OBJECTIVES: This study aims to investigate the causal relationship between genetically predicted blood metabolites and osteoporotic fracture risk in individuals aged over 60 years, focusing on their role in bone metabolism and osteoporosis (OP). MATERIALS AND METHODS: Using Mendelian randomization (MR), we analyzed 1,400 blood metabolites selected for their involvement in metabolic and inflammatory pathways relevant to bone health. Bone mineral density (BMD) at the femoral neck served as a proxy for fracture risk, with reduced BMD defined as T-score ≤-1.0. Fourteen metabolites were associated with osteopenia, determined by T-score being lower than -1 at the femoral neck. The genome-wide association study (GWAS) data from the European Bioinformatics Institute (GCST005349) included 22,504 cases and 23.7 million SNPs from individuals of European ancestry aged ≥60 years. Genetic associations were evaluated using Inverse Variance Weighted (IVW), MR-Egger, and MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods. RESULTS: After stringent screening, 14 metabolites were significantly associated with OP risk (p<
0.05, false discovery rate [FDR] <
0.2). The AMP-to-alanine ratio (odds ratio [OR]=0.900, 95% confidence interval [CI]: 0.845-0.958) was protective, while tauro-beta-muricholate (OR=0.855), glycosyl-N-stearoylsphingosine (OR=1.065), and the mannose-to-glycerol ratio (OR=1.116) increased risk. Sensitivity analyses confirmed robust results without heterogeneity or pleiotropy. CONCLUSION: This study identifies blood metabolites as potential causal markers for osteoporotic fracture risk, offering insights for risk assessment and prevention in the elderly.