HemoglobinA1c Is a Risk Factor for Changes of Bone Mineral Density: A Mendelian Randomization Study

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2022 Aug 4

PMID 35923623

Authors

Xiaoxiao Ji

Jianqiao Hong

Zihao Qu

Weinan Yang

Yibo Wang

Jiyan Lin

Congsun Li

Jie Wang

Haochen Mou

Mingmin Shi

Chenhe Zhou

Wei Wang

Changjian Lin

Shigui Yan

Haobo Wu

Affiliations

Soon will be listed here.

Abstract

Background: As a valuable blood glucose measurement, HemoglobinA1c (HbA1c) is of great clinical value for diabetes. However, in previous observational studies, studies on its effect on bone mineral density (BMD) have different results. This study aimed to use Mendelian randomization (MR) to assess the effect of HbA1c on bone mineral density and fracture risk, and try to further explore whether this association was achieved through glycemic or non-glycemic factors.

Methods: Take HbA1c measurement as exposure, and BMD estimated from quantitative heel ultrasounds (eBMD) and bone fractures as outcomes. Two-Sample MR Analysis was conducted to assess the causal effect of HbA1C on heel BMD and risk fracture. Then, we performed the analysis using two subsets of these variants, one related to glycemic measurement and the other to erythrocyte indices.

Results: Genetically increased HbA1C was associated with the lower heel eBMD [odds ratio (OR) 0.91 (95% CI 0.87, 0.96) per %-unit, P = 3 × 10-4(IVW)]. Higher HbA1C was associated with lower heel eBMD when using only erythrocytic variants [OR 0.87 (0.82, 0.93), P=2× 10-5(IVW)]; However, when using only glycemic variants, this casual association does not hold. In further MR analysis, we test the association of erythrocytic traits with heel eBMD.

Conclusion: Our study revealed the significant causal effect of HbA1c on eBMD, and this causal link might achieve through non-glycemic pathways (erythrocytic indices).

Citing Articles

Association between waist-to-height ratio and osteoporosis in the National Health and Nutrition Examination Survey: a cross-sectional study.

Li H, Qiu J, Gao Z, Li C, Chu J Front Med (Lausanne). 2025; 11:1486611.

PMID: 39744530 PMC: 11688312. DOI: 10.3389/fmed.2024.1486611.

Development and internal validation of a clinical prediction model for osteopenia in Chinese middle-aged and elderly men: a prospective cohort study.

Li T, Zeng J, Pan Z, Hu F, Cai X, Wang X BMC Musculoskelet Disord. 2024; 25(1):394.

PMID: 38769526 PMC: 11103995. DOI: 10.1186/s12891-024-07526-7.

Causal effects of circulating vitamin levels on the risk of heart failure: a Mendelian randomization study.

Guan B, Chen X, Liu Y, Zhou H, Yang M, Zheng H J Geriatr Cardiol. 2023; 20(3):195-204.

PMID: 37091260 PMC: 10114193. DOI: 10.26599/1671-5411.2023.03.007.

Reduced High-Density Lipoprotein Cholesterol Is an Independent Determinant of Altered Bone Quality in Women with Type 2 Diabetes.

Dule S, Barchetta I, Cimini F, Passarella G, Dellanno A, Filardi T Int J Mol Sci. 2023; 24(7).

PMID: 37047445 PMC: 10095189. DOI: 10.3390/ijms24076474.

Causal relationship between Type 1 diabetes and osteoporosis and fracture occurrence: a two-sample Mendelian randomization analysis.

Tang Y, Zhang L, Ye D, Zhao A, Liu Y, Zhang M Osteoporos Int. 2023; 34(6):1111-1117.

PMID: 37012460 DOI: 10.1007/s00198-023-06734-6.

