Rethinking Denosumab Discontinuation: State of the Art and Proposal of an Innovative Algorithm for Fracture Risk Management Post-Denosumab
Year: 2025
Type: preprint
Abstract: Background. Denosumab discontinuation is associated with a sharp rebound in bone turnover and increased incidence of (multiple vertebral) fractures within months. Current strategies often rely on a fixed serum C-terminal telopeptide (CTX) threshold to guide antiresorptive re-initiation, but are 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 for osteoporosis. 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 can lead to a substantial risk of overtreatment or missed intervention. Our proposed delta-RCV framework interprets significant CTX changes based on intra-individual variability, and it integrates with complementary tools for bone status evaluation. Conclusion. Our dynamic, patient-specific approach based on CTX trajectories, RCV thresholds, and multimodal risk stratification may improve treatment timing, and reduce fracture risk postdenosumab. Due to these complexities, a careful and planned denosumab prescription and discontinuation, should be mandatory.
Authors: M, Filippo Maria Bolamperti, Alberto Vassallo, Gaia Tamellini, Luca Acanfora
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4413638607