Duration of Bisphosphonate Drug Holidays in Osteoporosis Patients: A Narrative Review of the Evidence and Considerations for Decision-Making

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.