Unveiling the Causal Relationship Between Osteoporosis and Circulating Metabolites from a Genetic Perspective

Objectives: Osteoporosis (OP) is a major public health concern characterized by increased bone fragility.This study aimed to investigate the causal relationship between circulating metabolites, particularly lipid-related metabolites, and OP using Mendelian Randomization (MR).Methods: A bidirectional two-sample MR approach was applied using summary statistics from large-scale Genome-Wide Association Studies (GWAS) comprising 484,598 individuals of European ancestry.Genetic variants associated with circulating metabolites were selected as instrumental variables.Causal effects were estimated using inverse variance weighting (IVW), weighted median, and MR-Egger methods.Sensitivity analyses were conducted to assess heterogeneity and pleiotropy.Results: MR analyses indicated a potential causal relationship between higher levels of monounsaturated fatty acids (MUFA) and a reduced risk of OP (OR = 0.997; 95% CI: 0.994-0.999;P = 0.013).Conversely, increased total lipids in lipoprotein particles were associated with a higher OP risk (OR = 1.002; 95% CI: 1.000-1.004;P = 0.031).In addition, OP was inversely associated with total lipids (OR = 0.269; 95% CI: 0.095-0.759;P = 0.013) and triglycerides (OR = 0.259; 95% CI: 0.090-0.745;P = 0.012) in chylomicrons and extremely large very-low-density lipoproteins.No evidence of pleiotropy or heterogeneity was detected.Conclusion: This study provides genetic evidence for causal links between lipid metabolism and OP, suggesting that circulating lipid metabolites may serve as potential biomarkers for risk stratification and prevention.