Bo Abrahamsen

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.

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.

INTRODUCTION: osteoporosis is a common disease, and the incidence of osteoporotic fractures is expected to rise with the growing elderly population. Immediately following, and probably several years after a hip fracture, patients, both men and women, have a higher risk of dying compared to the general population regardless of age. The aim of this study was to assess excess mortality following hip fracture and, if possible, identify reasons for the difference between mortality for the two genders. METHODS: this is a nationwide register-based cohort study presenting data from the National Hospital Discharge Register on mortality, comorbidity and medication for all Danish patients (more than 41,000 persons) experiencing a hip fracture between 1 January 1999 and 31 December 2002. Follow-up period was until 31 December 2005. RESULTS: we found a substantially higher mortality among male hip fracture patients than female hip fracture patients despite men being 4 years younger at the time of fracture. Both male and female hip fracture patients were found to have an excess mortality rate compared to the general population. The cumulative mortality at 12 months among hip fracture patients compared to the general population was 37.1% (9.9%) in men and 26.4% (9.3%) in women. In the first year, the risk of death significantly increased for women with increasing age (hazard ratio, HR: 1.06, 95% confidence interval, CI: 1.06-1.07), the number of comedications (HR 1.04, 95% CI 1.03-1.05) and the presence of specific Charlson index components and medications described below. For men, age (HR 1.07, 95% CI 1.07-1.08), number of comedications (HR 1.06, 95% CI 1.04-1.07) and presence of different specific Charlson index components and medications increased the risk. Long-term survival analyses revealed that excess mortality for men compared with women remained strongly significant (HR 1.70, 95% CI 1.65-1.75, P < 0.001), even when controlled for age, fracture site, the number of medications, exposure to drug classes A, C, D, G, J, M, N, P, S and for chronic comorbidities. CONCLUSION: excess mortality among male patients cannot be explained by controlling for known comorbidity and medications. Besides gender, we found higher age and multimorbidity to be related to an increased risk of dying within the first year after fracture; acute complications might be one of the explanations. This study emphasises the need for particular rigorous postoperative diagnostic evaluation and treatment of comorbid conditions in the male hip fracture patient.