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

Abstract

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 bone mineral density (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 a US representative cohort NHANES III (n = 3638) and the Hong Kong Osteoporosis Study (HKOS; n = 1128). Two-sample Mendelian randomization (MR), employing genetic data from a large-scale genome-wide association study (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 LDL-C and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the drugs’ effects on BMD. Results In the NHANES III cohort, each standard deviation (SD) decrease in LDL-C was associated with a 0.045 SD increase in femoral neck BMD (95% CI: 0.009 − 0.081; P = 0.015). A similar increase in BMD was observed in the HKOS at femoral neck and lumbar spine. In MR analysis, a decrease in genetically predicted LDL-C was associated with an increase in TB-BMD {estimate per SD decrease, 0.038 [95% confidence interval (CI): 0.002 − 0.074]; P = 0.038} and eBMD [0.076 (0.042 − 0.111); P = 1.20x10−5]. Reduction in TB-BMD was causally associated with increased LDL-C [0.035 (0.033 − 0.066); P = 0.034]. Statins’ LDL-C-lowering proxies were associated with increased TB-BMD [0.18 (0.044 − 0.316); P = 9.600x10−3] and eBMD [0.143 (0.062 − 0.223); P = 5.165x10−4]. Conclusions Negative causal association exists between LDL-C level and BMD. Statins’ LDL-C-lowering effect increases BMD, suggesting their protective effect on bone.

A phenome-wide association study of ABO blood groups

“…Despite few systematic studies of the relation of blood group with body composition, we found similar associations. Blood type O was associated with both lower LDL-c and higher bone mineral density, consistent with a Mendelian randomization study showing a negative causal association between them [54]. O was also associated with lower body fat and higher muscle mass and vital capacity, similar to the short-term effects of testosterone [55].…”

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population

“…As this analysis is cross-sectional, we are unable to determine whether increased β-CTX causes decreased triglyceride levels or vice versa, yet a recent analysis did not find evidence of a causal pathway between triglycerides and BMD after accounting for pleiotropy, consistent with the lack of any causal effect of triglycerides on bone turnover. 30 In adolescents, we observed the opposite direction of effect between β-CTX and triglycerides, after adjustment for covariates:…”

Use of Mendelian Randomization to Examine Causal Inference in Osteoporosis

“…In terms of constitutive factors, a causal association was observed between later age at menarche and reduced FN and LS BMD in adults (32), and reduced LS BMD in adolescents (33). A study in children found a causal association between BMI/adiposity and BMD (34).…”