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The Effect of Plasma Lipids and Lipid-Lowering Interventions on Bone Mineral Density: A Mendelian Randomization Study |
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| Authors: | Jie Zheng Marie-Jo Brion John P Kemp Nicole M Warrington Maria-Carolina Borges Gibran Hemani Tom G Richardson Humaira Rasheed Zhen Qiao Philip Haycock Mika Ala-Korpela George Davey Smith Jon H Tobias David M Evans |
| Affiliation: | 1. Medical Research Council (MRC) Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK;2. University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia;3. Medical Research Council (MRC) Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK;4. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway;5. Medical Research Council (MRC) Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Australia Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Australia;6. Musculoskeletal Research Unit, University of Bristol, Bristol, UK |
| Abstract: | 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. |
| Keywords: | STATINS PLASMA LIPIDS BONE MINERAL DENSITY |