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For osteoporosis, should medications take a holiday?
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A drug holiday is used for multiple medications, from those used to treat HIV to osteoporosis. The word “holiday” can be misleading in osteoporosis therapy, as it connotes that the break in treatment is transient.
Bisphosphonates differ from many medications in that they persist in the bone for years and are still released over a number of years, even long after administration. Thus, there is apparently a persisting anti-fracture effect, even after the medication is discontinued. Along with concern over serious, albeit rare side effects (such as osteonecrosis of the jaw), as a result, some have suggested the use of drug holidays. If one is used, how long should the drug holiday be? Data from multiple randomized, placebo-controlled trials have shown that bisphosphonates are generally safe, are well tolerated and effectively reduce fracture risk over 3 to 5 years. Long-term effects are less clear.
Evidence from extension trials are conflicting, but seem to suggest that there are no long-term benefits of using bisphosphonates after 5 years. An example is the FLEX study, which studied 10 years of alendronate compared with 5 years in more than 1,000 postmenopausal women. Ten years of bisphosphonate treatment in women with low or moderate fracture risk did not significantly reduce asymptomatic vertebral fractures.
Diab and Watts advocate stratifying according to fracture risk:
- Low fracture risk: do not treat; discontinue bisphosphonate if it was started. Consider restarting if patient meets guidelines.
- Mild fracture risk: stop treatment after 3 to 5 years. Continue the drug holiday until the patient sustains a fracture or there is a significant loss of bone mineral density
- Moderate fracture risk: After treating for 5 to 10 years, consider a 3- to 5-year drug holiday. This may be curtailed if a fracture or significant decline in BMD occurs.
- High fracture risk: Treat for 10 years, offer a 1- to 2-year drug holiday, then treat the same as mild and moderate fracture risk.
Although an increase in bone turnover markers (BTM) or a decline in BMD has been advocated as a guide to when to end a drug holiday, there is insufficient data on whether these changes point to fracture risk. Diab and Watts ultimately advise using clinical judgment, although they acknowledge that BMD and BTM are used to guide decisions on when to end a drug holiday.
Edward C. Chao
An abstract presented at the American Society for Bone and Mineral Research annual meeting examined 28,620 women in a retrospective cohort study. Women aged at least 45 years on bisphosphonates for 3 or more years, and who had taken at least a 12-month drug holiday, were compared with those who had at least a 50% adherence rate.
A drug holiday was associated with an unadjusted rate ratio of 0.87 (95% CI, 0.81-0.94) for fractures related to osteoporosis. For hip fractures only, the rate ratio was 1.0 (95% CI, 0.9-1.2). There were no differences in risks for any fracture or hip fractures only. The hazard ratios for any osteoporosis-related fracture and hip fracture were 0.9 (95% CI, 0.8-1) and 0.84 (95% CI, 0.68-1.03), respectively, after adjusting for comorbidities, baseline fall and fracture risk, and other bone-active medication.
Expert opinion and uncertainty are the dominant themes of this topic. We should consider other factors, such as patient preference. We await more research.
Black DM. JAMA. 2006;296:2927-2938.
Diab DL. Ther Adv Musculoskelet Dis. 2013;5:107-111.
Edward C. Chao, DO, is associate professor of clinical medicine at University of California, San Diego, and staff physician at VA Medical Center, San Diego. He reports no relevant financial disclosures.