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

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

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.

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.

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.