Impact of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk: real-world evidence from a retrospective cohort study

UNLABELLED: Bisphosphonate drug holidays can reduce rare adverse effects, but their skeletal impact is unclear. In this retrospective cohort study, ALN holiday caused modest BMD loss and BTMs rise without increased fracture risk; effects of ZOL holiday were minimal. This study suggests bisphosphonate drug holidays are safe for selected patients with regular monitoring. PURPOSE: Bisphosphonate (BP) drug holiday prevents rare adverse effects of BPs in osteoporotic patients, but its effect on bone mineral density (BMD), bone turnover markers (BTMs), and fracture risk is still unclear. This study aimed to investigate BMD/BTM variations and clinical fracture risk for patients undergoing BP drug holidays. METHODS: In this single-center retrospective cohort study, patients who received ≥4.5 years of alendronate (ALN) or ≥3 doses of zoledronate (ZOL) were included. BMD at the lumbar spine (LS), femoral neck (FN), and total hip (TH), BTMs, and 3-year fracture incidence were assessed between drug holiday (ALN: n = 71; ZOL: n = 20) and ongoing treatment groups (ALN: n = 59; ZOL: n = 47). RESULTS: Compared with ongoing ALN therapy, initiating drug holiday resulted in moderate declines in BMD at LS (-2.23%, 95% CI: -3.70% to -0.76%), TH (-1.62%, 95% CI: -2.68% to -0.56%), and FN (-1.89%, 95% CI: -3.49% to -0.28%) within 1 year. BTMs all rose significantly over 1 year, yet remained below pretreatment levels for at least 3 years. In contrast, there were no significant differences in BMD (1-year LS: -0.47%, 95% CI: -2.38% to 1.43%, TH: -1.07%, 95% CI: -2.77% to 0.64%) and BTM changes between ZOL groups at 1- and 2-year follow-up. No significant differences in clinical fragility fractures were observed between ALN groups (9.9% vs. 6.8%; HR 1.45) and ZOL groups (5% vs. 6.4%). CONCLUSION: Our findings support that BP drug holidays are feasible for selected patients with adequate BMD. ZOL conferred more sustained skeletal protection than ALN, particularly at the LS, whereas ALN discontinuation was associated with earlier and more pronounced BMD decline and BTM elevation; annual monitoring of BMD and BTMs appears particularly important during the ALN drug holiday period.