The regulatory effects of PD-1/PD-L1 inhibitors on bone metabolism: opportunities and challenges in osteoporosis management

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.