Roles of Sex Hormones in Mediating the Causal Effect of Vitamin D on Osteoporosis: A Two-step Mendelian Randomization Study

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2023 Apr 21

PMID 37082118

Authors

Yongwei Du

Baohui Xie

Maoyuan Wang

Yanbiao Zhong

Zhimai Lv

Yun Luo

Qiwei He

Zhen Liu

Affiliations

Soon will be listed here.

Abstract

Background: Although 25-hydroxyvitamin D [25(OH)D] is a risk factor for osteoporosis, it is not clear whether sex hormones mediate this casual association. We aimed to explore how sex hormones affect the association between 25(OH)D and osteoporosis to provide meaningful insights on the underlying mechanisms from a genetic perspective.

Methods: Genetic variations in 25(OH)D, total testosterone (TT), androstenedione (A4), estradiol (E2), and testosterone/17β-estradiol (T/E2) were determined through summary statistics. Taking osteoporosis as the outcome (FinnGen biobank, 332,020 samples), we conducted a Mendelian randomization (MR) analysis to establish the association between 25(OH)D and these sex hormones. The two-step MR analysis quantified the mediatory effects of sex hormones on osteoporosis. The results were further verified by pleiotropy and heterogeneity analyses.

Results: MR results showed that 25(OH)D (OR= 1.27, = 0.04) and TT (OR= 1.25, = 0.04) had a causal effect on osteoporosis. No significant associations were observed between the other sex hormones (A4, E2, and T/E2) and osteoporosis (>0.05). Sensitivity analysis (>0.05) confirmed the robustness of the MR results. The two-step MR analysis provided evidence that the mediatory effect of TT was 0.014 (the percentage of TT mediation was 5.91%). Moreover, the direct effect of 25(OH)D on osteoporosis was 0.221. A4, E2, and T/E2 were not considered as potential mediators of the role of 25(OH)D as a risk factor for OP.

Conclusion: This study, through MR analysis, showed that TT mediates the causal effect of 25(OH)D on osteoporosis. Interventions targeting TT, therefore, have the potential to substantially reduce the burden of osteoporosis attributable to high 25(OH)D.

Citing Articles

Mendelian randomization studies of risk and protective factors for osteoporosis: a systematic review and meta-analysis.

Ji W, Pan B, Chen X, Lao Z, Yang W, Qian Y Front Endocrinol (Lausanne). 2025; 15:1486188.

PMID: 39886030 PMC: 11779621. DOI: 10.3389/fendo.2024.1486188.

References

Pott J, Horn K, Zeidler R, Kirsten H, Ahnert P, Kratzsch J . Sex-Specific Causal Relations between Steroid Hormones and Obesity-A Mendelian Randomization Study. Metabolites. 2021; 11(11). PMC: 8624973. DOI: 10.3390/metabo11110738. View

Reid I, Billington E . Drug therapy for osteoporosis in older adults. Lancet. 2022; 399(10329):1080-1092. DOI: 10.1016/S0140-6736(21)02646-5. View

Burgess S, Scott R, Timpson N, Davey Smith G, Thompson S . Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015; 30(7):543-52. PMC: 4516908. DOI: 10.1007/s10654-015-0011-z. View

Verbanck M, Chen C, Neale B, Do R . Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018; 50(5):693-698. PMC: 6083837. DOI: 10.1038/s41588-018-0099-7. View

Zhao J, Xia W, Nie M, Zheng X, Wang Q, Wang X . The levels of bone turnover markers in Chinese postmenopausal women: Peking Vertebral Fracture study. Menopause. 2011; 18(11):1237-43. DOI: 10.1097/gme.0b013e31821d7ff7. View

Salari N, Darvishi N, Bartina Y, Larti M, Kiaei A, Hemmati M . Global prevalence of osteoporosis among the world older adults: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021; 16(1):669. PMC: 8590304. DOI: 10.1186/s13018-021-02821-8. View

Hemani G, Tilling K, Davey Smith G . Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 2017; 13(11):e1007081. PMC: 5711033. DOI: 10.1371/journal.pgen.1007081. View

Mohamad N, Soelaiman I, Chin K . A concise review of testosterone and bone health. Clin Interv Aging. 2016; 11:1317-1324. PMC: 5036835. DOI: 10.2147/CIA.S115472. View

Wright N, Looker A, Saag K, Curtis J, Delzell E, Randall S . The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014; 29(11):2520-6. PMC: 4757905. DOI: 10.1002/jbmr.2269. View

10.

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

11.

Tabatabaei-Malazy O, Salari P, Khashayar P, Larijani B . New horizons in treatment of osteoporosis. Daru. 2017; 25(1):2. PMC: 5297185. DOI: 10.1186/s40199-017-0167-z. View

12.

Srivastava S, Toraldo G, Weitzmann M, Cenci S, Ross F, Pacifici R . Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation. J Biol Chem. 2000; 276(12):8836-40. DOI: 10.1074/jbc.M010764200. View

13.

Wang L, Lv S, Li F, Yu X, Bai E, Yang X . Vitamin D Deficiency Is Associated With Metabolic Risk Factors in Women With Polycystic Ovary Syndrome: A Cross-Sectional Study in Shaanxi China. Front Endocrinol (Lausanne). 2020; 11:171. PMC: 7136495. DOI: 10.3389/fendo.2020.00171. View

14.

Ibrahim M, Zambruni M, Melby C, Melby P . Impact of Childhood Malnutrition on Host Defense and Infection. Clin Microbiol Rev. 2017; 30(4):919-971. PMC: 5608884. DOI: 10.1128/CMR.00119-16. View

15.

Vieth R . Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999; 69(5):842-56. DOI: 10.1093/ajcn/69.5.842. View

16.

Yuan C, Qian Z, Babic A, Morales-Oyarvide V, Rubinson D, Kraft P . Prediagnostic Plasma 25-Hydroxyvitamin D and Pancreatic Cancer Survival. J Clin Oncol. 2016; 34(24):2899-905. PMC: 5012662. DOI: 10.1200/JCO.2015.66.3005. View

17.

LeBoff M, Greenspan S, Insogna K, Lewiecki E, Saag K, Singer A . The clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2022; 33(10):2049-2102. PMC: 9546973. DOI: 10.1007/s00198-021-05900-y. View

18.

Holick M, Binkley N, Bischoff-Ferrari H, Gordon C, Hanley D, Heaney R . Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96(7):1911-30. DOI: 10.1210/jc.2011-0385. View

19.

Grant W, Whiting S, Schwalfenberg G, Genuis S, Kimball S . Estimated economic benefit of increasing 25-hydroxyvitamin D concentrations of Canadians to or above 100 nmol/L. Dermatoendocrinol. 2016; 8(1):e1248324. PMC: 5129897. DOI: 10.1080/19381980.2016.1248324. View

20.

Revez J, Lin T, Qiao Z, Xue A, Holtz Y, Zhu Z . Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat Commun. 2020; 11(1):1647. PMC: 7118120. DOI: 10.1038/s41467-020-15421-7. View