A univariate and multivariate Mendelian randomization study of the causal association of arterial stiffness with bone mineral density and osteoporosis

  • Bowen Hong Department of Traumatology and Orthopedics, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi 214000, China; Nanjing University of Chinese Medicine, Nanjing 210000, China
  • Shaoshuo Li Department of Traumatology and Orthopedics, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi 214000, China; Nanjing University of Chinese Medicine, Nanjing 210000, China
  • Yi Zhou Department of Traumatology and Orthopedics, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi 214000, China; Nanjing University of Chinese Medicine, Nanjing 210000, China
  • Jiapeng Ye Department of Traumatology and Orthopedics, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine, Changzhou 213000, China
  • Mao Wu Department of Traumatology and Orthopedics, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi 214000, China; Nanjing University of Chinese Medicine, Nanjing 210000, China
  • Yang Shao Department of Traumatology and Orthopedics, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi 214000, China; Nanjing University of Chinese Medicine, Nanjing 210000, China
  • Jianwei Wang * Department of Traumatology and Orthopedics, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi 214000, China; Nanjing University of Chinese Medicine, Nanjing 210000, China
Article ID: 4561
DOI: https://doi.org/10.18282/po4561
Keywords: causal association; arterial stiffness; bone mineral density; osteoporosis; Mendelian randomization

Abstract

This investigation employed Mendelian randomization (MR) analysis to explore the causal associations of arterial stiffness with bone loss or osteoporosis. Genetic instruments for arterial stiffness index (ASI) were identified in previous genome-wide association studies, with single-nucleotide polymorphisms (SNPs) subjected to rigorous selection criteria. The causal links between ASI and osteoporosis and bone mineral density (BMD) (femoral neck, forearm, lumbar spine) were examined using the inverse variance weighted (IVW) method. Leave-one-out (for SNPs) and reverse MR analyses were also performed. An increased ASI was causally related to a decreased forearm BMD risk (IVW method; odds ratio [OR] = 0.593, 95% confidence interval [CI]: 0.408–0.862); no other causal links were identified. The multivariate MR analyses confirmed persistent links between ASI and forearm BMD after adjusting for body mass index (OR = 0.551, 95% CI: 0.309–0.983) or type 2 diabetes mellitus (OR = 0.690, 95% CI: 0.547–0.872). The reverse MR analysis identified no significant effects of BMD or osteoporosis on ASI. Overall, increased ASI was causally associated with reduced forearm BMD.

Published
2025-08-18

Copyright (c) 2025 Author(s)

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This work is licensed under a Creative Commons Attribution 4.0 International License.

References

1. Azeez TA. Osteoporosis and cardiovascular disease: a review. Molecular Biology Reports. 2022; 50(2): 1753-1763. doi: 10.1007/s11033-022-08088-4

2. Rodríguez-Gómez I, Gray SR, Ho FK, et al. Osteoporosis and Its Association with Cardiovascular Disease, Respiratory Disease, and Cancer: Findings From the UK Biobank Prospective Cohort Study. Mayo Clinic Proceedings. 2022; 97(1): 110-121. doi: 10.1016/j.mayocp.2021.07.019

3. Tousoulis D. Arterial stiffness: A clinical index or a research tool?. Hellenic Journal of Cardiology. 2019; 60(2): 69-71. doi: 10.1016/j.hjc.2019.03.010

4. Baykara M, Ozturk C, Elbuken F. The assessment of relationship between bone mineral density and arterial stiffness in turkish women. Diagnostic and Interventional Radiology; 2011. doi: 10.4261/1305-3825.dir.5330-11.1

5. Berger M, Fesler P, Roubille C. Arterial stiffness, the hidden face of cardiovascular risk in autoimmune and chronic inflammatory rheumatic diseases. Autoimmunity Reviews. 2021; 20(9): 102891. doi: 10.1016/j.autrev.2021.102891

6. Liu W, Zhang L, Gao Y, et al. The association of arterial stiffness index with cerebrovascular and cardiometabolic disease: A Mendelian randomization study. International Journal of Stroke. 2022; 17(10): 1145-1150. doi: 10.1177/17474930211066432

7. Said MA, Eppinga RN, Lipsic E, et al. Relationship of Arterial Stiffness Index and Pulse Pressure with Cardiovascular Disease and Mortality. Journal of the American Heart Association. 2018. doi: 10.1161/jaha.117.007621

8. Wang M, Huang J, Wu T, et al. Arterial Stiffness, Genetic Risk, and Type 2 Diabetes: A Prospective Cohort Study. Diabetes Care. 2022; 45(4): 957-964. doi: 10.2337/dc21-1921

9. Raisi-Estabragh Z, Biasiolli L, Cooper J, et al. Poor Bone Quality is Associated with Greater Arterial Stiffness: Insights from the UK Biobank. Journal of Bone and Mineral Research. 2020; 36(1): 90-99. doi: 10.1002/jbmr.4164

10. EL-Bikai R, Tahir MR, Tremblay J, et al. Association of age-dependent height and bone mineral density decline with increased arterial stiffness and rate of fractures in hypertensive individuals. Journal of Hypertension. 2015; 33(4): 727-735. doi: 10.1097/hjh.0000000000000475

11. Guo L, Zhang N, Zhang Y, et al. Arterial stiffness and risk of new-onset fragility fracture in Chinese men and women: The Kailuan cohort study. Bone. 2024; 180: 116991. doi: 10.1016/j.bone.2023.116991

