Deciphering Fracture Risk: A Comprehensive Analysis of Blood Metabolites via Mendelian Randomization.

Purpose: The study aims to explore the complex relationship between plasma metabolites and fracture risk, addressing the gap in comprehensive analysis of 1,400 plasma metabolites and their potential causal association with fracture risk. Methods: The study employed bidirectional Mendelian Randomization (MR) analysis using data from European ancestry GWASs. It examined the potential causal relationships of 1,400 unique blood metabolites with fracture risk, using various statistical tols and sensitivity analyses in R language. Results: The study identified 89 metabolites significantly associated with fracture risk, with 36 showing protective effects and 53 as risk factors. The study identified 89 metabolites significantly associated with fracture risk. Of these, 36 showed a protective effect (OR < 1) and 53 were identified as risk factors (OR > 1). Three metabolites demonstrated consistent associations across various methods: (1) 2R3R-dihydroxybutyrate showed a positive effect on fracture risk with an OR of 1.005 (p = 0.0002, 95% CI: 1.002 to 1.008) using the IVW method. Other methods, including MR-Egger and weighted median, did not show significant results. (2) 1-stearoyl-2-arachidonoyl-gpc (18:0/20:4) had a consistent positive association with fracture risk across different methods, with an OR of 1.003 (p = 0.0003, 95% CI: 1.001 to 1.005) using IVW. Similar results were obtained with MR-Egger and weighted median methods. (3) Adenosine 5'-diphosphate (ADP) to glycerol 3-phosphate ratio showed a positive association with an OR of 1.006 (p= 0.00003, 95% CI: 1.003 to 1.009) using IVW. However, the MR-Egger and other methods did not show statistical significance. Conclusions:The study provided new insights into the biochemical mechanisms of fractures, highlighting the significant role of specific metabolites in fracture risk. It suggests potential targets for future fractures prevention and treatment strategies.