Purpose of the Review <p>Denosumab (Dmab) is a human monoclonal anti-RANKL antibody that inhibits osteoclast-mediated bone resorption and sequentially improves bone mineral density (BMD) status. Although various treatment options are available for osteoporosis management, a rebound phase following Dmab discontinuation has emerged as a major crisis in osteoporosis care. The review examines and summaries the latest evidences on the molecular- and cellular mechanisms underlying rebound bone resorption and discuss potential therapeutic strategies to mitigate the adverse rebound resorption complications associated with Dmab discontinuation.</p> Recent Findings <p>Studies highlight the osteocyte–OPG axis as a key regulator of rebound resorption, alongside rapid activation of the osteoclast precursor pool in Dmab withdrawal, can promote RANKL-mediated osteoclastogenesis. In osteocytes, enhanced release of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), can intensify the adverse effects associated with rebound resorption. Recent work suggests that OPG-Fc fusion proteins could help restore RANKL–OPG balance, though their clinical utility remains to be explored. Pilot studies indicate that optimizing the timing of sequential therapy and exploring combinational regimens with denosumab with osteoanabolic or estrogen-modulating agents may offer promising strategies to prevent rebound bone loss, compared to monotherapy; however, long-term validation is required.</p> Summary <p>Although recent studies have provided insights into the mechanisms underlying rebound resorption following denosumab withdrawal, the precise molecular signalling remain incompletely understood. This gap in knowledge limits the development of optimal strategies for maintaining BMD and preventing fractures in osteoporosis management. Further research, including the exploration of novel sequential or combination therapies, is essential to mitigate rebound associated complications and improve long-term skeletal health.</p>