August 20, 2020

Atypical femur fractures rise with longer bisphosphonate use

While rare, the risk of atypical femur fractures increases with longer bisphosphonate use, especially after 5 years and among Asian women.

Contacts: Terry Kanakri



PASADENA, Calif. — In a study published in the New England Journal of Medicine, Kaiser Permanente Southern California research scientists report that while atypical femur fracture risk is rare, it does increase with longer use of bisphosphonate to treat osteoporosis, especially after 5 years. Asian women had approximately 5 times the risk of these fractures with prolonged bisphosphonate use compared to white women.

“Atypical femur fractures with bisphosphonate use are extremely rare, particularly compared to the fractures that the bisphosphonates prevent,” said the study’s lead author Dennis M. Black, PhD, a professor of epidemiology and biostatistics with the University of California, San Francisco, and an adjunct investigator with Kaiser Permanente Southern California Department of Research & Evaluation. “However, this study found that atypical femur fracture risk does increase with length of bisphosphonate use, a risk that may be reduced by taking a break from using bisphosphonates, often referred to as a ‘drug holiday.’”

Dennis M. Black, PhD

Dennis M. Black, PhD, adjunct investigator with Kaiser Permanente Southern California Department of Research & Evaluation

Bisphosphonates have been used since the 1990s as an effective medication to reduce the risk of hip, spine, and other fractures among aging women with osteoporosis. However, in 2006 reports began to emerge about women who were taking the bisphosphonates developing unusual fractures in their thigh bones. While some small studies on this condition have been conducted, they had mixed results. Researchers in this current study looked at the issue among a large, ethnically and racially diverse patient population. The study also provides important new insights into whether the risk of these fractures decreases once the drug is stopped. 

Kaiser Permanente and UCSF researchers studied the electronic health records of nearly 200,000 bisphosphonate-treated women 50 years old and older from Kaiser Permanente in Southern California from Jan. 1, 2007, to Nov. 30, 2017. Among 196,129 women studied, 277 sustained atypical femur fractures.

Among the findings:

  • The risk of atypical femur fracture was very low for women with 3 to 5 years of treatment: 1 to 2 cases for each 10,000 women. 
  • The benefits of treatment were overwhelmingly positive compared to atypical femur fracture risk: For 3 to 5 years of treatment, 100 to 200 osteoporotic fractures could be prevented for each atypical femur fracture associated with treatment. 
  • Beyond 5 years atypical fracture risk increased, suggesting that treatment duration should be limited in women at higher atypical femur fracture risk.
  • Atypical femur fracture and other fracture risk could be predicted, which means treatment can be personalized based on risk factors such as age, bone density, weight, and race.
  • Among all racial and ethnic groups, Asian women had the highest risk of atypical femur fractures with bisphosphonate use, approximately 5 times higher than other groups, suggesting that they may benefit more from shorter courses of therapy.
  • Discontinuing bisphosphonate therapy is associated with a rapid decline in atypical femur fracture risk, going from 4.5 fractures per 10,000 women in current users to 1.8 per 10,000 one year after stopping the medication and 0.5 per 10,000 2 years after stopping.

“Despite these findings, the risk of atypical femur fracture remains very low compared with risk of hip and other fractures, which bisphosphonates are used to reduce,” said the senior author of the article, Annette L. Adams, PhD, of Kaiser Permanente Southern California. “We also found that the risk varies greatly between racial and ethnic groups, which tells us that the recommendations for treatment regimens and drug holidays to reduce atypical femur fracture risk should be tailored to each patient.”

The study shows physicians the importance of personalized treatment plans, said study co-author Richard Dell, MD, an orthopedic surgeon at Kaiser Permanente Downey Medical Center.

“This study shows that the personalization of treatment plans based on individual risk factors can dramatically reduce the already low risk of atypical femur fracture,” Dr. Dell said, “and enhance the fracture-reduction benefit of bisphosphonate treatment.”

About the Kaiser Permanente Southern California Department of Research & Evaluation

The Department of Research & Evaluation conducts high-quality, innovative research into disease etiology, prevention, treatment, and care delivery. Investigators conduct epidemiologic research, health services research, biostatistics research, and behavioral research as well as clinical trials. Major areas of study include chronic disease, infectious disease, cancer, drug safety and effectiveness, and maternal and child health. Headquartered in Pasadena, California, the department focuses on translating research to practice quickly to benefit the health and lives of Kaiser Permanente Southern California members and the general public. Visit

About Kaiser Permanente

For 75 years, Kaiser Permanente has been committed to shaping the future of health and health care — and helping our members, patients, and communities experience more healthy years. We are recognized as one of America’s leading health care providers and not-for-profit health plans. Since July 21, 1945, Kaiser Permanente’s mission has been to provide high-quality, affordable health care services and to improve the health of our members and the communities we serve. We currently serve 12.4 million members in 8 states and the District of Columbia. Care for members and patients is focused on their total health and guided by their personal Permanente Medical Group physicians, specialists, and team of caregivers. Our expert and caring medical teams are empowered and supported by industry-leading technology advances and tools for health promotion, disease prevention, state-of-the-art care delivery, and world-class chronic disease management. Kaiser Permanente is dedicated to care innovations, clinical research, health education, and the support of community health.