Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant associations between AFFs and BP use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is low, ranging from 3.2 to 50 cases per 100,000 person-years. However, long-term use may be associated with higher risk ($100 per 100,000 personyears). BPs localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair the processes by which stress fractures normally heal. When BPs are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.

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. ß

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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.

Fragility fractures are common, affecting almost one in two older women and one in three older men. Every fragility fracture signals increased risk of future fractures as well as risk of premature mortality. Despite the major health care impact worldwide, currently there are few systems in place to identify and "capture" individuals after a fragility fracture to ensure appropriate assessment and treatment (according to national guidelines) to reduce future fracture risk and adverse health outcomes. The Task Force reviewed the current evidence about different systematic interventional approaches, their logical background, as well as the medical and ethical rationale. This included reviewing the evidence supporting cost-effective interventions and developing a toolkit for reducing secondary fracture incidence. This report presents this evidence for cost-effective interventions versus the human and health care costs associated with the failure to address further fractures. In particular, it summarizes the evidence for various forms of Fracture Liaison Service as the most effective intervention for secondary fracture prevention. It also summarizes the evidence that certain interventions, particularly those based on patient and/or community-focused educational approaches, are consistently, if unexpectedly, ineffective. As an international group, representing 36 countries throughout Asia-Pacific, South America, Europe, and North America, the Task Force reviewed and summarized the international data on barriers encountered in implementing risk-reduction strategies. It presents the ethical imperatives for providing quality of care in osteoporosis management. As part of an implementation strategy, it describes both the quality improvement methods best suited to transforming care and the research questions that remain outstanding. The overarching outcome of the Task Force's work has been the provision of a rational background and the scientific evidence underpinning secondary fracture prevention and stresses the utility of one form or another of a Fracture Liaison Service in achieving those quality outcomes worldwide. © 2012 American Society for Bone and Mineral Research.