Relationship between statin drugs and bone density: a drug target-mediated Mendelian randomization study

doi:10.12307/2024.555

Abstract

Abstract: BACKGROUND: Observational studies have suggested that statin drugs may have a protective effect on bone density, making them a potential treatment option for osteoporosis.
OBJECTIVE: To evaluate the causal relationship between drug target-mediated lipid phenotypes and bone mineral density (BMD) using Mendelian randomization methods.
METHODS: We obtained single nucleotide polymorphismsrelated to statin drugs and BMD data from the IEU Open GWAS database. The primary analysis method was the inverse variance weighted method, and we also used weighted median, simple median, weighted mode, and MR-Egger regression. We used β values and 95% confidence intervals (CI) to assess the causal relationship between statin drugs and BMD. Additionally, we conducted sensitivity analyses to validate the results, assessed heterogeneity using Cochran’s Q test, examined for horizontal pleiotropy using the MR-Egger intercept test, and performed leave-one-out analyses to determine if individual or multiplesingle nucleotide polymorphism influenced the results.
RESULTS AND CONCLUSION: There was a significant association between the statin target of action, 3-hydroxy-3-methyl glutaryl coenzyme A reductase-mediated low-density lipoprotein cholesterol, and heel bone BMD (β=-0.086, 95% CI: -0.117 to -0.055, P=5.42×10-8) and whole-body BMD (β=-0.193, 95% CI: -0.288 to -0.098, P=7.35×10-5). The findings of this study support the protective effect of statin drugs on BMD. These findings not only deepen our understanding of the relationship between cholesterol-related genes and bone health but also reveal potential therapeutic targets for improving BMD.

Key words: statin drugs, bone mineral density, Mendelian randomization, genome-wide association study, causal relationship

CLC Number:

Ma Weiwei, Xiong Yong, Chen Honggu, Huang Wenzhuo, Huang Xin, Zhou Xiaohong. Relationship between statin drugs and bone density: a drug target-mediated Mendelian randomization study[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(27): 4340-4345.

