The effect of plasma lipids and lipid lowering interventions on bone mineral density: a Mendelian randomization study

Several epidemiological studies have reported a relationship between statin treatment and increased bone mineral density (BMD) and reduced fracture risk, but the mechanism underlying the purported relationship is unclear. We used Mendelian randomization (MR) to assess whether this relationship is explained by a specific effect in response to statin use, or by a general effect of lipid-lowering. We utilized 400 single nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels as exposure. The outcome results were obtained from a heel estimated BMD (eBMD) GWAS from the UK Biobank and DXA BMD at four body sites and fracture GWASs from the GEFOS consortium. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels on BMD and fracture. Univariate MR analyses suggested a causal effect of LDL-C on eBMD (β = -0.06; standard deviation change in eBMD per standard deviation change in LDL-C, 95% CI=-0.08 to -0.04; P = 4x10-6), total body BMD (β =-0.05, 95%CI=-0.08 to -0.01, P=6x10-3) and potentially on lumbar spine BMD. Multivariable MR suggested that the effects of LDL-C on eBMD and total body BMD were independent of HDL-C and triglycerides. Sensitivity MR analyses suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in the HMGCR region showed similar effects on eBMD (β = -0.083; -0.132 to -0.034; P = 0.001) to those excluding these SNPs (β= -0.063; -0.090 to -0.036; P = 8x10-6). Bidirectional MR analyses provided some evidence for a causal effect of eBMD on plasma LDL-C levels. Our results suggest that effects of statins on eBMD and total body BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis.