Atypical femur fracture data support bisphosphonate ‘drug holiday’ after 5 years
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Risk for atypical femur fractures with bisphosphonate therapy, while rare, was strongly associated with duration of use beyond about 5 years and was quickly and dramatically reduced after discontinuing, study data show.
However, risks for osteoporotic and hip fractures, which are more common, are reduced with continuing therapy.
“Atypical fractures are extremely rare compared with much more common hip and other osteoporotic fractures that can be prevented with bisphosphonate therapy,” Dennis M. Black, PhD, professor of epidemiology and biostatistics at the University of California, San Francisco, and an adjunct investigator at Kaiser Permanente Southern California, told Healio. “We also were reassured to find that the atypical femur fracture risk was strongly associated with duration of use beyond about 5 years and was quickly and dramatically reduced after discontinuing. This strongly supports the concept of a ‘drug holiday,’ a temporary discontinuation of bisphosphonates after 5 years or so of treatment.”
In a prospective study published in The New England Journal of Medicine, Black and colleagues analyzed data from 196,129 women aged at least 50 years receiving bisphosphonate therapy, who were enrolled in the Kaiser Permanente Southern California health care system; women were followed from 2007 to November 2017. The primary outcome was atypical femur fracture. Data on risk factors, including bisphosphonate use, were obtained from electronic health records. Fractures were radiographically adjudicated.
Researchers modeled a risk-benefit profile for 1 to 10 years of bisphosphonate use to compare associated atypical fractures with other fractures prevented.
Within the cohort, researchers observed 277 atypical femur fractures. After adjustment, risk for atypical fracture increased with longer duration of bisphosphonate use.
Compared with less than 3 months of bisphosphonate therapy, the HR for atypical femur fracture was 8.86 (95% CI, 2.79-28.2) for 3 to 5 years of therapy and rose markedly to 43.51 (95% CI, 13.7-138.15) for 8 years or more of bisphosphonate therapy.
Other risk factors included race; HR for Asian adults vs. white adults was 4.84 (95% CI, 3.57-6.56).
Height, weight and glucocorticoid use were also risk factors for atypical femur fracture, according to researchers.
Bisphosphonate discontinuation was associated with a rapid decrease in the risk for atypical fracture; however, a decrease in the risks for osteoporotic and hip fractures during 1 to 10 years of bisphosphonate use “far outweighed” the increased risk for atypical fracture among white adults. The association was less pronounced for Asian adults, Black said.
“After 3 years, 149 hip fractures were prevented and two bisphosphonate-associated atypical fractures occurred in whites, as compared with 91 and eight, respectively, in Asians,” the researchers wrote.
“The benefits of bisphosphonates and other osteoporosis treatments, including the reduction of the devastating consequences of hip and other fractures, far outweigh the risk for atypical fractures,” Black said. “Risks for atypical femur fracture can be greatly reduced by using drug holidays in many patients. The benefits far outweigh risks among white adults and other ethnic groups that we studied apart from Asian adults, where the balance was more modest. Clinicians might want to focus osteoporosis treatment in Asian women to those at higher risk for hip and spine fractures, for example, those aged 70 years or older or with very low bone density. Shorter duration of therapy and use of a drug holiday might be particularly valuable in Asian patients.”
Black said more research on the pathogenesis of atypical fractures is needed, including why these are more common among Asian Americans.
“Development of risk algorithms for atypical femur fracture that can be used to guide clinical decisions about starting bisphosphonates and taking drug holidays in individual patients is needed,” Black said. “The risk for atypical femur fracture can then be balanced against the benefits for other fracture reductions among individual patients.”
For more information:
Dennis M. Black, PhD, can be reached at dennis.black@ucsf.edu.
Perspective
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Jacqueline Center, MBBS, PhD
This study adds to the literature regarding atypical femur fractures. They have used a large population of various ethnicities and have adjudicated the atypical femur fractures from fracture reports.
The authors confirm what others have found regarding increased risk with longer duration of bisphosphonate use and among Asian women. It should be noted that this study only included women and not men, so it cannot be generalized. Most importantly, the risk for atypical femur fracture is far outweighed by the benefit in terms of fractures prevented, although this is based on modelling of data and not actual numbers. However, it is very clear that the number of hip fractures that occurred far outweighed the number of atypical femur fractures.
Some important other results from the study include the fact that cessation of bisphosphonate therapy was associated with a very rapid reduction in risk for atypical femur fracture — this was previously shown in another study, but the data are much clearer in this study. Notably, steroid use for at least 1 year was associated with increased risk. It was interesting that women aged 65 years and younger and women aged at least 85 years had lower risk for atypical femur fracture than middle-aged women. I would have liked to see more data exploring this to really understand these differences.
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