Traditional Chinese medicine regulating Wnt/β-catenin and OPG/RANKL/RANK pathways in osteoporosis: a narrative review based on bone coupling and pathological subtype differences.

BACKGROUND: Osteoporosis (OP) is characterized by bone coupling imbalance-insufficient osteoblast-mediated formation and excessive osteoclast-mediated resorption. Among multiple signaling networks involved in bone remodeling, the canonical Wnt/beta-catenin pathway and the osteoprotegerin/receptor activator of nuclear factor-kappaB ligand/receptor activator of nuclear factor-kappaB axis, namely the OPG/RANKL/RANK axis, were selected because they represent two central and mutually interacting regulatory systems governing osteoblast differentiation and osteoclastogenesis. Traditional Chinese Medicine (TCM) offers multi-target potential for regulating bone homeostasis.

OBJECTIVE: This narrative review examines TCM interventions targeting Wnt/β-catenin and OPG/RANKL/RANK pathways in OP, emphasizing bone coupling and pathological subtype differences.

METHODS: Structured literature searches (PubMed, Web of Science Core Collection, CNKI, Wanfang, cqVIP; 2000-2025) with OCEBM/SYRCLE evidence grading were conducted.

CONCLUSION: TCM suggests bidirectional bone coupling regulation through multi-target mechanisms, but evidence remains predominantly preclinical (Levels 4-5). Pharmacokinetic barriers (low oral bioavailability of icariin, berberine), safety concerns (Xianling Gubao hepatotoxicity), and lack of fracture-endpoint RCTs limit clinical translation. Future research should prioritize target-engagement biomarkers, bone-targeted delivery, and adequately powered RCTs.