Atypical Femur Fractures Without Bisphosphonate Exposure (AFFwB): A Retrospective Report of 21 Cases

<b>Background/Objectives:</b> Atypical femoral fractures (AFFs) are rare and classically linked to long-term bisphosphonate therapy, but many occur without such exposure. We aimed to characterize atypical femoral fractures without bisphosphonate exposure (AFFwB) in older adults and to explore biochemical patterns using principal component analysis (PCA). <b>Methods:</b> We conducted a retrospective study of patients ≥65 years admitted with femoral fractures (January 2019-September 2024). AFFs were identified from ICD-9 codes and confirmed according to 2014 ASBMR criteria by two blinded reviewers. Demographic, clinical, densitometric, and metabolic data were collected. Correlations between biochemical variables were assessed, and PCA was applied to PTH, vitamin D, BMD, ALP, calcium, and creatinine. <b>Results:</b> Among 932 femoral fractures, 36 met AFF criteria, including 21 AFFwB cases. AFFwB patients were mostly women, and fractures were predominantly diaphyseal. Vitamin D insufficiency/deficiency and osteoporosis were observed in 77% and 66.7% of cases, respectively. Strong correlations were found between PTH and vitamin D and between PTH and ALP. PCA identified four components explaining 88.2% of variance, corresponding to endocrine-mineral regulation, bone turnover, renal function, and BMD as an independent domain. Exploratory comparison with bisphosphonate-exposed AFF suggested higher vitamin D levels and lower ALP in treated patients. <b>Conclusions:</b> In this cohort, AFFs occurred both in patients without bisphosphonate exposure and in those receiving antiresorptive therapy, indicating that AFFs may arise through different pathways. These findings suggest that both insufficient bone quality and excessive remodeling suppression can ultimately lead to atypical fractures. Further studies are needed to clarify these findings.