Introduction: To identify and validate lipid metabolites associated with changes in bone mineral density (BMD) and fracture risk through integrated Mendelian randomization (MR) and observational analyses.

Methods: Two-sample MR analysis was first performed to uncover potential causal relationships between 32 lipid classes and 576 lipid species and BMD and fractures. Identified signatures were subsequently validated in an independent cohort (N=492), where lipids, BMD, and fracture status were measured at two time-points, 8 years. The false discovery rate method was employed to control multiple testing. Linear and log binomial mixed-effects models were used to analyze lipid associations with hip BMD and fracture risk, respectively.

Results: Two-sample MR revealed seven lipid classes causally associated with BMD and/or fractures, including acylcarnitine (AC), cholesteryl ester (CE), sphingomyelin (SM), phosphatidylinositol (PI), GM3 ganglioside (GM3), alkylphosphatidylcholine (PC(O)) and triacylglycerol (TG). Causal associations were found between eighteen lipid species across these classes and BMD, and ten lipid species were associated with fractures. Validation in an independent longitudinal cohort confirmed associations for total SM, SM(d18:1/16:0), SM(d18:2/24:0), and CE(18:3) with hip BMD change (β ranging from -0.036 to -0.012, p<1.13×10-2). Total SM, total GM3, and SM(d18:2/18:1), SM(d18:2/22:0), SM(d18:2/17:0) were associated with an increased risk of fractures (RR ranging from 1.038 to 1.290, p<5×10-2) over an 8-year period.

Conclusions: Our findings suggest that alterations in lipid metabolism play a causal role in bone remodelling and fracture risk. This warrants further investigation into the mechanisms of lipid-mediated BMD changes and the potential for identifying patients at ‘high risk’ of osteoporotic fracture.