Rethinking Denosumab Discontinuation: State of the Art and Proposal of an Innovative Algorithm for Fracture Risk Management Post-Denosumab

Corresponding author: [email protected] Abstract Background. Denosumab discontinuation is associated with a sharp rebound in bone turnover and increased incidence of multiple vertebral fractures within months. Current post-discontinuation strategies often rely on a fixed serum C-terminal telopeptide (CTX) threshold of 0.28 ng/mL to guide antiresorptive re-initiation, but this cut-off is based on weak evidence and ignores patient-specific biological variability. Objective. To critically examine the limitations of CTX-guided post-denosumab management and propose a dynamic, individualized approach based on reference change value (RCV), longitudinal CTX trends, and complementary clinical tools. Methods. This narrative review integrates data from observational studies, pathophysiological principles, and clinical practice guidelines. Relevant literature was identified using PubMed, Scopus and Google Scholar, focusing on fracture risk after denosumab discontinuation, CTX, bone turnover markers (BTMs), bone mineral density (BMD), trabecular bone score (TBS), and emerging therapeutic alternatives. The delta-RCV model was developed by applying the statistical concept of biological variability to individualized CTX monitoring. Results. Evidence suggests as a fixed CTX threshold lacks specificity and sensitivity, with substantial risk of overtreatment or missed intervention. The proposed delta-RCV framework interprets significant CTX changes based on intra-individual variability (>25–30%). The model integrates CTX dynamics with complementary tools (classical and emerging) for bone status evaluation. Conclusion. A dynamic, patient-specific approach based on CTX trajectories, RCV thresholds, and multimodal risk stratification might improve treatment timing, and reduce fracture risk post-denosumab. However, in the absence of clear evidence, a cautious initial prescription is essential, and, when appropriate, extending denosumab treatment beyond the standard 10 years may be a valuable option for high-risk patients. Keywords: osteoporosis; denosumab; denosumab discontinuation; post-denosumab rebound; fracture risk; CTX; reference change value.