Managing Rebound Bone Loss After Denosumab Discontinuation: Mechanisms, Risk Stratification, and Sequential Therapy

Abstract: Denosumab is a fully human monoclonal antibody targets receptor activator of nuclear factor kappa-&Bgr; ligand (RANKL), potently suppresses bone resorption, increases bone mineral density (BMD), and reduces vertebral, hip, and non-vertebral fracture risk. However, its pharmacokinetic reversibility renders discontinuation clinically hazardous. This narrative review synthesizes current evidence on the mechanisms, clinical consequences, and risk determinants of rebound bone loss following denosumab discontinuation and critically evaluates available preventive strategies. Upon denosumab cessation, rapid restoration of RANKL bioavailability triggers a pathological osteoclast overshoot, driven by accumulated osteoclast precursors and unopposed RANK-RANKL signaling. The resulting rebound in bone turnover produces accelerated BMD loss and markedly elevated multiple vertebral fracture risk, with real-world cohorts documenting incidences of up to 10% within 12-18 months of unmanaged cessation, and hip and vertebral fractures in this setting have been associated with substantial excess mortality in observational studies. Sequential antiresorptive therapy, principally intravenous zoledronic acid or oral alendronate, is the most widely recommended approach; risedronate consistently fails to provide adequate skeletal protection. Treatment duration critically modulates rebound severity, with longer denosumab therapy, particularly beyond approximately three years is associated with greater post-discontinuation bone loss and reduced protection from a single bisphosphonate infusion, warranting intensified monitoring and management in this group. Anabolic agents, including teriparatide, are generally not recommended as primary sequential therapy, whereas romosozumab is promising only when initiated early in carefully selected patients. Serial serum C-terminal telopeptide (CTX) monitoring provides a practical framework for guiding therapeutic transitions and identifying inadequate bone turnover suppression. Safe denosumab management requires structured, individualized planning that integrates risk stratification, biochemical monitoring, and a pre-defined sequential therapy strategy established at the time of prescription, not at the point of cessation. Keywords: osteoporosis, denosumab discontinuation, rebound bone loss, sequential therapy, vertebral fractures, bone turnover markers, serum CTX