Complement dysregulation in osteoporosis: a novel mechanism of osteoimmunology

Osteoporosis is a multifactorial metabolic bone disease characterized by bone remodeling imbalance, chronic inflammation, hormonal dysregulation, and immune microenvironment disturbance. Recent studies in osteoimmunology have revealed that the complement system, beyond its traditional anti-infective function, plays a crucial role in bone metabolism. Activation products such as C3a and C5a generated through the classical, lectin, and alternative pathways directly regulate the differentiation and function of osteoblasts and osteoclasts, thereby influencing bone remodeling. Complement also modulates the bone marrow microenvironment by regulating the lineage commitment and immunoregulatory capacity of BMSCs. Dysregulated complement activation interacts with age-related changes including chronic inflammation, estrogen deficiency, and immune reprogramming, constituting an important mechanism in osteoporosis. Evidence from animal and clinical studies further indicates that targeting C3/C5 and their receptors holds therapeutic potential to mitigate bone loss and enhance bone regeneration. This review highlights the central role of complement in bone metabolism and osteoporosis progression, and discusses its prospects as a therapeutic target, offering new perspectives for immune-based interventions.