Effectiveness of Sequential Treatment with Zoledronic Acid Following Discontinuation of Denosumab in Osteoporosis: A Narrative Review

Denosumab is a recently developed anti-osteoporosis agent widely applied in the treatment of osteoporosis in postmenopausal women. As a potent inhibitor of bone resorption, it significantly increases bone mineral density, lowers elevated bone turnover rates, and reduces fracture risk. Because denosumab does not bind to the bone matrix, its effects decrease rapidly after discontinuation, a process commonly known as the "rebound effect." Research has shown that administering zoledronic acid after stopping denosumab can help preserve bone density and reduce the likelihood of vertebral fractures. However, the exact effectiveness of this sequential approach and the factors influencing it, including the duration of prior denosumab treatment, timing, and frequency of zoledronic acid administration, remain insufficiently understood. To address these uncertainties, this review evaluates the effects of sequential zoledronic acid therapy on subsequent changes in bone density, bone turnover markers, fracture risk, and adverse reactions. We also examined in detail the dosage strategies, administration intervals of zoledronic acid, and length of preceding denosumab use across studies, aiming to assist clinicians in designing more evidence-based and clinically relevant sequential treatment protocols.