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) genomewide association study (GWAS) from the UK Biobank and dual-energy X-ray absorptiometry (DXA) BMD at four body sites and fracture GWAS 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% confidence interval [CI] = -0.08 to -0.04; p = 4 × 10-6 ), total body BMD (β = -0.05, 95% CI = -0.08 to -0.01, p = 6 × 10-3 ) 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 = .001) to those excluding these SNPs (β = -0.063; -0.090 to -0.036; p = 8 × 10-6 ). 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. © 2020 American Society for Bone and
Mineral Research.