Denosumab Discontinuation: the Abaloparatide plus Bisphosphonate Metronomic Sequential Approach
Year: 2025
Type: preprint
Abstract: Background . Discontinuing denosumab (Dmab) causes a rapid increase in bone resorption, loss of bone mineral density (BMD), and clusters of rebound-associated vertebral fractures (RAFV). Current approaches, such as intravenous (IV) zoledronate (Zol), oral bisphosphonates (BPs), teriparatide (TPTD), romosozumab (Romo), selective estrogen receptor modulators (SERMs), and menopausal hormone therapy (MHT), have failed to provide protection consistently. Methods . We conducted a brief narrative review of randomized controlled trials (RCTs), observational cohorts, and mechanistic studies, as well as expert position papers (2015-2025), that focused on post-Dmab strategies and mechanistic models of remodeling. Results . Evidence consistently shows that Zol often requires repeated infusions and fails to prevent BMD decline or RAFV, especially after long-term Dmab therapy. Oral BPs are weaker and have limited adherence, TPTD worsens rebound resorption, and Romo provides only modest benefits. SERMs and MHT are largely ineffective. Once RAFV occurs, clinical outcomes remain poor despite rescue therapy. S. Bolamperti et al. suggested that complete osteoclast suppression abolishes coupling signals essential for bone formation, while BPs cannot neutralize osteomorph-driven resorption. Hypothesis . We suggest that a metronomic BP regimen (low doses or extended intervals), combined (initially) with abaloparatide (Abalo) and guided by personalized monitoring of the C-terminal telopeptide of type I collagen (CTX), may limit osteoclast activity without stopping anabolic signaling, thus preventing fractures and maintaining bone-forming capacity. Conclusions : A biologically informed, modulatory approach is a promising hypothesis that warrants future clinical testing and could redefine the paradigm of post-Dmab osteoporosis management.
Authors: M, Alberto Vassallo, Fanny Valsecchi, Filippo Maria Bolamperti
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4413919562