Risk factors for atypical femur fractures with and without bisphosphonate treatment: a national nested case-control...

Atypical femur fractures (AFF) are rare stress fractures linked to long-term bisphosphonate (BP) use. However, since some patients develop AFF without BP exposure (BP-naïve), additional mechanisms have been proposed. In this study, we tested medication use, clinical characteristics, and femoral geometry. We started with a hypothesis that BP-naïve patients would have additional risk factors in these areas compared with BP-users. We included 172 patients aged ≥55 yr who sustained AFF in Sweden between 2008 and 2010. Among them, 134 had used BPs prior to the fracture and 38 had not. All fractures met the 2014 ASBMR major criteria for AFF. Data on medication use, comorbidities, and demographics were extracted from national registers, and radiographs were reviewed to assess femoral geometry. All statistical models were adjusted for sex and age. We found that among BP-naïve patients, male sex was more common (21.1%) than among BP-users (3.0%). Additionally, BP-naïve patients were less likely to use calcium supplementation (23.7% vs 90.3%, OR 0.04, 95% CI 0.01-0.10), corticosteroids (13.2% vs 35.8%, OR 0.18, 95% CI 0.05-0.52), proton pump inhibitors (23.7% vs 41.8%, OR 0.36, 95% CI 0.14-0.85), and beta-blockers (28.9% vs 47.0%, OR 0.43, 95% CI 0.18-0.97). Moreover, BP-naïve patients had fewer diagnosed bone disorders, including osteoporosis (5.3% vs 34.3%, OR 0.10, 95% CI 0.02-0.38). Bisphosphonate-naïve patients did have a higher lateral-to-medial cortical thickness ratio (1.00 vs 0.90, p < .01); however, other geometric differences were minor and did not support the hypothesis. The absence of identifiable mechanisms for stress fracture formation suggests that future research should test factors not captured in registry data or femoral geometry. Possibly, physical activity levels or subtle bone metabolic conditions may be contributing to the pathogenesis of AFF, particularly in BP-naïve individuals.