Relationship between Thyroid Hormone Sensitivity Indices and Osteoporosis in Patients with Normal Thyroid Function Type 2 Diabetes Mellitus

doi:10.12114/j.issn.1007-9572.2024.0629

Abstract

Abstract:

Background

With the increasing aging population, the prevalence of osteoporosis in patients with type 2 diabetes mellitus (T2DM) is rising year by year. It has also been found that impaired sensitivity to thyroid hormone is associated with abnormal bone metabolism. However, there are few studies on the relationship between thyroid hormone sensitivity and the risk of osteoporosis in patients with T2DM.

Objective

To analyze the relationship between thyroid hormone sensitivity index and osteoporosis in T2DM patients with normal thyroid function.

Methods

This cross-sectional study included 723 T2DM patients with normal thyroid function admitted to the Department of Endocrinology of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School from 2022 to 2023. Based on the results of bone mineral density (BMD) measurements, the patients were divided into three groups: normal bone mass group (n=362), osteopenia group (n=291), and osteoporosis group (n=70). The thyroid feedback quotient index (TFQI), thyroid-stimulating hormone index (TSHI), thyroid-stimulating hormone resistance index (TT4RI), and the ratio of free triiodothyronine to free thyroxine (FT₃/FT₄) were measured and calculated in each patient to assess thyroid hormone sensitivity. One-way analysis of variance (ANOVA) and chi-square test were used for intergroup comparisons. Spearman's rank correlation analysis and ultivariate Logistic regression analysis were employed to explore the association between thyroid hormone sensitivity indices and the risk of osteoporosis in T2DM patients. The receiver operating characteristic curve (ROC curve) was used to evaluate the value of TFQI in predicting osteoporosis

Results

The osteoporosis group had higher age, proportion of females, diabetes duration, systolic blood pressure, 2-hour postprandial glucose (2 hPG), high-density lipoprotein cholesterol (HDL-C), and TFQI compared with the normal bone mass group (P<0.05). In contrast, BMI, alanine aminotransferase (ALT), diastolic blood pressure, creatinine, triglycerides, FT₃, and FT₃/FT₄ were lower in the osteoporosis group than in the normal bone mass group (P<0.05). The osteoporosis group also had higher age, proportion of females, diabetes duration, systolic blood pressure, 2 hPG, HDL-C, and TFQI compared with the osteopenia group (P<0.05), while ALT, creatinine, triglycerides, FT₃, and FT₃/FT₄ were lower (P<0.05). Spearman rank correlation analysis showed that the occurrence of osteoporosis in T2DM patients was positively correlated with TFQI (r_s=0.553, P<0.001) and negatively correlated with FT₃ and FT₃/FT₄ (r_s=-0.098, P=0.009; r_s=-0.080, P=0.031). Multivariate Logistic regression analysis revealed that, after adjusting for confounding factors, TFQI was positively associated with the risk of osteoporosis in T2DM patients (OR=6.612, 95%CI=5.793-8.192, P<0.05). The area under the ROC curve (AUC) for predicting the risk of osteoporosis in T2DM patients using TFQI was 0.831 (95%CI=0.794-0.867), with a best cutoff value of -0.029. The sensitivity and specificity were 100.0% and 55.4%, respectively.

Conclusion

Elevated levels of TFQI are associated with a higher risk of osteoporosis in T2DM patients with normal thyroid function, suggesting that reduced central sensitivity to thyroid hormone in this population is related to the development of osteoporosis.

Key words: Diabetes mellitus, type 2, Osteoporosis, Bone mineral density, Thyroid gland, Thyroid hormones, Forecasting

摘要：

背景

随着老龄化的加剧，2型糖尿病（T2DM）并发骨质疏松症患病率逐年上升，同时发现甲状腺激素敏感性受损与骨代谢异常发生相关，但目前关于T2DM患者甲状腺激素敏感性与骨质疏松症发生风险的相关研究较少。

目的

分析甲状腺功能正常的T2DM患者甲状腺激素敏感性指数与骨质疏松症的关系。

方法

选取2022—2023年南京大学医学院附属鼓楼医院内分泌科收治的甲状腺功能正常的T2DM患者723例，并依据骨密度（BMD）测定结果将其分为三组：骨量正常组（n=362）、骨量减少组（n=291）以及骨质疏松症组（n=70）。分别测量并计算患者的甲状腺反馈分位指数（TFQI）、促甲状腺激素指数（TSHI）、促甲状腺素抵抗指数（TT4RI）和游离三碘甲状腺原氨酸与游离甲状腺素比值（FT₃/FT₄），以评估甲状腺激素敏感性。采用单因素方差分析、χ²检验进行组间比较；采用Spearman秩相关分析、多因素Logistic回归分析探究T2DM患者甲状腺激素敏感性指数与骨质疏松症发生风险的关联。采用受试者工作特征曲线（ROC曲线）评估TFQI预测骨质疏松症的价值。

