MONTREAL -- Drug holidays among women receiving bisphosphonates markedly reduced the risk of atypical femur fractures, a researcher reported here.
"Drug holidays are increasing being used as a method for managing the rare adverse outcomes associated with long-term bisphosphonate use, such as osteonecrosis of the jaw and atypical femoral fractures, so treatment of osteoporosis has really become an exercise in balancing the risk of these adverse events with the antifracture benefits of the treatment," said Annette L. Adams, PhD, of Kaiser Permanente Southern California in Pasadena, in a presentation at the American Society for Bone and Mineral Research (ASBMR) annual meeting.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Currently there are two open questions about drug holidays in these patients. One is what happens to the traditional osteoporosis-related fractures, such as those of the hip and spine. While current evidence suggests that there's not a big risk -- at least in the short term -- it's still an open question, she said.
The other question is what happens to the risk of atypical femoral fractures during a drug holiday. It's been suggested that there is a reduction of as much as 70%, but there is limited research, and this remains an open question as well.
Among 152,934 women (ages ≥50) enrolled in the Kaiser Permanente healthcare plan during the years 2007 to 2015, a drug holiday of 3 to 5 years was associated with a 44% reduction in risk of atypical femur fractures during the first year after stopping (HR 0.56, 95% CI 0.38-0.82) compared with those remaining on treatment, Adams reported.
Eligible patients had used any bisphosphonate and had at least one pretreatment bone mineral density total hip scan. Atypical femur fractures (subtrochanteric or femoral shaft fractures) were verified by physician review of x-rays.
A drug holiday was considered any discontinuation of bisphosphonate therapy for ≥3 months.
The analysis included adjustments for age, race, smoking, height, history of fractures, use of glucocorticoids, pretreatment total hip T-score, and duration of bisphosphonate use.
By September 2015, there had been 148 incident atypical femoral fractures, for an incidence rate of 1.70 per 10,000 person-years.
Women who experienced an atypical femoral fracture tended to be younger -- clustering in the 65 to 85 age range, with few being in the 85-plus group -- and to be Asian compared with those who did not have an atypical femoral fracture. Asian women had an almost five-fold increased risk compared with other races. "Surprisingly, pretreatment bone mineral density did not seem to play a large role in the risk," she said.
On a univariate analysis comparing the incidence rates according to time since stopping bisphosphonate, those who had stopped within the last 3 months had an incidence rate of 4.6 per 10,000 person-years, while those who had a drug holiday of at least a year had an incidence rate of 1.5 per 10,000. After the first year, the rate dropped even further, to 0.6 per 10,000, she said.
During years 1 to 4 after bisphosphonate discontinuation, the risk of atypical femoral fractures decreased by 80% (HR 0.20, 95% CI 0.10-0.37) among discontinuers versus ongoing users after adjusting for all potential confounders. After 4 years, the risk decrease was 78% (HR 0.22, 95% CI 0.08-0.59).
"These results suggest that a drug holiday of 3 to 5 years would likely markedly reduce the risk of atypical femoral fractures among long-term bisphosphonate users, and supports the notion that a drug holiday can be a way of balancing the risk of these events and the benefits of bisphosphonate treatment," Adams concluded.
Strengths of the study included its large population, which was representative of the population of Southern California, and its comprehensive longitudinal pharmacy data that allowed the researchers to capture bisphosphonate exposures in great detail. A limitation was the lack of information on why the women discontinued treatment.
In a session describing the highlights of the meeting, ASBMR past president John Bilezikian, MD, of Columbia University in New York City, noted that there were major differences in atypical femoral fractures and in conventional osteoporotic fractures as described by Kenneth Saag, MD, in a previous ASBMR presentation.
"We really need to come up with a balance," Bilezikian said.
Disclosures
Adams disclosed support from Merck.
Primary Source
American Society for Bone and Mineral Research
Adams A, et al "Do drug holidays reduce atypical femur fracture risk? Results from the Southern California Osteoporosis Cohort Study" ASBMR 2018; Abstract 1005.