Bisphosphonate Use and Risk of Atypical Femoral Fractures: A Danish Case Cohort Study with Blinded Radiographic Review

CONTEXT: Prolonged bisphosphonate (BP) treatment for osteoporosis prevents hip and other fractures but causes atypical femoral fractures (AFF).

OBJECTIVE: To establish the relationship between patterns of BP use and the risk of AFF and hip fractures. Other potential risk factors for AFF were also examined.

DESIGN: Population-based case-cohort study.

SETTING: The Danish National Healthcare system maintains longitudinal records of medication use, healthcare utilization, and x-ray images.

PARTICIPANTS: Among all 1.9 million Danish adults ≥50, those with subtrochanteric or femoral shaft fractures between 2010-2015 (n = 4,973) were identified and compared to a random sample (n = 37,021).

PREDICTORS: Bisphosphonate use was collected from 1995-2015.

MAIN OUTCOME MEASURES: Fracture radiographs (n = 4,769) were reviewed by blinded study radiologists to identify AFFs (n = 181) using established criteria. Traditional hip fractures in the random sample (n = 691) were identified by ICD-10.

RESULTS: Compared to <1 year of BP use, 5-7 years of use was associated with a 7-fold increase in AFF [adjusted HR = 7.29 (CI: 3.07,17.30)]; the risk of AFF fell quickly after discontinuation. The 5-year number-needed-to-harm for one AFF was 1,424, while the 5-year number-needed-to-treat to prevent one hip fracture was 56. Glucocorticoid and proton pump inhibitor use were independently associated with increased AFF risk. Thirty-one percent of those with AFF had no BP exposure.

CONCLUSIONS: The risk of AFF increases with duration of BP use but the beneficial effects of BP therapy in adults ≥50 dramatically exceed this increased risk. Nearly one-third of those with AFF have no BP exposure.