The causality between plasma lipid types and osteoporosis: a bi-directional two-sample Mendelian randomization study

Abstract Background Previous research has shown an association between lipid metabolism and skeletal health; however, the causal direction between specific plasma lipid types and osteoporosis remains unclear. Here, we evaluated the causal relationship between 179 plasma lipid types and osteoporosis-related phenotypes, including quantitative heel ultrasounds (eBMD) and fractures, through bi-directional Mendelian randomization (MR). Methods Genetic instruments from large-scale genome-wide association studies (GWAS) were used to conduct a two-sample MR analysis to determine causality. A total of 179 plasma lipid data from a comprehensive GWAS dataset and osteoporosis-related phenotypic data (including eBMD and fractures) from the GEFOS consortium were included in the analysis. Bi-directional MR analysis was employed to test the direction of causality. Results Several significant causality between lipid species and osteoporosis-related phenotypes were identified. Specifically, certain phosphatidylcholines and sterol esters were significantly associated with increased fracture risk. In this study, sterol ester (27:1/20:4) levels (OR [95% CI] = 1.038 [1.019, 1.057], P = 8.95E-05), phosphatidylcholine (20:4_0:0) levels (OR [95% CI] = 1.051 [1.027, 1.076], P = 3.58E-05), and phosphatidylcholine (17:0_20:4) levels (OR [95% CI] = 1.049 [1.025, 1.073], P = 5.73E-05) resulted as risk factors for osteoporotic fractures, highlighting the complex role of lipid metabolism in skeletal health. Conversely, the protective effect of sterol ester (27:1/20:3) levels on eBMD (OR [95% CI] = 0.966 [0.952, 0.980], P = 3.30E-06) suggested potential therapeutic targets for osteoporosis management. Conclusion Our MR analysis revealed causal relationships between specific plasma lipid species and osteoporosis-related phenotypes. These findings provide new insights into the causal pathways between plasma lipids and osteoporosis, highlighting the therapeutic potential of lipid modulation, furthering the understanding of osteoporosis pathophysiology, and laying the foundation for targeted interventions.