结果

骨质疏松症组年龄、女性所占比例、糖尿病病程、收缩压、餐后2 h血糖（2 hPG）、高密度脂蛋白胆固醇（HDL-C）、TFQI高于骨量正常组，舒张压、BMI、丙氨酸氨基转移酶（ALT）、肌酐、三酰甘油、FT₃、FT₃/FT₄低于骨量正常组（P<0.05）；骨质疏松症组年龄、女性所占比例、糖尿病病程、收缩压、2 hPG、HDL-C、TFQI高于骨量减少组，ALT、肌酐、三酰甘油、FT₃和FT₃/FT₄低于骨量减少组（P<0.05）。Spearmen秩相关分析结果显示，T2DM患者并发骨质疏松症与TFQI呈正相关（r_s=0.553，P<0.001），与FT₃和FT₃/FT₄呈负相关（r_s=-0.098，P=0.009；r_s=-0.080，P=0.031）。多因素Logistic回归分析结果显示，经调整混杂因素后，TFQI是T2DM患者并发骨质疏松症的危险因素（OR=6.612，95%CI=5.793~8.192，P<0.05）。TFQI预测T2DM患者并发骨质疏松症风险的ROC曲线下面积（AUC）为0.831（95%CI=0.794~0.867），最佳截断值为-0.029，灵敏度、特异度分别为100.0%、55.4%。

结论

甲状腺功能正常T2DM患者TFQI水平的升高与更高的骨质疏松症发生风险相关，提示在该群体中甲状腺激素中枢敏感性降低与骨质疏松症的发生有关。

关键词: 糖尿病，2型, 骨质疏松, 骨密度, 甲状腺, 甲状腺激素类, 预测

CLC Number:

R 587.1 R 681

ZHANG Yuan,CHEN Guanhua,LYU Shanshan, et al. Relationship between Thyroid Hormone Sensitivity Indices and Osteoporosis in Patients with Normal Thyroid Function Type 2 Diabetes Mellitus[J]. Chinese General Practice, 2025, 28(29): 3653-3659. DOI: 10.12114/j.issn.1007-9572.2024.0629.
张媛,陈冠华,吕珊珊等. 甲状腺功能正常的2型糖尿病患者甲状腺激素敏感性指标与骨质疏松症的关系研究[J]. 中国全科医学, 2025, 28(29): 3653-3659. DOI: 10.12114/j.issn.1007-9572.2024.0629.

