Bisphosphonates and the risk of atypical femur fractures

Black, Dennis M.; Condra, Katherine; Adams, Annette L.; Eastell, Richard

Affiliations

¹University of California, San Francisco, Department of Epidemiology & Biostatistics, United States of America

²Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA, United States of America

³San Francisco VA Health Care System, Department of Endocrinology & Metabolism, San Francisco, United States of America

⁴University of Sheffield, Department of Oncology & Metabolism, United Kingdom

Abstract and keywords

Bisphosphonates are effective in reducing hip and other fractures. However, concerns about atypical femur fractures (AFFs) have contributed to substantially decreased bisphosphonate use, and hip fracture rates may be increasing. Despite this impact, important uncertainties remain regarding AFF risks including the association between bisphosphonate use and other risk factors such as BMD, age, weight, and race.

To address this evidence gap, a cohort study of 196,129 women ≥50 years of age in the Southern California Kaiser Permanente HMO women (with ≥1 bisphosphonate prescription) were studied; the primary outcome was radiographically-adjudicated AFF between 2007 and 2017. Risk factors including bisphosphonate use and race were obtained from electronic health records. Multivariable Cox models were used for analysis. Benefit-risk was modeled for 1–10 years of bisphosphonates to compare fractures prevented vs. AFFs associated. Among 196,129 women, 277 (0.1%) sustained AFFs. After multivariable adjustment, AFF risk increased with longer bisphosphonate duration: hazard ratio (HR) increased from HR = 8.9 (95%CI: 2.8,28) for 3–5 years to HR = 43.5 (13.7138.1) for >8 years. Hip BMD, surprisingly, was not associated with AFF risk. Other risk factors included Asian ancestry (HR = 4.8 (3.6, 6.6)), short stature, overweight, and glucocorticoid use. Bisphosphonate discontinuation was associated with rapid decrease in AFF risk. Decreases in osteoporotic and hip fractures risk during 1–10 years of bisphosphonates far outweighed the increase AFF risk in Caucasians, but less so in Asians. In Caucasians, after 3 years 149 hip fractures were prevented with 2 AFFs associated compared to 91 and 8 in Asians.

The evidence for several potential mechanisms is summarized with femoral geometry being the most likely to explain AFF risk differences between Asians and Caucasians. The results from this new study add to the evidence base for AFF risk factors and will help inform clinical decision-making for individual patients about initiation and duration of bisphosphonate therapy and drug holidays.

Keywords: Fracture; Atypical femur fracture; Osteoporosis; Bisphosphonates

Links

DOI: 10.1016/j.bone.2021.116297

PubMed: 34920168

WoS: 000773552400002

History

Received: 2021-08-31

Revised: 2021-12-7

Accepted: 2021-12-8

Online: 2021-12-14

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