Abstract
Bisphosphonates are first-line therapy for osteoporosis, with alendronate, risedronate, and zoledronate as the main treatments used globally. After one year of therapy, bisphosphonates are retained in bone for extended periods with extended anti-fracture effects after discontinuation. Due to this continued fracture protection and the potential for rare adverse events associated with long-term use (atypical femoral fractures and osteonecrosis of the jaw), a drug holiday of two to three years is recommended for most patients after long-term bisphosphonate therapy. The recommendation for a drug holiday up to three years is derived primarily from extensions of pivotal trials with alendronate and zoledronate and select surrogate marker studies. However, certain factors may modify the duration of bisphosphonate effects on a drug holiday and warrant consideration when determining an appropriate time off-therapy. In this narrative review, we recall what is currently known about drug holidays and discuss what we believe to be the primary considerations and areas for future research regarding drug holiday duration: total bisphosphonate exposure, type of bisphosphonate used, bone mineral density and falls risk, and patient sex and body weight.
Highlights
Osteoporosis is a disease characterized by low bone mineral density (BMD) and increased fracture risk
We summarize what is currently known about bisphosphonate drug holidays and outline four considerations that may influence clinical decision-making and future research regarding the duration of a bisphosphonate drug holiday once initiated
All fracture risk factors are important to consider when initiating the drug holiday, here we focus on factors that are most likely to change during a drug holiday
Summary
Osteoporosis is a disease characterized by low bone mineral density (BMD) and increased fracture risk. Extensions of randomized controlled trials have shown that for many patients, the risk of most types of fracture does not increase after discontinuation of long-term alendronate therapy [14] Given these anti-fracture effects after stopping treatment, guidelines advise that patients at a low to moderate risk of fracture undergo a two- to three-year drug holiday from bisphosphonate treatment after three to five years of therapy [11,17,18]. Drug holidays are discouraged with non-bisphosphonate osteoporosis treatments, denosumab, due to short-lived anti-fracture effects after discontinuation [17,19,20], and rebound vertebral fracture risk [21,22,23]. Initiating a drug holiday following bisphosphonate therapy among patients at low to moderate fracture risk is generally accepted, many questions remain regarding the optimal duration. We summarize what is currently known about bisphosphonate drug holidays and outline four considerations that may influence clinical decision-making and future research regarding the duration of a bisphosphonate drug holiday once initiated
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