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Bisphosphonates are the most widely prescribed pharmacologic treatment for osteoporosis and reduce fracture risk in postmenopausal women by up to 50%. However, in the past decade these drugs have been associated with atypical femoral fractures (AFFs), rare fractures with a transverse, brittle morphology. The unusual fracture morphology suggests that bisphosphonate treatment may impair toughening mechanisms in cortical bone. The objective of this study was to compare the compositional and mechanical properties of bone biopsies from bisphosphonate-treated patients with AFFs to those from patients with typical osteoporotic fractures with and without bisphosphonate treatment. Biopsies of proximal femoral cortical bone adjacent to the fracture site were obtained from postmenopausal women during fracture repair surgery (fracture groups, n = 33) or total hip arthroplasty (nonfracture groups, n = 17). Patients were allocated to five groups based on fracture morphology and history of bisphosphonate treatment [+BIS Atypical: n = 12, BIS duration: 8.2 (3.0) y; +BIS Typical: n = 10, 7.7 (5.0) y; +BIS Nonfx: n = 5, 6.4 (3.5) y; -BIS Typical: n = 11; -BIS Nonfx: n = 12]. Vibrational spectroscopy and nanoindentation showed that tissue from bisphosphonate-treated women with atypical fractures was harder and more mineralized than that from bisphosphonate-treated women with typical osteoporotic fractures. In addition, fracture mechanics measurements showed that tissue from patients treated with bisphosphonates had deficits in fracture toughness, with lower crack-initiation toughness and less crack deflection at osteonal boundaries than that of bisphosphonate-naïve patients. Together, these results suggest a deficit in intrinsic and extrinsic toughening mechanisms, which contribute to AFFs in patients treated with long-term bisphosphonates.

ABSTRACT 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 person-years). 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. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The authors discusses the task force appointed by the American Society for Bone and Mineral Research (ASBMR) due to reports that link the long-term use of biphosphonate (BP) to atypical femur fractures. They agree that the group of multidisciplinary experts reviewing the reports could help in providing insights on the pathogenesis of femur fractures. Also discussed are the development of case definition for subsequent studies, the definition of the major and minor features and evaluation of preclinical data on the effects of BP.

Abstract: Background context: Fusion of the spine requires de novo bone formation and remodeling, processes that rely heavily on the action of the osteoblast and osteoclast. Bisphosphonate drugs and intermittent parathyroid hormone (PTH) therapy are widely prescribed to treat osteoporosis and act on the osteoblast/osteoclast complex. The impact of these medications on spine fusion is not known. Purpose: To evaluate the available evidence on the potential impact of bisphosphonates and PTH on fusion rate and fusion quality in spinal arthrodesis. Study design: A systematic review of the literature. Patient Sample: All available literature regarding the impact of bisphosphonates and PTH on spinal fusion. Outcome measures: Fusion rate and histologic, microstructural, or biomechanical measures of fusion quality. Methods: A systematic review of the literature published between 1980 and 2011 was conducted using major electronic databases. The results of studies meeting criteria for inclusion were then aggregated and examined for consensus on the effect of these medications on spine fusion. Results: The literature contained 18 animal studies and one clinical trial investigating the impact of these medications on spine fusion. Most animal studies evaluating the impact of bisphosphonates on fusion rate have not found statistically significant changes with treatment, although this fact may be attributable to low statistical power. The animal literature does suggest that bisphosphonate therapy results in a less histologically mature fusion mass; however, the impact of these changes on fusion mass biomechanics is unclear. The only available human study suggests that these bisphosphonates may increase the radiographically defined fusion rate but did not demonstrate an impact on clinical outcome. In animals, PTH improves the fusion rate and fusion mass microstructure, but data on its effect on fusion mass biomechanics are lacking. No studies have evaluated the impact of PTH on spine fusion in humans. Conclusions: In animals, bisphosphonate therapy appears to impede maturation of the fusion mass, with an unclear effect on mechanical strength. This effect was not seen in the lone human study, which suggested that these medications improved the radiographically defined fusion rate. The available animal studies on intermittent PTH treatment suggest that it may improve fusion rate and fusion mass microstructure. Given the widespread use of these agents, further investigation into their impact on human spine fusion is necessary to inform the care of patients with osteoporosis who are undergoing spine surgery. [Copyright &y& Elsevier]