Immune Cells as Mediators of Lipidome Influence on Osteoporosis: Evidence from a Mediation Analysis.

: Although clinical studies have indicated a possible association between dyslipidemia and osteoporosis, the underlying genetic basis and mechanistic pathways remain insufficiently defined. Most prior research has concentrated on conventional lipid markers, which are prone to confounding and limit causal inference. Exploring lipidomic profiles offers a more comprehensive view of lipid metabolism and may reveal novel genetic links beyond traditional lipid traits. Additionally, alterations in immune cell function, often triggered by metabolic disturbances, may contribute to osteoporosis development; however, the potential mediating role of immune cells in the lipid-bone axis has not been systematically investigated. : A total of 179 lipid species across 13 lipid classes were analyzed in 7174 Finnish individuals from the GeneRISK cohort. Genome-Wide Association Study (GWAS) summary statistics for osteoporosis and 731 immune cell immunophenotypes were sourced from the GWAS Catalog. A two-step, two-sample Mendelian randomization analysis, using inverse variance weighting (IVW), was conducted to explore the potential causal effects of lipids on osteoporosis and the mediating role of immune cells in the relationship between lipids and osteoporosis. : Mendelian randomization analysis indicated that triacylglycerol levels of 48:0 were possibly associated with an increased risk of osteoporosis (IVW: odds ratio [OR] 1.1320, 95% CI 1.0401-1.2321; = 0.004), while triacylglycerol levels of 48:3 appeared to be associated with a reduced risk of osteoporosis (IVW: OR 0.9053, 95% CI 0.8364-0.9800; = 0.014). Two statistically significant mediating effects were identified: First, IgD- CD38dim %B cells appeared to partially negatively mediate the association between triacylglycerol levels of 48:3 and osteoporosis, with a negative mediating effect of -0.00669 (95% CI: -0.0214, 0.00805), which accounted for 6.73% of the total effect. That is, the protective effect of triacylglycerol levels of 48:3 against osteoporosis was attenuated by IgD- CD38dim %B cells. Second, HLA DR++ monocytes% leukocytes also partially negatively mediated this relationship, with a mediating effect of -0.023 (95% CI: -0.0434, -0.00266), accounting for 23.2% of the total effect. This indicates that other immune cells, HLA DR++ monocytes %leukocytes, resisted the protective effect of triacylglycerol levels of 48:3 against osteoporosis, with a weakening effect stronger than that of IgD- CD38dim %B cells. : Our findings contribute to the growing understanding of the potential causal relationships and shared pathogenic mechanisms between dyslipidemia and osteoporosis. The results suggest that the potential genetic effects of plasma lipid metabolites on osteoporosis may be partially down-regulated by specific kinds of immune cells.