Figures/Tables 4

References 18

[1]	SUN H, SAEEDI P, KARURANGA S，et al. IDF Diabetes Atlas：Global，regional and country-level diabetes prevalence estimates for 2021 and projections for 2045[J]. Diabetes Res Clin Pract，2022,183:109119. DOI：10.1016/j.diabres.2021.109119.
[2]	中华医学会骨质疏松和骨矿盐疾病分会，章振林.原发性骨质疏松症诊疗指南（2022）[J].中国全科医学，2023,26(14):1671-1691. DOI: 10.12114/j.issn.1007-9572.2019.00.116
[3]	FAROOQUI K J, MITHAL A, KERWEN A K，et al. Type 2 diabetes and bone fragility-an under-recognized association[J]. Diabetes Metab Syndr，2021,15(3):927-935. DOI：10.1016/j.dsx.2021.04.017.
[4]	LACLAUSTRA M, MORENO-FRANCO B, LOU-BONAFONTE J M，et al. Impaired sensitivity to thyroid hormones is associated with diabetes and metabolic syndrome[J]. Diabetes Care，2019,42(2):303-310. DOI：10.2337/dc18-1410.
[5]	SUN Y, TENG D, ZHAO L，et al. Impaired sensitivity to thyroid hormones is associated with hyperuricemia，obesity，and cardiovascular disease risk in subjects with subclinical hypothyroidism[J]. Thyroid，2022,32(4):376-384. DOI：10.1089/thy.2021.0500.
[6]	LAKATOS P, SZILI B, BAKOS B，et al. Thyroid hormones，glucocorticoids，insulin，and bone[J]. Handb Exp Pharmacol，2020,262:93-120. DOI：10.1007/164_2019_314.
[7]	CHEN S, HUANG W C, ZHOU G W，et al. Association between sensitivity to thyroid hormone indices and bone mineral density in US males[J]. Int J Endocrinol，2022,2022:2205616. DOI：10.1155/2022/2205616.
[8]	RAFF H, MAGILL S B. Is the hypothalamic-pituitary-adrenal axis disrupted in type 2 diabetes mellitus?[J]. Endocrine，2016,54(2):273-275. DOI：10.1007/s12020-016-1108-1.
[9]	ALBERTI K G, ZIMMET P. Definition，diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation[J]. Diabet Med，1998,15(7):539-553. DOI：10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S. PMID: 9686693.
[10]	GU Y Q, LI H H, BAO X，et al. The relationship between thyroid function and the prevalence of type 2 diabetes mellitus in euthyroid subjects[J]. J Clin Endocrinol Metab，2017,102(2):434-442. DOI：10.1210/jc.2016-2965.
[11]	AUBERT C E, FLORIANI C, BAUER D C，et al. Thyroid function tests in the reference range and fracture：individual participant analysis of prospective cohorts[J]. J Clin Endocrinol Metab，2017,102(8):2719-2728. DOI：10.1210/jc.2017-00294.
[12]	QIN Z Z, MUHANHALI D, LING Y. Impaired thyroid hormone sensitivity increases risk of cardiovascular events in patients undergoing coronary angiography[J]. J Clin Endocrinol Metab，2024,109(6):1550-1564. DOI：10.1210/clinem/dgad735.
[13]	LIU C, HUA L, LIU K，et al. Impaired sensitivity to thyroid hormone correlates to osteoporosis and fractures in euthyroid individuals[J]. J Endocrinol Invest，2023,46(10):2017-2029. DOI：10.1007/s40618-023-02035-1.
[14]	DUNCAN BASSETT J H, NORDSTRÖM K, BOYDE A，et al. Thyroid status during skeletal development determines adult bone structure and mineralization[J]. Mol Endocrinol，2007,21(8):1893-1904. DOI：10.1210/me.2007-0157.
[15]	MONFOULET L E, RABIER B, DACQUIN R，et al. Thyroid hormone receptor β mediates thyroid hormone effects on bone remodeling and bone mass[J]. J Bone Miner Res，2011,26(9):2036-2044. DOI：10.1002/jbmr.432.
[16]	SUN L, ZHU L L, LU P，et al. Genetic confirmation for a central role for TNFα in the direct action of thyroid stimulating hormone on the skeleton[J]. Proc Natl Acad Sci USA，2013,110(24):9891-9896. DOI：10.1073/pnas.1308336110.
[17]	MULLUR R, LIU Y Y, BRENT G A. Thyroid hormone regulation of metabolism[J]. Physiol Rev，2014,94(2):355-382. DOI：10.1152/physrev.00030.2013.
[18]	BENHADI N, FLIERS E, VISSER T J，et al. Pilot study on the assessment of the setpoint of the hypothalamus-pituitary-thyroid axis in healthy volunteers[J]. Eur J Endocrinol，2010,162(2):323-329. DOI：10.1530/EJE-09-0655.

