Mechanisms and management strategies for exacerbated bone loss following denosumab discontinuation

Denosumab is a first-line therapy for osteoporosis, yet the rebound increase in bone turnover markers, rapid bone loss, and elevated fracture risk following its discontinuation have become major challenges in clinical management. This review systematically summarizes the potential mechanisms underlying exacerbated bone loss after denosumab withdrawal and the corresponding sequential treatment strategies. Current mechanistic studies have focused on several hypotheses, including the accumulation of osteomorphs and osteoclast precursors, imbalance in the RANKL/OPG ratio, uncoupling of bone remodeling, and osteocyte-mediated aberrant microdamage repair, which collectively contribute to the burst activation of bone resorption upon treatment cessation. To address this risk, international consensus recommends proactive sequential antiresorptive therapy for patients discontinuing denosumab. For short-term users (≤2.5 years), sequential administration of a single dose of zoledronic acid or alendronate can effectively preserve bone mineral density. For long-term users (>2.5 years), zoledronic acid should be initiated 6 months after the last dose, accompanied by intensive monitoring based on bone turnover markers and repeated dosing as needed. Additionally, emerging strategies such as early transition to romosozumab or alternating use with bisphosphonates have shown potential. Future studies are required to validate the underlying mechanisms in humans and to optimize sequential treatment regimens through prospective trials, thereby enabling individualized therapy and safe discontinuation.