Hayes et al.  recently reported a study that aimed at examining the comparative risks of drug holidays after long-term (≥3 years, 80% adherence) oral bisphosphonate treatment. This was a population-based cohort study that used province-wide health care administrative databases that provided comprehensive coverage to 120,000 Ontario residents aged 65 years or older. Data were collected between November 2000 and March 2020 in those who had long-term risedronate therapy and a drug holiday matched 1:1 with those who had long-term alendronate therapy and a drug holiday. Primary outcome was hip fracture within 3 years after at least 120-day ascertainment period, with exclusion of those who died, had a hip or vertebral fracture, entered long-term care, or started another osteoporosis therapy during this 120-day time window. Secondary analyses included shorter follow-up and sex-specific estimates. A total of 25,077 propensity score-matched pairs were eligible (average age 81 years; 81% women). Hip fracture rates were higher among risedronate than alendronate drug holidays (12.4 and 10.6 events, respectively, per 1,000 patient-years). The association was attenuated with shorter drug holidays (1 year: HR, 1.03 [95% CI, 0.85-1.24]; 2 years: HR, 1.14 [95% CI, 0.96-1.32]). Finally, the researchers concluded that drug holidays after long-term treatment with risedronate were associated with a small increase in risk for hip fracture compared to alendronate drug holidays. The authors noted that they used health care administrative data that did not contain certain important fracture risk factors, which were therefore not included in the study analyses.
Among the most important questions relevant to chronic medication therapy are the following: is treatment meant to be taken for life? Or should we stop it after a while, and if so, when? Bisphosphonates are the pillar medications for prevention and treatment of osteoporosis. Their effect on bone strength starts slowly after initiation of therapy and accumulates throughout several years, and then stabilizes . The study of Hayes et al.  was not aimed at collecting fracture data on the active treatment phase. On the other hand, there is a concern related to potential side-effects of this therapy . Osteonecrosis of the jaw occurs infrequently (1 in 10,000–100,000 patient-years), and a duration-dependent risk of sub-trochanteric or femoral shaft fractures with atypical radiologic features becomes evident after 2 to 3 years of therapy, with an incidence of about 1 in 1,000 patients after 8 to 10 years of therapy. Despite the uncommon occurrence of such adverse events, this serves as a reason for stopping treatment after 5-7 years and entering what has received a nick-name of “drug holiday”. The other issue to be considered is the fact that protection from fracture wane slowly (over 1–5 years) when treatment is stopped. This is the reason why population studies, like that of Hayes et al.  are needed. I don’t think that the data comparing alendronate with risendronate are so important, since as the authors themselves have stated “we emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy”. The important findings are those related to the effect of the drug holiday period on fracture risk. During the 3-year follow-up, 3.3% of all patients had a hip fracture (11.5 hip fractures per 1000 person-years).
Thus, both bisphosphonate therapy and drug holiday have pro’s and cone’s and in each and every patient all these factors must be weighed against the individual degree of fracture risk, and a rational decision if and when to withhold therapy and for how long this should be done. The 2021 NAMS position statement  includes detailed information on this complex issue and summarizes the options for the post drug holiday strategy in high-risk patients as follows: “continuing on the bisphosphonate or switching to denosumab or an osteoanabolic agent is recommended”.
Amos Pines, MD
Sackler Faculty of Medicine, Tel-Aviv University, Israel
- Hayes KN, Brown KA, Cheung AM, Kim SA, Juurlink DN, Cadarette SM. Comparative Fracture Risk During Osteoporosis Drug Holidays After Long-Term Risedronate Versus Alendronate Therapy: A Propensity Score-Matched Cohort Study. Ann Intern Med. 2022;175(3):335-343.
- Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab. 2010;95(4):1555-65.
- Management of Osteoporosis in Postmenopausal Women: The 2021 Position Statement of The North American Menopause Society’’ Editorial Panel. Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. 2021;28(9):973-997.
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