12. van Dijk SC, de Jongh RT, Enneman AW, et al. Arterial stiffness is not associated with bone parameters in an elderly hyperhomocysteinemic population. Journal of Bone and Mineral Metabolism. 2015; 34(1): 99-108. doi: 10.1007/s00774-015-0650-x

13. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics. 2014; 23(R1): R89-R98. doi: 10.1093/hmg/ddu328

14. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ; 2018. doi: 10.1136/bmj.k601

15. Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Medicine; 2022. doi: 10.1186/s12916-022-02657-x

16. Fung K, Ramírez J, Warren HR, et al. Genome-wide association study identifies loci for arterial stiffness index in 127,121 UK Biobank participants. Scientific Reports; 2019. doi: 10.1038/s41598-019-45703-0

17. Zheng H, Forgetta V, Hsu Y, et al. Whole‐genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015; 526(7571): 112-117. doi: 10.1038/nature14878

18. Larsson SC, Butterworth AS, Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. European Heart Journal. 2023; 44(47): 4913-4924. doi: 10.1093/eurheartj/ehad736

19. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. International Journal of Epidemiology. 2015; 44(2): 512-525. doi: 10.1093/ije/dyv080

20. Chen X, Hong X, Gao W, et al. Causal relationship between physical activity, leisure sedentary behaviors and COVID-19 risk: a Mendelian randomization study. Journal of Translational Medicine. 2022; 20(1). doi: 10.1186/s12967-022-03407-6

21. Bowden J, Davey Smith G, Haycock PC, et al. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genetic Epidemiology. 2016; 40(4): 304-314. doi: 10.1002/gepi.21965

22. Zeng Y, Cao S, Yang H. The causal role of gastroesophageal reflux disease in anxiety disorders and depression: A bidirectional Mendelian randomization study. Frontiers in Psychiatry; 2023. doi: 10.3389/fpsyt.2023.1135923

23. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. International Journal of Epidemiology. 2017; 46(6): 1985-1998. doi: 10.1093/ije/dyx102

24. 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. Nature Genetics. 2018; 50(5): 693-698. doi: 10.1038/s41588-018-0099-7

25. Xuereb RA, Magri CJ, Xuereb RG. Arterial Stiffness and its Impact on Cardiovascular Health. Current Cardiology Reports. 2023; 25(10): 1337-1349. doi: 10.1007/s11886-023-01951-1

26. Laurent S, Cockcroft J, Van Bortel L, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. European Heart Journal. 2006; 27(21): 2588-2605. doi: 10.1093/eurheartj/ehl254

27. Toussaint ND, Lau KK, Strauss BJ, et al. Relationship between vascular calcification, arterial stiffness and bone mineral density in a cross‐sectional study of prevalent Australian haemodialysis patients. Nephrology. 2009; 14(1): 105-112. doi: 10.1111/j.1440-1797.2008.01056.x

28. Kim NL, Suh HS. Correlation of Arterial Stiffness and Bone Mineral Density by Measuring Brachial-Ankle Pulse Wave Velocity in Healthy Korean Women. Korean Journal of Family Medicine. 2015; 36(6): 323. doi: 10.4082/kjfm.2015.36.6.323

29. Cheng T, Zhang YC, Fan KY, et al. Genetic Evidence Supporting a Causal Association Between mTOR-Dependent EIF-4E Circulating Protein Level and Osteoporosis. Advances in Therapy. 2023; 40(11): 4987-4998. doi: 10.1007/s12325-023-02676-x

30. Donato AJ, Machin DR, Lesniewski LA. Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circulation Research. 2018; 123(7): 825-848. doi: 10.1161/circresaha.118.312563

31. Frisoli Jr A, Paes AT, Kimura AD, et al. Measuring forearm bone density instead of lumbar spine bone density improves the sensitivity of diagnosing osteoporosis in older adults with cardiovascular diseases: Data from SARCOS study. Bone Reports. 2021; 15: 101134. doi: 10.1016/j.bonr.2021.101134

32. Biver E, Durosier-Izart C, Chevalley T, et al. Evaluation of Radius Microstructure and Areal Bone Mineral Density Improves Fracture Prediction in Postmenopausal Women. Journal of Bone and Mineral Research. 2017; 33(2): 328-337. doi: 10.1002/jbmr.3299

33. Jankowski LG, Warner S, Gaither K, et al. Cross-calibration, Least Significant Change and Quality Assurance in Multiple Dual-Energy X-ray Absorptiometry Scanner Environments: 2019 ISCD Official Position. Journal of Clinical Densitometry. 2019; 22(4): 472-483. doi: 10.1016/j.jocd.2019.09.001

34. Baim S, Binkley N, Bilezikian JP, et al. Official Positions of the International Society for Clinical Densitometry and Executive Summary of the 2007 ISCD Position Development Conference. Journal of Clinical Densitometry. 2008; 11(1): 75-91. doi: 10.1016/j.jocd.2007.12.007

35. Tap L, Kirkham FA, Mattace-Raso F, et al. Unraveling the Links Underlying Arterial Stiffness, Bone Demineralization, and Muscle Loss. Hypertension. 2020; 76(3): 629-639. doi: 10.1161/hypertensionaha.120.15184

36. Ramasamy SK, Kusumbe AP, Schiller M, et al. Blood flow controls bone vascular function and osteogenesis. Nature Communications. 2016; 7(1). doi: 10.1038/ncomms13601

37. Chen Y, Zhao X, Wu H. Arterial Stiffness. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020; 40(5): 1078-1093. doi: 10.1161/atvbaha.120.313131