The effect of plasma lipids and lipid‐lowering interventions on bone mineral density:​ a Mendelian randomization study

Zheng, Jie; Brion, Marie‐Jo; Kemp, John P.; Warrington, Nicole M.; Borges, Maria‐Carolina; Hemani, Gibran; Richardson, Tom G.; Rasheed, Humaira; Qiao, Zhen; Haycock, Philip; Ala‐Korpela, Mika; Smith, George Davey; Tobias, Jon H.; Evans, David M.

Affiliations

¹Medical Research Council (MRC) Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK

²Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

³University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia

⁴K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway

⁵Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Australia

⁶Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland

⁷NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland

⁸Department 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

⁹Musculoskeletal Research Unit, University of Bristol, Bristol, UK

Abstract and keywords

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.

Keywords: STATINS; PLASMA LIPIDS; BONE MINERAL DENSITY

Links

DOI: 10.1002/jbmr.3989

PubMed: 32163637

WoS: 000547662100004

History

Received: 2019-11-13

Revised: 2020-01-14

Accepted: 2020-02-18

Online: 2020-03-12

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2022	Ker A, Kao P-E. Methodological considerations on the association between dietary inflammatory potential and musculoskeletal health. J Bone Miner Res. December 2022;37(12):2678-2679.
2021	Zhang Q, Greenbaum J, Shen H, Zhao L-J, Zhang W-D, Sun C-Q, Deng H-W. Detecting causal relationship between metabolic traits and osteoporosis using multivariable Mendelian randomization. Osteoporos Int. April 2021;32(4):715-725.