Thyroid dysfunction and osteoporosis: a bidirectional, two-sample Mendelian randomization study_West China Medical Journal

Authors：

LI Zhengpeng ¹ ,  ZHANG Xiaoyun ^1,2 , WU Ruiqi ¹ , LI Kunjian ¹ , ZENG Hao ¹ , XIANG Kelin ¹ , LI Yongjin ¹

1. Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530000, P. R. China;
2. Department of Orthopedics, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530000, P. R. China;

Corresponding author：

ZHANG Xiaoyun, Email: zhangxiaoyun520@126.com

Keywords：

Hypothyroidism; hyperthyroidism; Hashimoto thyroiditis; Mendelian randomization; osteoporosis

DOI：

10.7507/1002-0179.202403222

Video：

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Objective To explore the potential causal relationship between thyroid dysfunction and osteoporosis (OP) through bidirectional two-sample Mendelian randomization (MR) analysis to provide genetic evidence for the risk association between thyroid dysfunction and OP, and provide reference for early prevention and treatment of OP. Methods Causal relationships were estimated based on data from genome-wide association studies for hypothyroidism (n=410141), hyperthyroidism (n=460499), Hashimoto thyroiditis (n=395640), and OP (n=212778). The inverse variance weighted method was used as the main analysis method, and the other four methods were used as the supplementary analysis methods to evaluate the causal effect of thyroid dysfunction and OP. Results The results of inverse variance weighted method showed that hypothyroidism [odds ratio (OR)=1.097, 95% confidence interval (CI) (1.017, 1.183), P=0.017], hyperthyroidism [OR=1.089, 95%CI (1.000, 1.186), P=0.049] and Hashimoto thyroiditis [OR=1.190, 95%CI (1.054, 1.343), P=0.005] were positively correlated with the causal effect of OP. The results of reverse MR analysis did not support that OP would increase the risk of hypothyroidism, hyperthyroidism or Hashimoto thyroiditis (P>0.05). In the bidirectional MR analyses, there was no heterogeneity in Cochran Q detection, MR-Egger intercept test results showed that there was no horizontal pleotropy, and the leave-one-out method analysis results showed that the MR analysis results were reliable. Conclusion Hypothyroidism, hyperthyroidism, and Hashimoto thyroiditis increase the risk of OP, while OP is not found to increase the risk of thyroid dysfunction in reverse studies.

Citation： LI Zhengpeng, ZHANG Xiaoyun, WU Ruiqi, LI Kunjian, ZENG Hao, XIANG Kelin, LI Yongjin. Thyroid dysfunction and osteoporosis: a bidirectional, two-sample Mendelian randomization study. West China Medical Journal, 2024, 39(10): 1617-1624. doi: 10.7507/1002-0179.202403222 Copy

