These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small. (Funded by the Swedish Research Council.).

Background and purposeUse of bisphosphonates in women is associated with higher risk of atypical femoral fractures. The risk in terms of timing of use and type of bisphosphonate, and in men, remains unclear.Patients and methodsWe reviewed radiographs of 5,342 Swedish women and men aged 55 years or more who had had a fracture of the femoral shaft in the 3-year period 2008–2010 (97% of those eligible), and found 172 patients with atypical fractures (93% of them women). We obtained data on medication and comorbidity. The risk of atypical fracture associated with bisphosphonate use was estimated in a nationwide cohort analysis. In addition, we performed a case-control analysis with comparison to 952 patients with ordinary shaft fractures. A short report of the findings has recently been presented (Schilcher et al. 2014a). Here we provide full details.ResultsThe age-adjusted relative risk (RR) of atypical fracture associated with bisphosphonate use was 55 (95% CI: 39–79) in women and 54 (CI: 15–192) in men. In bisphosphonate users, women had a 3-fold higher risk than men (RR = 3.1, CI: 1.1–8.4). Alendronate users had higher risk than risedronate users (RR = 1.9, CI: 1.1–3.3). The RR after 4 years or more of use reached 126 (CI: 55–288), with a corresponding absolute risk of 11 (CI: 7–14) fractures per 10,000 person-years of use. The risk decreased by 70% per year since last use.InterpretationWomen have a higher risk of atypical femoral fracture than men. The type of bisphosphonate used may affect risk estimates and the risk decreases rapidly after cessation.

Background Recent case reports have identified an association between long-term bisphosphonate treatment and stress fractures of the femoral shaft. The risk of such fractures in bisphosphonate users has not been determined.Methods We identified women over 55 years of age with the specific fracture pattern by searching the operation registry of the hospitals in 2 healthcare districts. Prevalence of bisphosphonate treatment was provided by a Swedish national registry covering all drugs delivered to all individuals since 2005.Results The number of women on bisphosphonate treatment was 3,087. Of these, 5 had femoral stress fractures. They had been taking bisphosphonates for 3.5 to 8.5 years. The incidence density for a patient on bisphosphonate was 1/1,000 per year (95% CI: 0.3–2). In the remaining 88,869 women who were not taking bisphosphonates, there were 3 stress fractures. Thus, their risk (without correction for inhomogeneity in age distribution) was 46 times less (95% CI: 11–200).Interpretation These results are rough estimations based on a comparatively small material. Still, a treatment-associated incidence density of 1/1,000 is acceptable, considering that bisphosphonate treatment is likely to reduce the incidence density of any fracture by 15/1,000 according to a large randomized trial (Black et al. 1996).

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Background and purposeThe pathophysiology behind bisphosphonate-associated atypical femoral fractures remains unclear. Histological findings at the fracture site itself may provide clues.Patients and methodsBetween 2008 and 2013, we collected bone biopsies including the fracture line from 4 complete and 4 incomplete atypical femoral fractures. 7 female patients reported continuous bisphosphonate use for 10 years on average. 1 patient was a man who was not using bisphosphonates. Dual-energy X-ray absorptiometry of the hip and spine showed no osteoporosis in 6 cases. The bone biopsies were evaluated by micro-computed tomography, infrared spectroscopy, and qualitative histology.ResultsIncomplete fractures involved the whole cortical thickness and showed a continuous gap with a mean width of 180 µm. The gap contained amorphous material and was devoid of living cells. In contrast, the adjacent bone contained living cells, including active osteoclasts. The fracture surfaces sometimes consisted of woven bone, which may have formed in localized defects caused by surface fragmentation or resorption.InterpretationAtypical femoral fractures show signs of attempted healing at the fracture site. The narrow width of the fracture gap and its necrotic contents are compatible with the idea that micromotion prevents healing because it leads to strains within the fracture gap that preclude cell survival.

Methods: In a previous nationwide study, 59 atypical and 218 ordinary fractures were diagnosed. The atypical fractures were defined by their stress-type fracture pattern.All fractures were now re-assessed by a physician in training, without information about bisphosphonate use. The fracture angle (0 -180 degrees) was measured.Presence of local lateral cortical thickening (a callus reaction), more than 2 fragments, or a medial spike was noted. The reader then made a judgment whether the fracture appeared as an atypical fracture based on the ASBMR criteria. Interpretation: Stress fractures of the femoral shaft are a specific entity, which is easily diagnosed on radiographs and strongly related to bisphosphonate use.Differences in diagnostic criteria may partially explain the large differences in relative risk between different population-based studies.

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