Bisphosphonate drug holidays: we reap what we sow.

Abstract

The concept that our patients need to interrupt or stop bisphosphonate therapy for osteoporosis after 5 years of oral bisphosphonate therapy and after 3 years of intravenous bisphosphonate therapy has gained considerable traction worldwide. It has been our observation that some physicians (and even entire health authority regions) are automatically stopping bisphosphonates in patients who are taking osteoporosis medication without consideration for the patient’s risk of fracture. In addition, some physicians have mistakenly extended this concept to other antiresorptives such as raloxifene and denosumab where bone density gains are quickly lost with discontinuation. Has this concept of a bisphosphonate holiday been useful to us as clinicians and appropriate for our patients? The concept of a drug holiday seemed logical at first, based on the pharmacokinetics of bisphosphonates and concerns about long-term adverse events. The concept became more widely discussed after long-term bisphosphonate studies such as the Fracture Intervention Trial (FIT) and Long-Term Extension (FLEX) Trial, were published [1], and the FDA published its opinion in 2011, suggesting reevaluation of the need for continued bisphosphonate therapy beyond 3–5 years in individual patients not at high risk [2]. Bisphosphonates have long-term residence in the bone [3]. This-long term residence in the bone means that after prolonged use, the bisphosphonate remains in the bone and due to reduced bone turnover is slowly excreted and recycled, resulting in a persistent but waning antiresorptive effect [4]. We have learned about the incidence of rare side effects with long-term therapy. The incidence of these side effects (osteonecrosis of the jaw [ONJ] and atypical femoral fracture [AFF)]) is rare and increases with exposure with an inflection point of 4 years for ONJ [5] and 5 years for AFF. [6] The American Society for Bone and Mineral Research (ASBMR) (7) estimated ONJ incidence as between 1 in 10, 000 and less than 100,000 patient-treatment years [7]. The AAOMS [8] using data from Lo [5] estimated 210/100,000 patient years. The incidence of AFF appears related to duration of exposure. Dell [6] using radiographic review of claims data found a rate of AFF of 2/100,000 after 2 years exposure and 78/100,000 after 8 years of exposure. Schilcher (9) estimated an incidence rate of 50/100,000 person years. Furthermore, it is not clear that BP discontinuation reduces AFF risk in the first years after discontinuation. Although one observational study estimated a 70 % reduction in risk of AFF with every year after discontinuation [9], in a subsequent more detailed report from the same group [10] it appears that this estimate, which is based on short-term drug data, is derived from a case–control analysis comparing conventional femoral shaft fractures with atypical fractures. Thus, a drug holiday could shift the balance towards typical rather than atypical Members of the International Osteoporosis Foundation Epidemiology/ Quality of Life Working Group include: B Abrahamsen, J Adachi, F Borgstrom, O Bruyere, P Clark, C Cooper, E Dennison, M Diaz Curiel, HP Dimai, N Harvey, M Hiligsmann, JA Kanis, E Lau, P Lips, ME Lewiecki, E Lorenc, E McCloskey, A Papaioannou, D Prieto Alhambra, S Ortolani, S Silverman, M Sosa, P Szulc, and N Yoshimura