Atypical Femoral Fractures over the Decades: Bisphosphonates Still Dominate the Landscape

Objectives Despite strong evidence supporting their effectiveness in preventing fragility fractures, fewer than 20% of patients receive anti-osteoporotic therapy after a fracture. This gap is partly due to rare adverse events, including atypical femoral fractures (AFFs) linked to bisphosphonate (BP) use. The impact of denosumab on AFF risk remains uncertain. This study aimed to determine whether bisphosphonates remain the predominant treatment associated with AFFs, or whether denosumab also contributes. Methods A retrospective analysis identified cases coded as “closed fracture of the femoral shaft” from January 2008 to October 2025 (N = 686). Among 372 patients aged >40 years, and after excluding traumatic and polytrauma cases, AFFs were confirmed radiologically. Eighty patients presented AFFs (sometimes bilateral), mean age 75.2 years: 40 during 2008 - 2015 (early cohort) and 40 during 2016 - 2025 (recent cohort). Cohorts were comparable for age and biochemical parameters (creatinine, phosphate, ionized calcium, vitamin D, CTX). Treatment data were missing for 8 patients, and duration for 18. Among patients with data (n = 62), all had received bisphosphonates- ongoing or within 1 year- or had transitioned to denosumab (≥2 doses; mean ± SD 11.25 ± 7.7 years). Results In the early cohort (n = 35), 33 patients were on bisphosphonates at AFF, 2 on denosumab after 5 and 9 years of prior BP therapy (2 and 4 doses). In the recent cohort (n = 38), all patients were on antiresorptives and had prior BP exposure (10.35 ± 6.5 years). Eleven were on denosumab (mean 5 ± 4 years), all with prior BP (9 ± 5.5 years). One had 13 years of denosumab, 6 had 5-9 years- equal to or exceeding prior BP duration in 5 cases. The remaining 4 had 2-4 doses of denosumab after long-term BP (10-20 years orally or several years IV). Comparing labs within 1-month post-AFF (denosumab >5 years, n = 5, compared with others in the recent cohort, n = 9), serum creatinine and CTX were significantly lower (p < 0.01). Conclusion Bisphosphonates remain the main treatment associated with AFFs despite increased denosumab use. Most AFFs under denosumab occurred after prior BP exposure, but some followed minimal BP treatment, suggesting a potential long-term contribution of denosumab. Extended denosumab therapy (>5 years) accounted for 15% of AFFs, half after brief BP exposure. Further analyses are needed to identify risk factors and better define cumulative risk from long-term antiresorptive therapy.