AFF With Bisphosphonates Highest in Asians, Study Confirms

Nancy A. Melville

August 19, 2020

The latest findings regarding the risk for atypical femur fracture (AFF) with use of bisphosphonates for osteoporosis show a significant increase in risk when treatment extends beyond 5 years. The risk is notably higher risk among Asian compared to White women. However, the benefits in fracture reduction still appear to far outweigh the risk for AFF, shows the new study.

The research, published this week in The New England Journal of Medicine, importantly adds to findings from smaller studies by showing effects in a population of nearly 200,000 women in a diverse cohort, said Angela M. Cheung, MD, PhD, in commenting on the study to Medscape Medical News.

"This study answers some important questions ― Kaiser Permanente Southern California is a large health maintenance organization with a diverse racial population," said Cheung, director of the Center of Excellence in Skeletal Health Assessment and Osteoporosis Program at the University of Toronto, Toronto, Canada.

"This is the first study that included a diverse population to definitively show that Asians are at a much higher risk of atypical femur fractures than Caucasians," she emphasized.

Although AFFs are rare, concerns about them remain pressing in the treatment of osteoporosis, Cheung noted.

"This is a big concern for clinicians ― they want to do no harm," she said.

Risk for AFF Increases With Longer Duration of Bisphosphonate Use

For the study, Dennis M. Black, PhD, of the Departments of Epidemiology and Biostatistics and Orthopedic Surgery at the University of California, San Francisco, and colleagues identified women aged 50 years or older enrolled in the Kaiser Permanente Southern California system who were treated with bisphosphonates and were followed from January 2007 to November 2017.

Among the 196,129 women identified in the study, 277 AFFs occurred.

After multivariate adjustment, compared with those treated for less than 3 months, for women who were treated for 3 to 5 years, the hazard ratio (HR) for experiencing an AFF was 8.86. For therapy of 5 to 8 years, the HR increased to 19.88, and for those treated with bisphosphonates for 8 years or longer, the HR was 43.51.

The risk for AFF declined quickly upon bisphosphonate discontinuation; compared with current users, the HR dropped to 0.52 within 3 to 15 months after the last bisphosphonate use. It declined to 0.26 at more than 4 years after discontinuation.

The risk for AFF with bisphosphonate use was higher for Asian women than for White women (HR, 4.84); this did not apply to any other ethnic groups (HR, .99).

Other risk factors for AFF included shorter height (HR, 1.28 per 5-cm decrement), greater weight (HR, 1.15 per 5-kg increment), and glucocorticoid use (HR, 2.28 for glucocorticoid use of 1 or more years).

Among White women, the number of fractures prevented with bisphosphonate use far outweighed the risk for bisphosphonate-associated AFFs.

For example, among White women, during a 3-year treatment period, there were two bisphosphonate-associated AFFs, whereas 149 hip fractures and 541 clinical fractures were prevented, the authors say.

After 5 years, there were eight AFFs, but 286 hip fractures and 859 clinical fractures were prevented.

Although the risk-benefit ratio among Asian women still favored prevention of fractures, the difference was less pronounced ― eight bisphosphonate-associated AFFs had occurred at 3 years, whereas 91 hip fractures and 330 clinical fractures were prevented.

The authors note that previous studies have also shown Asian women to be at a disproportionately higher risk for AFF.

An earlier Kaiser Permanente Southern California case-series study showed that 49% of 142 AFFs occurred in Asian patients, despite the fact that those patients made up only 10% of the study population.

Various Factors Could Cause Higher Risk in Asian Women

The reasons for the increased risk among Asian women are likely multifactorial and could include greater medication adherence among Asian women, genetic differences in drug metabolism and bone turnover, and, notably, increased lateral stress due to bowed Asian femora, the authors speculate.

Further questions include whether the risk is limited to Asians living outside of Asia and whether cultural differences in diet or physical activity are risk factors, they add.

"At this early stage, further research into the cause of the increased risk among women of Asian ancestry is warranted," they say.

Although the risk for AFF may be higher among Asian women, the incidence of hip and other osteoporotic fractures is lower among Asians as well as other non-White persons compared with White persons, they add.

The findings have important implications in how clinicians should discuss treatment options with different patient groups, Cheung said.

"I think this is one of the key findings of the study," she added.

"In this day and age of personalized medicine, we need to keep the individual patient in mind, and that includes their racial/ethnic background, genetic characteristics, sex, medical conditions and medications etc.

"So it is important for physicians to pay attention to this. The risk-benefit ratio of these drugs for Asians will be quite different compared to Caucasians," she said.

No Link Between Traditional Fracture Risk Factors and AFF, Study Shows

Interestingly, although older age, previous fractures, and lower bone mineral density are key risk factors for hip and other osteoporotic fractures in the general population, they do not significantly increase the risk for AFF with bisphosphonate use, the study also shows.

"In fact, the oldest women in our cohort, who are at highest risk for hip and other fractures, were at lowest risk for AFF," the authors write.

The collective findings "add to the risk–benefit balance of bisphosphonate treatment in these populations and could directly affect decisions regarding treatment initiation and duration."

Notable limitations of the study include the fact that most women were treated with one particular bisphosphonate, alendronate, and that other bisphosphonates were underrepresented, Cheung said.

"This study examined bisphosphonate therapy, but the vast majority of the women were exposed to alendronate, so whether women on risedronate or other bisphosphonates have similar risks is unclear," she observed.

"In addition, because they can only capture bisphosphonate use using their database, any bisphosphonate exposure prior to joining Kaiser Permanente will not be captured. So the study may underestimate the total cumulative duration of bisphosphonate use," she added.

The study received support from Kaiser Permanente and discretionary funds from the University of California, San Francisco. The study began with a pilot grant from Merck Sharp & Dohme, which had no role in the conduct of the study. Cheung has served as a consultant for Amgen. She chaired and led the 2019 ISCD Position Development Conference on Detection of Atypical Femur Fractures and currently is on the Osteoporosis Canada Guidelines Committee.

New Engl J Med. Published August 19, 2020. Abstract

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