1.	Anam AK, Insogna K. Update on osteoporosis screening and management. Med Clin North Am, 2021, 105(6): 1117-1134.
2.	Li J, Lu L, Liu Y, et al. Bone marrow adiposity during pathologic bone loss: molecular mechanisms underlying the cellular events. J Mol Med (Berl), 2022, 100(2): 167-183.
3.	Zeng Q, Li N, Wang Q, et al. The prevalence of osteoporosis in China, a nationwide, multicenter DXA survey. J Bone Miner Res, 2019, 34(10): 1789-1797.
4.	中华医学会骨质疏松和骨矿盐疾病分会. 原发性骨质疏松症诊疗指南(2022). 中华骨质疏松和骨矿盐疾病杂志, 2022, 15(6): 573-611.
5.	庞国明, 武楠, 倪青. 成人原发性甲状腺功能减退症病证结合诊疗指南. 世界中医药, 2023, 18(16): 2265-2272.
6.	中华医学会老年医学分会老年内分泌代谢疾病学组, 中华医学会内分泌学分会甲状腺学组. 中国老年人甲状腺疾病诊疗专家共识(2021). 中华内分泌代谢杂志, 2021, 37(5): 399-418.
7.	Chaker L, Razvi S, Bensenor IM, et al. Hypothyroidism. Nat Rev Dis Primers, 2022, 8(1): 30.
8.	Klubo-Gwiezdzinska J, Wartofsky L. Hashimoto thyroiditis: an evidence-based guide to etiology, diagnosis and treatment. Pol Arch Intern Med, 2022, 132(3): 16222.
9.	Dosiou C. Thyroid and fertility: recent advances. Thyroid, 2020, 30(4): 479-486.
10.	Kim BY, Kim SS, Park HK, et al. Assessment of the relationship between knee ultrasound and clinical symptoms in patients with thyroid dysfunction. J Int Med Res, 2020, 48(1): 300060519897701.
11.	Bojikian KD, Francis CE. Thyroid eye disease and myasthenia gravis. Int Ophthalmol Clin, 2019, 59(3): 113-124.
12.	Ahmadi N, Ahmadi F, Sadiqi M, et al. Thyroid gland dysfunction and its effect on the cardiovascular system: a comprehensive review of the literature. Endokrynol Pol, 2020, 71(5): 466-478.
13.	Branstetter RT, Islam RK, Toups CA, et al. Mechanisms and treatment options for hyperthyroid-induced osteoporosis: a narrative review. Cureus, 2023, 15(11): e48798.
14.	Vandenbroucke A, Luyten FP, Flamaing J, et al. Pharmacological treatment of osteoporosis in the oldest old. Clin Interv Aging, 2017, 12: 1065-1077.
15.	Delitala AP, Scuteri A, Doria C. Thyroid hormone diseases and osteoporosis. J Clin Med, 2020, 9(4): 1034.
16.	Wu J, Huang H, Yu X. How does Hashimoto’s thyroiditis affect bone metabolism?. Rev Endocr Metab Disord, 2023, 24(2): 191-205.
17.	Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
18.	Boef AG, Dekkers OM, le Cessie S. Mendelian randomization studies: a review of the approaches used and the quality of reporting. Int J Epidemiol, 2015, 44(2): 496-511.
19.	Tachmazidou I, Hatzikotoulas K, Southam L, et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet, 2019, 51(2): 230-236.
20.	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. Nat Genet, 2018, 50(5): 693-698.
21.	Burgess S, Bowden J, Fall T, et al. Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1): 30-42.
22.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
23.	刘明, 高亚, 杨珂璐, 等. 孟德尔随机化研究的报告规范(STROBE-MR)解读. 中国循证医学杂志, 2022, 22(8): 978-987.
24.	Sobh MM, Abdalbary M, Elnagar S, et al. Secondary osteoporosis and metabolic bone diseases. J Clin Med, 2022, 11(9): 2382.
25.	Williams GR, Bassett JHD. Thyroid diseases and bone health. J Endocrinol Invest, 2018, 41(1): 99-109.
26.	Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev, 2016, 37(2): 135-187.
27.	Duncan Bassett JH, Williams GR. Analysis of physiological responses to thyroid hormones and their receptors in bone. Methods Mol Biol, 2018, 1801: 123-154.
28.	Obling ML, Nicolaisen P, Brix TH, et al. Restoration of euthyroidism in women with Hashimoto’s thyroiditis changes bone microarchitecture but not estimated bone strength. Endocrine, 2021, 71(2): 397-406.
29.	Thayakaran R, Adderley NJ, Sainsbury C, et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ, 2019, 366: l4892.
30.	郑家深, 张源, 杨培庆, 等. 甲状腺功能异常对男性骨密度影响的研究. 中国骨质疏松杂志, 2020, 26(6): 885-888.
31.	Tuchendler D, Bolanowski M. Assessment of bone metabolism in premenopausal females with hyperthyroidism and hypothyroidism. Endokrynol Pol, 2013, 64(1): 40-44.
32.	Teng W. Levothyroxine and bone//Kahaly GJ. 70 years of levothyroxine. Cham (CH): Springer International Publishing AG, 2021: 97-107.
33.	Karimifar M, Esmaili F, Salari A, et al. Effects of levothyroxine and thyroid stimulating hormone on bone loss in patients with primary hypothyroidism. J Res Pharm Pract, 2014, 3(3): 83-87.
34.	高城翰, 关雪峰, 高天舒. 含富碘中药复方对 Graves 病致骨质疏松症的治疗作用. 中华中医药学刊, 2021, 39(8): 192-194.
35.	Wang H, Wu J, Wang B, et al. Progress in prevention and treatment of acute bone loss in orthopedics. Int J Endocrinol, 2023, 2023: 9373043.
36.	Srivastava RK, Sapra L. The rising era of “immunoporosis”: role of immune system in the pathophysiology of osteoporosis. J Inflamm Res, 2022, 15: 1667-1698.
37.	Lademann F, Tsourdi E, Hofbauer LC, et al. Thyroid hormone actions and bone remodeling - the role of the Wnt signaling pathway. Exp Clin Endocrinol Diabetes, 2020, 128(6-07): 450-454.
38.	宋慧芳. 绝经后女性桥本甲状腺炎与骨密度的相关性研究. 青岛: 青岛大学, 2021.
39.	Demartini Ade A, Kulak CA, Borba VC, et al. Bone mineral density of children and adolescents with congenital hypothyroidism. Arq Bras Endocrinol Metabol, 2007, 51(7): 1084-1092.
40.	Abe E, Marians RC, Yu W, et al. TSH is a negative regulator of skeletal remodeling. Cell, 2003, 115(2): 151-162.

