Abstract
Programmed death-1 (PD-1) and its ligand PD-L1 inhibitors have become pivotal agents in cancer immunotherapy, demonstrating significant efficacy across multiple malignancies. However, beyond regulating T cell activation, the PD-1/PD-L1 axis also exerts complex and critical effects on bone metabolism. Notably, both clinical observations and mechanistic studies have revealed a paradox: on one hand, PD-1/PD-L1 blockade appears to confer bone-protective benefits; on the other hand, it has been associated with bone-related adverse events (AEs) in up to 69% of patients, including pathological fractures and vertebral compression fractures. This review comprehensively explores the bidirectional regulatory effects of the PD-1/PD-L1 pathway on bone metabolism and investigates the underlying mechanisms contributing to these contradictory findings. The discrepancies may be attributed to a combination of clinical variables, microenvironmental conditions, cell-specific responses, and intricate interactions among multiple signaling pathways, including the Wnt/β-Catenin pathway and the PD-L1-PKM2 axis. We further examine the pathophysiological basis of osteoporosis and fragility fractures occurring during PD-1/PD-L1 inhibitor therapy, and argue for their recognition as a subclass of immune-related adverse events (irAEs). Finally, we propose a framework for bone health surveillance and stratified prevention strategies aimed at preserving antitumor efficacy while improving skeletal health and quality of life-offering novel insights into osteoporosis prevention and management in the context of immune checkpoint inhibition.