Potential causal effect of SLE on osteoporosis, and the mediation effect: a Mendelian randomisation study.

Objective: This study uses Mendelian randomisation (MR) to investigate the causal link between SLE and osteoporosis across different ethnic groups.

Methods: Genetic variants associated with SLE were identified from publicly available genome-wide association studies in European and East Asian populations. Two-sample MR (TSMR) analysis and meta-analysis with inverse variance weighting (IVW) assessed their effects on bone mineral density (BMD) and fracture risk. Multivariable MR (MVMR) analysis in East Asians adjusted for potential mediators, and two-step mediation analysis evaluated mediation effects of independent covariates.

Results: A meta-analysis of IVW results from TSMR in East Asian populations revealed a significant positive genetic association of SLE with osteoporosis (OR=1.023, CI 1.007 to 1.040, p<0.01). A similar, although weaker, association was observed in the European population (OR=1.001, CI 1.000 to 1.001, p<0.01). Furthermore, SLE was identified as a risk factor for reduced BMD in both East Asian (β=-0.0690, p<0.05) and European (β=-0.0109, p<0.05) populations, and for fracture risk in European (OR=1.002, p<0.05) populations, while no significant association was observed in the East Asian population (OR=1.010, p=0.705). MVMR analysis of East Asian data assessed mediation effects and found that the SLE-osteoporosis association was nullified after adjusting for cardiovascular disease and health status. Mediation analysis identified low-density lipoprotein cholesterol (LDL-C) and anti-inflammatory medication use as independent mediators, with mediation effects of 0.1170 and 0.0510, respectively. No significant heterogeneity or pleiotropy was detected.

Conclusions: SLE appears to be a causal risk factor for osteoporosis. LDL-C and anti-inflammatory medication use mediate this relationship, suggesting the importance of managing these factors in patients with SLE to reduce osteoporosis risk.