Unveiling the efficacy predictors and potential mechanisms of Semen Cuscutae against osteoporosis via machine learning and meta-analysis: a preclinical study

Purpose To systematically evaluate the anti-osteoporotic efficacy and underlying mechanisms of Semen Cuscutae and to explore potential experimental factors associated with treatment efficacy using an integration of meta-analysis and machine learning (ML). Methods A comprehensive search of eight databases (from inception to December 1, 2025) was conducted to identify randomized controlled trials of Semen Cuscutae in osteoporotic animal models. Meta-analysis was performed to assess Bone Mineral Density (BMD), bone histomorphometry, and inflammatory/metabolic markers. Additionally, an exploratory XGBoost model interpreted via SHapley Additive exPlanations (SHAP) was constructed to quantitatively rank ten experimental variables potentially associated with therapeutic efficacy. Results Fifteen studies were included in the final analysis. Meta-analysis demonstrated that Semen Cuscutae intervention significantly increased femoral and lumbar spine BMD, improved trabecular micro-architecture (increased BV/TV and Tb.Th; decreased Tb.Sp), and enhanced biomechanical strength. Mechanistically, Semen Cuscutae remodeled the osteoimmune microenvironment by suppressing pro-inflammatory cytokines (IL-6) and bone resorption markers (TRACP, CTX, RANKL), while ALP showed an increasing trend and osteogenic or reparative factors, including OPG, IGF, and TGF-β, were significantly upregulated. Exploratory ML analysis ranked “Species,” “Dose,” and “Treatment Duration” as the variables most strongly associated with therapeutic efficacy within the current dataset. Specifically, rat models exhibited superior therapeutic responsiveness compared to mice, and gender showed minimal predictive weight. Conclusion Semen Cuscutae exerts robust osteoprotective effects via coupled anti-inflammatory and osteogenic mechanisms. The exploratory ML-derived ranking suggests that species-specific dose scaling and treatment duration may be important considerations for future preclinical and translational studies of Semen Cuscutae . Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420261397983.