1. Anam AK, Insogna K. Update on osteoporosis screening and management. Med Clin North Am, 2021, 105(6): 1117-1134.
2. Li J, Lu L, Liu Y, et al. Bone marrow adiposity during pathologic bone loss: molecular mechanisms underlying the cellular events. J Mol Med (Berl), 2022, 100(2): 167-183.
3. Zeng Q, Li N, Wang Q, et al. The prevalence of osteoporosis in China, a nationwide, multicenter DXA survey. J Bone Miner Res, 2019, 34(10): 1789-1797.
4. 中华医学会骨质疏松和骨矿盐疾病分会. 原发性骨质疏松症诊疗指南(2022). 中华骨质疏松和骨矿盐疾病杂志, 2022, 15(6): 573-611.
5. 庞国明, 武楠, 倪青. 成人原发性甲状腺功能减退症病证结合诊疗指南. 世界中医药, 2023, 18(16): 2265-2272.
6. 中华医学会老年医学分会老年内分泌代谢疾病学组, 中华医学会内分泌学分会甲状腺学组. 中国老年人甲状腺疾病诊疗专家共识(2021). 中华内分泌代谢杂志, 2021, 37(5): 399-418.
7. Chaker L, Razvi S, Bensenor IM, et al. Hypothyroidism. Nat Rev Dis Primers, 2022, 8(1): 30.
8. Klubo-Gwiezdzinska J, Wartofsky L. Hashimoto thyroiditis: an evidence-based guide to etiology, diagnosis and treatment. Pol Arch Intern Med, 2022, 132(3): 16222.
9. Dosiou C. Thyroid and fertility: recent advances. Thyroid, 2020, 30(4): 479-486.
10. Kim BY, Kim SS, Park HK, et al. Assessment of the relationship between knee ultrasound and clinical symptoms in patients with thyroid dysfunction. J Int Med Res, 2020, 48(1): 300060519897701.
11. Bojikian KD, Francis CE. Thyroid eye disease and myasthenia gravis. Int Ophthalmol Clin, 2019, 59(3): 113-124.
12. Ahmadi N, Ahmadi F, Sadiqi M, et al. Thyroid gland dysfunction and its effect on the cardiovascular system: a comprehensive review of the literature. Endokrynol Pol, 2020, 71(5): 466-478.
13. Branstetter RT, Islam RK, Toups CA, et al. Mechanisms and treatment options for hyperthyroid-induced osteoporosis: a narrative review. Cureus, 2023, 15(11): e48798.
14. Vandenbroucke A, Luyten FP, Flamaing J, et al. Pharmacological treatment of osteoporosis in the oldest old. Clin Interv Aging, 2017, 12: 1065-1077.
15. Delitala AP, Scuteri A, Doria C. Thyroid hormone diseases and osteoporosis. J Clin Med, 2020, 9(4): 1034.
16. Wu J, Huang H, Yu X. How does Hashimoto’s thyroiditis affect bone metabolism?. Rev Endocr Metab Disord, 2023, 24(2): 191-205.
17. Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
18. Boef AG, Dekkers OM, le Cessie S. Mendelian randomization studies: a review of the approaches used and the quality of reporting. Int J Epidemiol, 2015, 44(2): 496-511.
19. Tachmazidou I, Hatzikotoulas K, Southam L, et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet, 2019, 51(2): 230-236.
20. 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. Nat Genet, 2018, 50(5): 693-698.
21. Burgess S, Bowden J, Fall T, et al. Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1): 30-42.
22. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
23. 刘明, 高亚, 杨珂璐, 等. 孟德尔随机化研究的报告规范(STROBE-MR)解读. 中国循证医学杂志, 2022, 22(8): 978-987.
24. Sobh MM, Abdalbary M, Elnagar S, et al. Secondary osteoporosis and metabolic bone diseases. J Clin Med, 2022, 11(9): 2382.
25. Williams GR, Bassett JHD. Thyroid diseases and bone health. J Endocrinol Invest, 2018, 41(1): 99-109.
26. Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev, 2016, 37(2): 135-187.
27. Duncan Bassett JH, Williams GR. Analysis of physiological responses to thyroid hormones and their receptors in bone. Methods Mol Biol, 2018, 1801: 123-154.
28. Obling ML, Nicolaisen P, Brix TH, et al. Restoration of euthyroidism in women with Hashimoto’s thyroiditis changes bone microarchitecture but not estimated bone strength. Endocrine, 2021, 71(2): 397-406.
29. Thayakaran R, Adderley NJ, Sainsbury C, et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ, 2019, 366: l4892.
30. 郑家深, 张源, 杨培庆, 等. 甲状腺功能异常对男性骨密度影响的研究. 中国骨质疏松杂志, 2020, 26(6): 885-888.
31. Tuchendler D, Bolanowski M. Assessment of bone metabolism in premenopausal females with hyperthyroidism and hypothyroidism. Endokrynol Pol, 2013, 64(1): 40-44.
32. Teng W. Levothyroxine and bone//Kahaly GJ. 70 years of levothyroxine. Cham (CH): Springer International Publishing AG, 2021: 97-107.
33. Karimifar M, Esmaili F, Salari A, et al. Effects of levothyroxine and thyroid stimulating hormone on bone loss in patients with primary hypothyroidism. J Res Pharm Pract, 2014, 3(3): 83-87.
34. 高城翰, 关雪峰, 高天舒. 含富碘中药复方对 Graves 病致骨质疏松症的治疗作用. 中华中医药学刊, 2021, 39(8): 192-194.
35. Wang H, Wu J, Wang B, et al. Progress in prevention and treatment of acute bone loss in orthopedics. Int J Endocrinol, 2023, 2023: 9373043.
36. Srivastava RK, Sapra L. The rising era of “immunoporosis”: role of immune system in the pathophysiology of osteoporosis. J Inflamm Res, 2022, 15: 1667-1698.
37. Lademann F, Tsourdi E, Hofbauer LC, et al. Thyroid hormone actions and bone remodeling - the role of the Wnt signaling pathway. Exp Clin Endocrinol Diabetes, 2020, 128(6-07): 450-454.
38. 宋慧芳. 绝经后女性桥本甲状腺炎与骨密度的相关性研究. 青岛: 青岛大学, 2021.
39. Demartini Ade A, Kulak CA, Borba VC, et al. Bone mineral density of children and adolescents with congenital hypothyroidism. Arq Bras Endocrinol Metabol, 2007, 51(7): 1084-1092.
40. Abe E, Marians RC, Yu W, et al. TSH is a negative regulator of skeletal remodeling. Cell, 2003, 115(2): 151-162.

West China Medical Journal

Thyroid dysfunction and osteoporosis: a bidirectional, two-sample Mendelian randomization study

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