Preclinical Evidence and Mechanisms of Icariin on Bone Health in Ovariectomized Rodent Models of Osteoporosis: A Systematic Review and Meta-Analysis

ETHNOPHARMACOLOGICAL RELEVANCE: Osteoporosis, particularly postmenopausal osteoporosis, is a major global health concern, and current drugs often come with serious side effects. Herba Epimedii has long been used in traditional Chinese medicine to strengthen bones. Icariin, its principal flavonoid, has shown osteoprotective potential in preclinical studies, yet a comprehensive evaluation of its efficacy remains lacking. AIM OF THE STUDY: To systematically evaluate the preclinical efficacy of icariin on bone density, microarchitecture, biomechanics, turnover markers, and its underlying mechanisms in ovariectomized (OVX) rodent models. MATERIALS AND METHODS: This study was registered with PROSPERO (CRD420261366889). A comprehensive search was conducted in PubMed, Embase, Web of Science, and Scopus up to April 16, 2026, to identify preclinical studies on icariin in OVX rodents. Effect sizes were pooled using random-effects models, and methodological quality was assessed using SYRCLE's Risk of Bias tool. RESULTS: Twenty-six studies (708 animals) were included. Icariin significantly increased femoral BMD (SMD = 1.91, 95% CI: 1.36-2.46) and lumbar spine BMD (SMD = 1.21, 95% CI: 0.80-1.63). Trabecular microarchitecture improved substantially, with increased BV/TV (SMD = 3.24), Tb.Th (SMD = 2.90), Tb.N (SMD = 2.53), and decreased Tb.Sp (SMD = -3.06), all P < 0.001. Biomechanical strength was enhanced (femur maximum load: SMD = 2.87, P = 0.002). Serum ALP (SMD = -1.55, P = 0.002), OCN (SMD = -2.87, P = 0.02), and CTX-I (SMD = -2.29, P < 0.001) were significantly reduced; TRACP-5b reduction was significant only at >100 mg/kg (SMD = -1.34, P < 0.001). Mechanistically, icariin modulates OPG/RANKL, Wnt/β-catenin, PI3K/Akt, and Nrf2/HO-1 pathways. CONCLUSION: This meta-analysis demonstrates that icariin effectively ameliorates OVX-induced bone loss in rodents, improving BMD, microarchitecture, biomechanics, and turnover markers through multiple pathways. These findings support icariin as a promising candidate for PMOP management, warranting clinical translation.