Abstract: BACKGROUND: Although previous studies have reported associations between lipids and the risk of osteoporotic pathological fractures, the specific causal relationships between lipid level and osteoporotic pathological fractures remain unclear. 
OBJECTIVE: To elucidate the causal relationship between lipids and osteoporotic pathological fractures using a two-sample bidirectional Mendelian randomization analysis.
METHODS: The data for 178 lipid metabolites were obtained from the IEU-GWAS database (developed by the MRC Integrative Epidemiology Unit at the University of Bristol, UK, which provides extensive summary data from genome-wide association studies), while osteoporotic pathological fracture data (from 173 619 European participants) were acquired from the FinnGen database (constructed by the Finnish national gene research program, focusing on investigating relationships between genomics and health/disease in the Finnish population). Osteoporotic pathological fracture data were used as the outcome variable, with lipids serving as exposures, for the bidirectional Mendelian randomization study to evaluate the causal effects of different lipids on osteoporotic pathological fractures. The UK Biobank database was employed as a validation set by switching the outcome variable to verify the findings horizontally.
RESULTS AND CONCLUSION: (1) The inverse variance weighted analysis indicated that each unit increase in sterol ester (27:1/20:2) levels was associated with a 25.55% increase in the risk of osteoporotic pathological fractures (odds ratio=1.256, 95% confidence interval: 1.001-1.575, P = 0.049), suggesting a significant positive correlation between elevated sterol ester levels and increased fracture risk. Reverse Mendelian randomization analysis revealed a significant negative association between osteoporotic pathological fractures and three types of phosphatidylcholine. Horizontal validation yielded consistent results, confirming sterol ester as a risk factor for osteoporotic pathological fractures. (2) The results indicate that sterol ester is a risk factor for osteoporotic pathological fractures, while phosphatidylcholine serves as a protective factor. These findings strengthen the evidence supporting the effect of lipids on the risk of osteoporotic pathological fractures. Although the GWAS data used in this study were derived from European populations, given the broad commonality of human genetics, the results provide valuable reference significance for improving osteoporosis in Chinese populations through lipid regulation.

Key words: osteoporotic fracture, lipid metabolism, sterol ester, Mendelian randomization, fracture risk, causal association, pathological mechanism