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.

中文翻译：

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血浆脂质和降脂干预对骨矿物质密度的影响：一项孟德尔随机研究。

几项流行病学研究报告了他汀类药物治疗与增加骨密度 (BMD) 和降低骨折风险之间的关系，但这种所谓关系的潜在机制尚不清楚。我们使用孟德尔随机化 (MR) 来评估这种关系是否可以通过对他汀类药物使用的特定效果或降脂的一般效果来解释。我们利用 400 个与血浆脂质水平密切相关的单核苷酸多态性 (SNP) 作为暴露。结果结果来自英国生物银行的足跟估计 BMD (eBMD) 全基因组关联研究 (GWAS) 和来自 GEFOS 联盟的四个身体部位的双能 X 射线骨密度测定 (DXA) BMD 和骨折 GWAS。我们对低密度脂蛋白胆固醇 (LDL-C) 进行了单变量和多变量 MR 分析，高密度脂蛋白胆固醇 (HDL-C) 和甘油三酯水平对 BMD 和骨折的影响。单变量 MR 分析表明 LDL-C 对 eBMD 有因果影响（β = −0.06；每个 LDL-C 标准差变化的 eBMD 标准差变化，95% 置信区间 [CI] = –0.08 至 -0.04；p = 4 × 10 ^-6 )、全身 BMD ( β = -0.05, 95% CI = –0.08 至 -0.01, p = 6 × 10 ^-3 ) 和潜在的腰椎 BMD。多变量 MR 表明 LDL-C 对 eBMD 和全身 BMD 的影响与 HDL-C 和甘油三酯无关。敏感性 MR 分析表明，LDL-C 结果对多效性具有稳健性。局限于HMGCR区域 SNP 的 LDL-C 的 MR 分析显示对 eBMD 有相似的影响（β = -0.083；-0.132 至 -0.034；p= .001) 到排除这些 SNP 的那些 ( β = −0.063；−0.090 至 −0.036；p = 8 × 10 ⁻⁶ )。双向 MR 分析为 eBMD 对血浆 LDL-C 水平的因果影响提供了一些证据。我们的结果表明，他汀类药物对 eBMD 和全身 BMD 的影响至少部分是由于它们的 LDL-C 降低作用。需要进一步的研究来检查改变血浆脂质水平在治疗骨质疏松症中的潜在作用。© 2020 美国骨骼和矿物研究协会。