Figures/Tables 6

References

[1] LI J, CHEN X, LU L, et al. The relationship between bone marrow adipose tissue and bone metabolism in postmenopausal osteoporosis. Cytokine Growth Factor Rev. 2020;52:88-98.
[2] XU Q, LI D, CHEN J, et al. Crosstalk between the gut microbiota and postmenopausal osteoporosis: Mechanisms and applications. Int Immunopharmacol. 2022;110:108998.
[3] MARTÍN-GONZÁLEZ C, GONZÁLEZ-REIMERS E, QUINTERO-PLATT G, et al. Lipid profile and bone mineral density in heavy alcoholics. Clin Nutr. 2018; 37(6 Pt A):2137-2143.
[4] LI S, GUO H, LIU Y, et al. Relationships of serum lipid profiles and bone mineral density in postmenopausal Chinese women. Clin Endocrinol (Oxf). 2015;82(1): 53-58.
[5] ALLA VM, AGRAWAL V, DENAZARETH A, et al. A reappraisal of the risks and benefits of treating to target with cholesterol lowering drugs. Drugs. 2013;73(10): 1025-1054.
[6] UZZAN B, COHEN R, NICOLAS P, et al. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone. 2007;40(6):1581-1587.
[7] LIN TK, CHOU P, LIN CH, et al. Long-term effect of statins on the risk of new-onset osteoporosis: A nationwide population-based cohort study. PLoS One. 2018; 13(5):e0196713.
[8] VAN DER BAAN FH, KLUNGEL OH, EGBERTS AC, et al. Pharmacogenetics in randomized controlled trials: considerations for trial design. Pharmacogenomics. 2011;12(10):1485-1492.
[9] GRECO M FD, MINELLI C, SHEEHAN NA, et al. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med. 2015;34(21):2926-2940.
[10] BOWDEN J, HOLMES MV. Meta-analysis and Mendelian randomization: A review. Res Synth Methods. 2019;10(4):486-496.
[11] SEKULA P, DEL GRECO MF, PATTARO C, et al. Mendelian Randomization as an Approach to Assess Causality Using Observational Data. J Am Soc Nephrol. 2016;27(11):3253-3265.
[12] LIU L, ZENG P, XUE F, et al. Multi-trait transcriptome-wide association studies with probabilistic Mendelian randomization. Am J Hum Genet. 2021;108(2):240-256.
[13] FERENCE BA. Interpreting the Clinical Implications of Drug-Target Mendelian Randomization Studies. J Am Coll Cardiol. 2022;80(7):663-665.
[14] WISHART DS, FEUNANG YD, GUO AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1): D1074-D1082.
[15] SKRIVANKOVA VW, RICHMOND RC, WOOLF BAR, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021;326(16):1614-1621.
[16] WILLER CJ, SCHMIDT EM, SENGUPTA S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45(11):1274-1283.
[17] CAMACHO PM, PETAK SM, BINKLEY N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis-2020 Update. Endocr Pract. 2020;26(Suppl 1):1-46.
[18] ZHENG HF, FORGETTA V, HSU YH, et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015;526(7571):112-117.
[19] MORRIS JA, KEMP JP, YOULTEN SE, et al. An atlas of genetic influences on osteoporosis in humans and mice [published correction appears in Nat Genet. 2019;51(5):920]. Nat Genet. 2019;51(2):258-266.
[20] MEDINA-GOMEZ C, KEMP JP, TRAJANOSKA K, et al. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects. Am J Hum Genet. 2018;102(1):88-102.
[21] ZHANG X, GENG T, LI N, et al. Associations of Lipids and Lipid-Lowering Drugs with Risk of Vascular Dementia: A Mendelian Randomization Study. Nutrients. 2022;15(1):69.
[22] HUANG W, XIAO J, JI J, et al. Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study. Elife. 2021;10: e73873.
[23] HEMANI G, TILLING K, DAVEY SMITH G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data [published correction appears in PLoS Genet. 2017;13(12 ):e1007149]. PLoS Genet. 2017; 13(11):e1007081.
[24] YUAN S, XIONG Y, LARSSON SC. An atlas on risk factors for multiple sclerosis: a Mendelian randomization study. J Neurol. 2021;268(1):114-124.
[25] MASSON W, CORRAL P, BARBAGELATA L, et al. Reduction of cardiovascular events with the use of lipid-lowering medication in patients with familial hypercholesterolemia or severe primary hypercholesterolemia: A systematic review. J Clin Lipidol. 2022;16(5):562-573.
[26] BOWDEN J, DAVEY SMITH G, HAYCOCK PC, et al. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40(4):304-314.
[27] BURGESS S, THOMPSON SG. Interpreting findings from Mendelian randomization using the MR-Egger method [published correction appears in Eur J Epidemiol. 2017;32(5):391-392]. Eur J Epidemiol. 2017;32(5):377-389.
[28] JIA N, DONG L, LU Q, et al. The causal effect of schizophrenia on fractures and bone mineral density: a comprehensive two-sample Mendelian randomization study of European ancestry. BMC Psychiatry. 2023;23(1):692.
[29] LAWLOR DA, HARBORD RM, STERNE JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133-1163.
[30] BOWDEN J, DAVEY SMITH G, BURGESS S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512-525.
