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Bisphosphonate ‘holidays’ exceeding 2 years linked to increased fractures



– Older women on bisphosphonate treatment for at least 3 years who then stopped taking the drug showed a 40% increased risk for hip fracture after they were off the bisphosphonate for more than 2 years, compared with women who never stopped using the drug, according to an analysis of more than 150,000 women in a Medicare database.

The implication of this observational-data finding is that drug holidays from a bisphosphonate regimen “may not be appropriate for all patients,” Kenneth G. Saag, MD, said at the European Congress of Rheumatology.

The finding seems to dispute a recent recommendation from the American College of Physicians (Ann Intern Med. 2017 June 6;166[11]:818-39) that drug treatment to prevent bone fractures in osteoporotic women should stop after 5 years, noted Dr. Saag, a rheumatologist and professor of medicine at the University of Alabama, Birmingham. The median duration of bisphosphonate treatment in the studied cohort before the drug use stopped was 5.5 years.

“Drug holidays [from a bisphosphonate] have become increasingly common” because of concerns about potential adverse effects from prolonged, continuous bisphosphonate treatment, especially the risk for osteonecrosis of the jaw and atypical femoral fractures, he said. These bisphosphonate stoppages are sometimes permanent and sometimes temporary, Dr. Saag noted. Ideally, assessment of the risks and benefits from a bisphosphonate drug holiday should occur in a randomized study, but in current U.S. practice such a trial would be “impossible because there is not equipoise around the decision of whether or not to stop,” he said.

Dr. Kenneth G. Saag, professor of medicine, University of Alabama, Birmingham Mitchel L. Zoler/MDedge News

Dr. Kenneth G. Saag

To try to gain insight into the impact of halting bisphosphonate treatment with observational data, Dr. Saag and his associates used records collected by Medicare on 153,236 women who started a new course of bisphosphonate treatment and remained on it for at least 3 years during 2006 to 2014. When selecting these women, the researchers also focused on those with at least 80% adherence to their bisphosphonate regimen, based on prescription coverage data. The analysis censored women who also received other treatments that can affect bone density, such as estrogen or denosumab (Prolia, Xgeva). The average age of the women was 79 years; two-thirds were aged 75 years or older. The median duration of follow-up information after bisphosphonate stoppage was 2.1 years. Forty percent of the women stopped their bisphosphonate treatment for at least 6 months, and 13% of the women who stopped treatment subsequently restarted a bisphosphonate drug. The most commonly used bisphosphonate was alendronate (Fosamax, Binosto), used by 72%, followed by zoledronic acid (Reclast, Zometa), used by 16%.

The analysis divided women who stopped their bisphosphonate treatment into subgroups based on the duration of stoppage, and showed that the rate of hip fracture was 40% higher among women who stopped treatment for more than 2 years but not more than 3 years, compared with the women who never interrupted their bisphosphonate treatment, a statistically significant difference, Dr. Saag said. In contrast, among women who halted bisphosphonate treatment for more than 1 year but not more than 2 years, the hip fracture risk was 20% higher than that of nonstoppers, also a statistically significant difference. These and all the other analyses the researchers ran adjusted for the possible impact from baseline differences in several demographic and clinical variables.

Dr. Saag cautioned that while the relatively increased risk for hip fracture from a prolonged halt to bisphosphonate treatment was 40%, the absolute increase in risk was “relatively modest,” representing an increased fracture rate of 0.5-1 additional fractures during every 100 patient years of follow-up.

For the endpoint of major osteoporotic fracture at any location, the risk was 10% higher among women who stopped treatment for more than 2 years but not for longer than 3 years, compared with nonstoppers.

The researchers also focused on two key subgroups. Among women who only took alendronate, a drug holiday of more than 2 years was linked with a statistically significant 20% rise in hip fractures, compared with women who never stopped the drug. And among the 4% of studied women who had a history of a bone fracture because of bone fragility, stoppage of their bisphosphonate treatment for more than 2 years doubled their hip fracture rate, compared with similar women who did not stop their treatment.

The study received no commercial funding. Dr. Saag has been a consultant to and has received research funding from Amgen, Lilly, and Radius.

SOURCE: Curtis J et al. EULAR 2018 Congress, abstract OP0017.

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