References

Au Yeung S, Luo S, Schooling C . The Impact of Glycated Hemoglobin (HbA) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank. Diabetes Care. 2018; 41(9):1991-1997. DOI: 10.2337/dc18-0289. View

Davies N, Holmes M, Davey Smith G . Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018; 362:k601. PMC: 6041728. DOI: 10.1136/bmj.k601. View

Khaw K, Wareham N, Bingham S, Luben R, Welch A, Day N . Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med. 2004; 141(6):413-20. DOI: 10.7326/0003-4819-141-6-200409210-00006. View

Hodonsky C, Baldassari A, Bien S, Raffield L, Highland H, Sitlani C . Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics. BMC Genomics. 2020; 21(1):228. PMC: 7071748. DOI: 10.1186/s12864-020-6626-9. View

Rachner T, Khosla S, Hofbauer L . Osteoporosis: now and the future. Lancet. 2011; 377(9773):1276-87. PMC: 3555696. DOI: 10.1016/S0140-6736(10)62349-5. View

Korkmaz U, Korkmaz N, Yazici S, Erkan M, Baki A, Yazici M . Anemia as a risk factor for low bone mineral density in postmenopausal Turkish women. Eur J Intern Med. 2012; 23(2):154-8. DOI: 10.1016/j.ejim.2011.11.009. View

Nordwall M, Abrahamsson M, Dhir M, Fredrikson M, Ludvigsson J, Arnqvist H . Impact of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy and nephropathy: the VISS Study (Vascular Diabetic Complications in Southeast Sweden). Diabetes Care. 2014; 38(2):308-15. DOI: 10.2337/dc14-1203. View

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

Leong A, Chen J, Wheeler E, Hivert M, Liu C, Merino J . Mendelian Randomization Analysis of Hemoglobin A as a Risk Factor for Coronary Artery Disease. Diabetes Care. 2019; 42(7):1202-1208. PMC: 6609962. DOI: 10.2337/dc18-1712. View

10.

Burgess S, Thompson S . Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. PMC: 5506233. DOI: 10.1007/s10654-017-0255-x. View

11.

Klein K, Buse J . The trials and tribulations of determining HbA targets for diabetes mellitus. Nat Rev Endocrinol. 2020; 16(12):717-730. PMC: 11653296. DOI: 10.1038/s41574-020-00425-6. View

12.

Janghorbani M, Feskanich D, Willett W, Hu F . Prospective study of diabetes and risk of hip fracture: the Nurses' Health Study. Diabetes Care. 2006; 29(7):1573-8. DOI: 10.2337/dc06-0440. View

13.

Lane N . Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol. 2006; 194(2 Suppl):S3-11. DOI: 10.1016/j.ajog.2005.08.047. View

14.

English E, Lenters-Westra E . HbA1c method performance: The great success story of global standardization. Crit Rev Clin Lab Sci. 2018; 55(6):408-419. DOI: 10.1080/10408363.2018.1480591. View

15.

Wheeler E, Leong A, Liu C, Hivert M, Strawbridge R, Podmore C . Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. PLoS Med. 2017; 14(9):e1002383. PMC: 5595282. DOI: 10.1371/journal.pmed.1002383. View

16.

Hemani G, Zheng J, Elsworth B, Wade K, Haberland V, Baird D . The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018; 7. PMC: 5976434. DOI: 10.7554/eLife.34408. View

17.

Oh Y, Moon J, Cho B . Association between Hemoglobin Level and Bone Mineral Density in Korean Adults. J Bone Metab. 2017; 24(3):161-173. PMC: 5613021. DOI: 10.11005/jbm.2017.24.3.161. View

18.

Oei L, Zillikens M, Dehghan A, Buitendijk G, Castano-Betancourt M, Estrada K . High bone mineral density and fracture risk in type 2 diabetes as skeletal complications of inadequate glucose control: the Rotterdam Study. Diabetes Care. 2013; 36(6):1619-28. PMC: 3661786. DOI: 10.2337/dc12-1188. View

19.

Fang L, Zhong S, Ma D, Li C, Hao Y, Gao Y . A cross-sectional study: an assessment of low muscle mass and osteoporosis in type 2 diabetes mellitus patients with a high glycated hemoglobin level. Ther Adv Chronic Dis. 2021; 12:20406223211026762. PMC: 8246566. DOI: 10.1177/20406223211026762. View

20.

Bry L, Chen P, Sacks D . Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clin Chem. 2001; 47(2):153-63. View