ITAM-Syk signaling mediates the rebound phenomenon after anti-RANKL antibody discontinuation.

Rebound bone loss following discontinuation of antiresorptive therapy, especially denosumab, represents a major clinical issue due to rapid osteoclast activation and increased fracture risk. However, the molecular basis of this phenomenon remains poorly understood. In this study, we investigated the role of the DAP12/TREM2-Syk signaling pathway in rebound-associated bone resorption using a murine model treated with and withdrawn from a RANKL-neutralizing antibody. Wild-type (WT) mice exhibited marked rebound bone loss, with elevated expression of DAP12/TREM2-related genes (Tyrobp and Trem2), increased infiltration of CD206