Positive effects of low LDL-C and statins on bone mineral density: an integrated epidemiological observation analysis and Mendelian Randomization study

Background: Low-density lipoprotein cholesterol (LDL-C) is suggested to play a role in osteoporosis but its association with bone metabolism remains unclear. Effects of LDL-C-lowering drugs on bone are also controversial. We aim to determine whether LDL-C is linked causally to BMD and assess the effects of LDL-C-lowering drugs on BMD. Methods: Association between blood lipid levels and BMD was examined by epidemiological observation analyses in US representative cohort NHANES III (N=3,638) and Hong Kong Osteoporosis Study (HKOS; N=1,128). Two-sample Mendelian Randomization (MR), employing genetic data from GWAS of blood lipids (N=188,577), total body BMD (TB-BMD) (N=66,628) and estimated BMD (eBMD) (N=142,487), was performed to infer causality between blood lipids and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the effects of drugs on BMD. Results: In NHANES III cohort, each SD decrease in LDL-C was associated with 0.045 SD increase in femoral neck BMD (95% CI: 0.009 to 0.081; P=0.015). A similar increase in BMD was observed in HKOS at femoral neck and lumbar spine. In MR analysis, decrease in genetically predicted LDL-C was associated with increase in TB-BMD [estimate per SD decrease, 0.038 (95% CI: 0.002 to 0.074); P=0.038] and eBMD [0.076 (0.042 to 0.111); P=1.20x10-5]. Reduction of TB-BMD was causally associated with increased LDL-C [0.035 (0.033 to 0.066); P=0.034]. LDL-C-lowering proxies of statins were associated with increased TB-BMD [0.18 (0.044 to 0.316); P=9.600x10-3] and eBMD [0.143 (0.062 to 0.223); P=5.165x10-4]. Conclusions: Negative causal association exists between LDL-C level and BMD. LDL-C-lowering effect of Statins increases BMD, suggesting its protective effect on bone.

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