Background: Atypical femoral fractures (AFFs) are rare but serious complications of antiresorptive therapy (ART), frequently misdiagnosed and managed inappropriately in acute care settings. Early recognition remains critical to avoid further harm.

Objective: To compare the clinical and biochemical characteristics of patients with AFFs and typical femoral fractures (TFFs) to identify features that may assist in diagnosis at the time of hospitalization.

Methods: A retrospective study was conducted across two tertiary hospitals in Queensland, Australia, from 2012 to 2022. Patients presenting with femoral shaft fractures were identified using ICD-10 codes. Fractures were classified radiologically using ASBMR criteria. Clinical characteristics, biochemical results, and discharge medications were extracted from electronic records. Between-group comparisons were performed using appropriate statistical tests.

Results: Of 869 identified fractures, 43 AFFs and 101 TFFs were confirmed. Patients with AFFs were more likely to have a prior diagnosis of osteoporosis (97.7% vs. 35.6%, p < 0.01), a history of fragility fracture (53.5% vs. 26.7%, p < 0.01), and prodromal symptoms (32.6% vs. 3%, p < 0.01). Biochemically, AFF patients had significantly lower alkaline phosphatase (median 56 vs. 83 IU/L, p < 0.01) and higher 25-hydroxyvitamin D levels (median 86.8 vs. 69.5 nmol/L, p = 0.01). Nearly one-quarter had ALP < 40 IU/L. Despite this, 51.3% of AFF patients were discharged on continued ART.

Conclusions: Patients with AFFs demonstrate distinct clinical and biochemical profiles at the time of hospital presentation, most notably suppressed ALP. These features may serve as diagnostic clues to prevent ongoing exposure to ART. Greater clinical vigilance is needed to ensure appropriate management and to consider alternative diagnoses such as hypophosphatasia in selected patients.