Increased Risk for Atypical Femur Fracture With Longer Bisphosphonate Use in Women With Osteoporosis

Bisphosphonate femur fracture
Bisphosphonate femur fracture
Researchers evaluated the association between risk for atypical fracture and duration of bisphosphonate use in women with osteoporosis.

Risk for atypical femur fracture was found to increase with longer duration of bisphosphonate use in women with osteoporosis, according to study results published in the New England Journal of Medicine. However, researchers noted the absolute risk for atypical femur fractures vs reductions in hip and osteoporotic fractures was low with bisphosphonate treatment.

While bisphosphonates effectively reduce the risk for hip and osteoporotic fractures, previous research has indicated that these drugs increase the risk for atypical femur fractures. Investigators sought to characterize the risk-benefit profile of bisphosphonates in women with osteoporosis.

The current prospective cohort study enrolled women aged ≥50 years who were members of the Kaiser Permanente Southern California healthcare system. Women who had received at least 1 prescription for oral or intravenous bisphosphonate for osteoporosis were eligible for inclusion in the study. The follow-up period was from January 1, 2007 to November 30, 2017. Demographic and clinical factors were extracted from electronic health records. The primary outcome was atypical femur fracture. Multivariable Cox models, which included risk factors with P <.2, were used to compare categories of duration of bisphosphonate use. The risk-benefit profile of bisphosphonates was modeled by comparing the number of bisphosphonate-associated atypical fractures to the number of other fractures prevented over 1 to 10 years of bisphosphonate use. The number of hypothetically prevented fractures was extrapolated using osteoporotic fracture rates from an untreated cohort from the Study of Osteoporotic Fractures. Risk-benefit calculations were stratified by race/ethnicity.

The analytic cohort included 196,129 women. The racial/ethnic distribution was 53.3% White, 24.0% Hispanic, 13.5% Asian, 5.9% Black, and 3.3% other or unknown. A total of 277 atypical fractures were observed during the follow-up period, at a cumulative incidence rate of 1.74 fractures per 10,000 patient-years. The incidence of atypical fractures increased with longer duration of bisphosphonate use. Compared to 0 to 0.25 years of bisphosphonate use, the adjusted hazard ratios (HRs) for atypical fracture with 3 to <5 years, 5 to <8 years, and ≥8 years of use were 8.86 (95% CI, 2.79-28.20), 19.88 (95% CI, 6.32-62.49), and 43.51 (95% CI, 13.70-138.15), respectively. Risk for atypical fracture decreased with an increase in time since bisphosphonate discontinuation.

Compared with women who were current users or who had discontinued bisphosphonates <3 months ago, women with >0.25 to 1.25 years, >1.25 to 4 years, and >4 years since the last bisphosphonate use had HRs of 0.52 (95% CI, 0.37-0.72), 0.21 (95% CI, 0.13-0.34), 0.26 (95% CI, 0.14-0.48), and 0.09 (95% CI, 0.01-0.83), respectively. Compared with White women, Asian women were at significantly increased risk for atypical fracture (HR, 4.84; 95% CI, 3.57-6.56), after adjusting for age, duration of use, smoking, body mass index, and glucocorticoid use.

After 3 years of bisphosphonate use, an estimated 149 hip fractures were prevented among White women. In addition, 2 bisphosphonate-associated atypical fractures were observed in White women, indicating a favorable risk-benefit profile. After 10 years, the ratio remained favorable: 591 hip fractures prevented vs 38 atypical fractures observed. The risk-benefit profile was favorable among Asian women at 3 years, though the ratio was smaller: 91 hip fractures prevented vs 8 atypical fractures. However, by 10 years, the number of atypical fractures (n=236) was only slightly less than the number of fractures prevented (n=360), suggesting a less favorable risk-benefit profile. Among Hispanic women, the risk-benefit balance was intermediate. Among Black women, too few atypical fractures were observed to weigh the risks and benefits.

Study limitations included the fact that since alendronate accounted for the majority of bisphosphonate treatment, the findings could not be extended to other medications and formulations, the limitation of the assessment of covariates to the Kaiser Permanente membership period, and that the risk-benefit comparison was only based on numbers of fractures.

“The absolute risk [for] atypical femur fracture remained very low as compared with reductions in the risk [for] hip and other fractures with bisphosphonate treatment,” the investigators concluded. “[A]lthough the risk-benefit balance appeared less favorable for Asian women.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383(8):743-753.