractures in this context.

Cost‐Effectiveness of Oral Bisphosphonates for Osteoporosis at Different Ages and Levels of Life Expectancy

To evaluate the cost-effectiveness of oral bisphosphonate therapy for osteoporosis in women at different ages and life expectancies. A Markov model was used to analyze oral bisphosphonate treatment for 5 years compared to no intervention. Women at each age were divided into life expectancy quartiles: the lowest 1% to 25% (sickest group), the two middle 26% to 75% (average health group), and the highest 76% to 100% of life expectancy (healthiest group). Simulations were performed for hypothetical cohorts at 5-year intervals with starting ages between 50 and 90 and for each life expectancy group and followed for up to 100 years or until death. Data sources included published fracture rates, costs, utility values, and mortality risks. Computer simulation using a societal perspective. Hypothetical cohort of women with various life expectancies beginning osteoporosis treatment between the age of 50 and 90 years. Cost per quality-adjusted life years (QALY) gained for 5 years of bisphosphonate therapy compared to no treatment. Cost-effectiveness was defined at a willingness-to-pay of $50,000. In the healthiest group, all costs were less than $18,000 per QALY. In the median quartiles of life expectancy, lifetime costs per QALY were less than $27,000 for patients at all ages; treatment became cost-saving at a starting age of 75 and remained so through a starting age of 85. Even in the sickest group, although osteoporosis treatment was not cost-saving, it remained cost-effective through a starting age of 90 with lifetime costs of less than $43,000 per QALY. Treatment with an oral bisphosphonate for 5 years was cost-effective for all women, regardless of quartile of life expectancy. Advanced age should not prevent consideration of osteoporosis treatment based on cost effectiveness, and strategies to improve care, such as nurse-led screening programs or electronic medical record tools, are needed.

Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women

Osteoporosis is associated with significant morbidity and mortality. Oral bisphosphonates have become a mainstay of treatment, but concerns have emerged that long-term use of these drugs may suppress bone remodeling, leading to unusual fractures. To determine whether prolonged bisphosphonate therapy is associated with an increased risk of subtrochanteric or femoral shaft fracture. A population-based, nested case-control study to explore the association between bisphosphonate use and fractures in a cohort of women aged 68 years or older from Ontario, Canada, who initiated therapy with an oral bisphosphonate between April 1, 2002, and March 31, 2008. Cases were those hospitalized with a subtrochanteric or femoral shaft fracture and were matched to up to 5 controls with no such fracture. Study participants were followed up until March 31, 2009. The primary analysis examined the association between hospitalization for a subtrochanteric or femoral shaft fracture and duration of bisphosphonate exposure. To test the specificity of the findings, the association between bisphosphonate use and fractures of the femoral neck or intertrochanteric region, which are characteristic of osteoporotic fractures, was also examined. We identified 716 women who sustained a subtrochanteric or femoral shaft fracture following initiation of bisphosphonate therapy and 9723 women who sustained a typical osteoporotic fracture of the intertrochanteric region or femoral neck. Compared with transient bisphosphonate use, treatment for 5 years or longer was associated with an increased risk of subtrochanteric or femoral shaft fracture (adjusted odds ratio, 2.74; 95% confidence interval, 1.25-6.02). A reduced risk of typical osteoporotic fractures occurred among women with more than 5 years of bisphosphonate therapy (adjusted odds ratio, 0.76; 95% confidence interval, 0.63-0.93). Among 52,595 women with at least 5 years of bisphosphonate therapy, a subtrochanteric or femoral shaft fracture occurred in 71 (0.13%) during the subsequent year and 117 (0.22%) within 2 years. Among older women, treatment with a bisphosphonate for more than 5 years was associated with an increased risk of subtrochanteric or femoral shaft fractures; however, the absolute risk of these fractures is low.

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.

Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday

Based upon interest in a bisphosphonate drug holiday, we evaluate the risk for hip fracture after bisphosphonate discontinuation. Among women compliant with bisphosphonates for > or = 2 years, the risk of hip fracture was increased after discontinuation, although with higher compliance and a longer duration of preceding bisphosphonate therapy, this risk was attenuated. Recent data suggest that hip fracture risk was not significantly increased among women receiving 5 years of bisphosphonate therapy who were subsequently randomized to placebo. We studied older women compliant with bisphosphonates > or = 2 years to evaluate the risk of hip fracture after bisphosphonate discontinuation. Using administrative databases from a large U.S. healthcare organization, we identified women initiating bisphosphonate therapy compliant (Medication Possession Ratio, MPR > or = 66%) for 2 years. We examined the rate of hip fracture among women who discontinued bisphosphonates versus those who remained on therapy. At 2 years, 9,063 women were eligible for analysis. Hip fracture incidence among women who discontinued bisphosphonates versus those who did not was 8.43 versus 4.67 per 1000 person years (p = 0.016). The adjusted hazard ratio of hip fracture per 90 days following discontinuation was 1.2 (1.1-1.3). For women with higher compliance at 2 years (MPR > or = 80%) or compliant for 3 years, there were no significant differences in risk associated with discontinuation. The rate of hip fracture was increased among women compliant with bisphosphonate therapy for 2 years who subsequently discontinued, suggesting that discontinuation is not advisable under these conditions. This association was attenuated with higher compliance and a longer duration of previous bisphosphonate therapy.