[31] WU X, ZHANG W, ZHAO X, et al. Investigating the relationship between depression and breast cancer: observational and genetic analyses. BMC Med. 2023;21(1):170.
[32] BOWDEN J, DEL GRECO MF, MINELLI C, et al. A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat Med. 2017;36(11):1783-1802.
[33] VERBANCK M, CHEN CY, NEALE B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases [published correction appears in Nat Genet. 2018;50(8):1196]. Nat Genet. 2018;50(5):693-698.
[34] MA W, ZHOU X, HUANG X, et al. Causal relationship between body mass index, type 2 diabetes and bone mineral density: Mendelian randomization. PLoS One. 2023;18(10):e0290530.
[35] WANG JS, TOKAVANICH N, WEIN MN. SP7: from Bone Development to Skeletal Disease. Curr Osteoporos Rep. 2023;21(2):241-252.
[36] XU J, CAO B, LI C, et al. The recent progress of endocrine therapy-induced osteoporosis in estrogen-positive breast cancer therapy. Front Oncol. 2023;13: 1218206.
[37] LIU Q, TOOKI T, DI D, et al. Role of lifestyle factors in mediating the effect of educational attainment on bone mineral density: a Mendelian randomization study. Arch Osteoporos. 2023;18(1):120.
[38] HE X, HU W, ZHANG Y, et al. Cellular senescence in skeletal disease: mechanisms and treatment. Cell Mol Biol Lett. 2023;28(1):88.
[39] LI Y, SI Y, MA Y, et al. Application and prospect of metabolomics in the early diagnosis of osteoporosis: a narrative review. Bioanalysis. 2023;15(22): 1369-1379.
[40] AN T, HAO J, SUN S, et al. Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos Int. 2017;28(1):47-57.
[41] LIU J, ZHU LP, YANG XL, et al. HMG-CoA reductase inhibitors (statins) and bone mineral density: a meta-analysis. Bone. 2013;54(1):151-156.
[42] WANG Z, LI Y, ZHOU F, et al. Effects of Statins on Bone Mineral Density and Fracture Risk: A PRISMA-compliant Systematic Review and Meta-Analysis. Medicine (Baltimore). 2016;95(22):e3042.
[43] REJNMARK L, OLSEN ML, JOHNSEN SP, et al. Hip fracture risk in statin users--a population-based Danish case-control study. Osteoporos Int. 2004; 15(6):452-458.
[44] XIONG M, XUE Y, ZHU W, et al. Comparative efficacy and safety of statins for osteoporosis: a study protocol for a systematic review and network meta-analysis. BMJ Open. 2022;12(5):e054158.
[45] REID IR, HAGUE W, EMBERSON J, et al. Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Long-term Intervention with Pravastatin in Ischaemic Disease. Lancet. 2001;357(9255):509-512.
[46] PEÑA JM, ASPBERG S, MACFADYEN J, et al. Statin therapy and risk of fracture: results from the JUPITER randomized clinical trial. JAMA Intern Med. 2015;175(2): 171-177.
[47] PEDERSEN TR, WILHELMSEN L, FAERGEMAN O, et al. Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol. 2000;86(3):257-262.
[48] WARREN T, MCALLISTER R, MORGAN A, et al. The Interdependency and Co-Regulation of the Vitamin D and Cholesterol Metabolism. Cells. 2021; 10(8):2007.
[49] PRABHU AV, LUU W, LI D, et al. DHCR7: A vital enzyme switch between cholesterol and vitamin D production. Prog Lipid Res. 2016;64:138-151.
[50] GÓMEZ-CORONADO D, LASUNCIÓN MA, MARTÍNEZ-BOTAS J, et al. Role of cholesterol metabolism in the anticancer pharmacology of selective estrogen receptor modulators. Semin Cancer Biol. 2021;73:101-115.
[51] YU D, LIAO JK. Emerging views of statin pleiotropy and cholesterol lowering. Cardiovasc Res. 2022;118(2):413-423.
[52] ABDUL-RAHMAN T, BUKHARI SMA, HERRERA EC, et al. Lipid Lowering Therapy: An Era Beyond Statins. Curr Probl Cardiol. 2022;47(12):101342.
[53] RAY KK. Changing the paradigm for post-MI cholesterol lowering from intensive statin monotherapy towards intensive lipid-lowering regimens and individualized care. Eur Heart J. 2021;42(3):253-256.
[54] OXLUND H, DALSTRA M, ANDREASSEN TT. Statin given perorally to adult rats increases cancellous bone mass and compressive strength. Calcif Tissue Int. 2001;69(5):299-304.
[55] TIAN L, YU X. Lipid metabolism disorders and bone dysfunction--interrelated and mutually regulated (review). Mol Med Rep. 2015;12(1):783-794.
[56] NIU J, DING G, ZHANG L. Effects of simvastatin on the osteogenic differentiation and immunomodulation of bone marrow mesenchymal stem cells. Mol Med Rep. 2015;12(6):8237-8240.
[57] XU R, SHI G, XU L, et al. Simvastatin improves oral implant osseointegration via enhanced autophagy and osteogenesis of BMSCs and inhibited osteoclast activity. J Tissue Eng Regen Med. 2018;12(5):1209-1219.
[58] CHAMANI S, LIBERALE L, MOBASHERI L, et al. The role of statins in the differentiation and function of bone cells. Eur J Clin Invest. 2021;51(7): e13534.