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.

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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.

PA has a patent on a process for coating metal implants with bisphosphonates, and shares in a company (Addbio AB) trying to commercialize the principle. PA also has received consulting reimbursement and grants from Eli Lilly & Co.VK and JS have no conflict of interest to declare. 3 Mini-abstractAn association between atypical fractures and general cortical thickness of the femoral shaft is often suggested in the literature. Our radiographic measurements of 59 atypical and 218 ordinary fractures now exclude a difference larger than 10 % in mean femoral cortical thickness (sum of lateral and medial) with 95% confidence. Abstract PurposeAn increased general cortical thickness in patients with fatigue fracture of the femoral shaft (atypical fractures) is commonly suggested. However, there is scarce data to support this. MethodsIn a published nationwide Swedish study, we identified by radiographic review 59 women with an atypical fracture during 2008. The femoral cortical thickness index (thickness / femoral diameter) of these women was now compared with the 218 ordinary fractures that occurred in the same region of the femur in a casecontrol design. The cortical thickness index 5 cm below the lesser trochanter was the primary variable. ResultsPatients with atypical fractures were younger. Without correction for age, they had a thicker cortex (i.e. higher index). However, the difference in cortical thickness disappeared after age correction. The 95% CI excludes a group mean difference exceeding 10% of total mean thickness. Similarly, there was no significant difference in cortical thickness between patients with or without bisphosphonate treatment, or between the ipsi-and contralateral femurs in patients with an atypical fracture. ConclusionThe concept of a generally increased cortical thickness in patients with atypical fractures needs further assesment.