ALTERATIONS IN LIPID METABOLISM ASSOCIATE WITH BONE MINERAL DENSITY CHANGE AND FRACTURE RISK

Background: Bone fracture is a major public health concern, with decreased bone mineral density (BMD) as a major risk factor. While the interplay between lipid metabolism and bone health has been suggested, comprehensive investigation of systemic lipidomics integrated with genetic analysis to determine the causal alterations in lipid metabolites associated with BMD change and fracture risk has not been done. Objectives: To identify lipids associated with BMD change and fracture risk by integrating lipidomics into genome-wide association studies (GWAS). Additionally, we sought to validate these lipid-BMD change and lipid-fracture risk associations in an independent population-based cohort study. Methods: Two-sample mendelian randomisation (MR) analysis was first performed to uncover potential causal relationships between 32 lipid classes and 576 lipid species (n=6,057) and BMD (n=365,403) and fractures (n=53,184 cases and n=373,611 controls) using summary-level data from the GWAS. Identified signatures were subsequently validated in an independent population-based cohort study where lipids, hip BMD and fracture were measured at two time-points with an 8-year apart in 492 participants. The false discovery rate method was employed to control multiple testing. Linear and log binominal mixed-effects regression models were used to analyse the associations of lipids with hip BMD and fracture risk over 8 years, 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 six lipid species (AC(16:1); CE(18:3; 20:1; 24:4; 24:5); SM(d18:1/16:0)) across these classes and BMD, and three lipid species (PC(O-38:5; O-40:5) and TG(56:6)[NL-20:4]) were associated with fractures. Validation in an independent longitudinal cohort confirmed associations between SM, SM(d18:1/16:0), and CE(18:3) with hip BMD change (β ranging from -0.036 to -0.012, P <0.00961). Furthermore, SM and GM3 were associated with the risk of fractures (RR ranging from 1.235 to 1.290, P <0.05) over an 8-year period. Conclusion: These findings suggest that alterations in lipid metabolism play a role in bone remodelling and fracture risk, and support investigating lipids for hip BMD change and identifying patients at ‘high risk’ of osteoporotic fracture. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared. DOI: 10.1136/annrheumdis-2024-eular.5045 Keywords: Bone, Biomarkers, Validation Citation: , volume 83, supplement 1, year 2024, page 644Session: Metabolic bone diseases and osteoporosis (Poster View)

Bone, Biomarkers, Validation