组别	例数	性别（男/女）	年龄（岁）	糖尿病病程（年）	收缩压（mmHg）	舒张压（mmHg）	BMI （kg/m²）	HbA_1c （%）	空腹血糖（mmol/L）
骨量正常组	362	310/52	62.3±6.9	12.54±6.88	126±13	79±9	24.4±2.2	8.18±1.79	7.61±2.11
骨量减少组	291	182/109^b	64.4±6.9	12.37±6.95	127±13	77±9^b	23.5±2.5^b	8.30±1.94	7.68±2.19
骨质疏松症组	70	15/55^bc	68.7±6.2^bc	15.47±7.63^bc	131±13^bc	76±9^b	23.1±2.6^b	8.40±1.85	8.07±2.66
F（χ²）值		128.878^a	27.934	5.904	3.039	8.398	15.899	0.617	1.320
P值		<0.001	<0.001	0.006	0.038	<0.001	<0.001	0.505	0.611
组别	2 hPG （mmol/L）	ALT （U/L）	AST （U/L）	肌酐（μmol/L）	尿酸（mmol/L）	三酰甘油（mmol/L）	总胆固醇（mmol/L）	HDL-C （mmol/L）	LDL-C （mmol/L）
骨量正常组	14.90±3.97	21.79±12.46	19.74±7.64	65.92±15.87	6.24±1.53	1.43±0.87	4.18±1.11	1.22±0.33	2.45±0.89
骨量减少组	15.13±4.11	20.80±12.77	19.82±8.87	62.06±16.27^b	6.01±1.43	1.42±0.87	4.35±1.15	1.26±0.32	2.57±0.95
骨质疏松症组	16.63±4.79^bc	17.58±9.57^bc	18.09±5.22	54.35±11.55^bc	5.84±1.56	1.21±0.54^bc	4.53±1.28	1.38±0.31^bc	2.69±1.07
F（χ²）值	5.207	3.474	1.427	17.381	3.055	1.990	3.433	7.198	2.537
P值	0.012	0.001	0.281	<0.001	0.059	0.211	0.066	<0.001	0.239
组别	血钙（mmol/L）	血磷（mmol/L）	TSH（mU/L）	FT₃（pmol/L）	FT₄（pmol/L）	TFQI	TSHI	TT4RI	FT₃/FT₄
骨量正常组	2.41±0.13	1.10±0.16	1.84±0.88	4.44±0.56	16.87±1.98	-0.23±0.28	2.75±0.54	30.75±14.66	0.27±0.04
骨量减少组	2.40±0.12	1.11±0.15	1.79±0.82	4.39±0.54	16.73±2.20	0.08±0.30^b	2.73±0.54	29.81±13.81	0.27±0.04
骨质疏松症组	2.41±0.13	1.11±0.16	1.94±0.86	4.20±0.57^bc	17.19±2.17	0.31±0.26^bc	2.86±0.57	33.01±14.49	0.25±0.04^bc
F（χ²）值	0.485	0.366	0.826	5.809	1.425	153.832	1.619	1.454	6.391
P值	0.751	0.359	0.354	0.003	0.185	<0.001	0.104	0.198	<0.001

组别	例数	性别（男/女）	年龄（岁）	糖尿病病程（年）	收缩压（mmHg）	舒张压（mmHg）	BMI （kg/m²）	HbA_1c （%）	空腹血糖（mmol/L）
骨量正常组	362	310/52	62.3±6.9	12.54±6.88	126±13	79±9	24.4±2.2	8.18±1.79	7.61±2.11
骨量减少组	291	182/109^b	64.4±6.9	12.37±6.95	127±13	77±9^b	23.5±2.5^b	8.30±1.94	7.68±2.19
骨质疏松症组	70	15/55^bc	68.7±6.2^bc	15.47±7.63^bc	131±13^bc	76±9^b	23.1±2.6^b	8.40±1.85	8.07±2.66
F（χ²）值		128.878^a	27.934	5.904	3.039	8.398	15.899	0.617	1.320
P值		<0.001	<0.001	0.006	0.038	<0.001	<0.001	0.505	0.611
组别	2 hPG （mmol/L）	ALT （U/L）	AST （U/L）	肌酐（μmol/L）	尿酸（mmol/L）	三酰甘油（mmol/L）	总胆固醇（mmol/L）	HDL-C （mmol/L）	LDL-C （mmol/L）
骨量正常组	14.90±3.97	21.79±12.46	19.74±7.64	65.92±15.87	6.24±1.53	1.43±0.87	4.18±1.11	1.22±0.33	2.45±0.89
骨量减少组	15.13±4.11	20.80±12.77	19.82±8.87	62.06±16.27^b	6.01±1.43	1.42±0.87	4.35±1.15	1.26±0.32	2.57±0.95
骨质疏松症组	16.63±4.79^bc	17.58±9.57^bc	18.09±5.22	54.35±11.55^bc	5.84±1.56	1.21±0.54^bc	4.53±1.28	1.38±0.31^bc	2.69±1.07
F（χ²）值	5.207	3.474	1.427	17.381	3.055	1.990	3.433	7.198	2.537
P值	0.012	0.001	0.281	<0.001	0.059	0.211	0.066	<0.001	0.239
组别	血钙（mmol/L）	血磷（mmol/L）	TSH（mU/L）	FT₃（pmol/L）	FT₄（pmol/L）	TFQI	TSHI	TT4RI	FT₃/FT₄
骨量正常组	2.41±0.13	1.10±0.16	1.84±0.88	4.44±0.56	16.87±1.98	-0.23±0.28	2.75±0.54	30.75±14.66	0.27±0.04
骨量减少组	2.40±0.12	1.11±0.15	1.79±0.82	4.39±0.54	16.73±2.20	0.08±0.30^b	2.73±0.54	29.81±13.81	0.27±0.04
骨质疏松症组	2.41±0.13	1.11±0.16	1.94±0.86	4.20±0.57^bc	17.19±2.17	0.31±0.26^bc	2.86±0.57	33.01±14.49	0.25±0.04^bc
F（χ²）值	0.485	0.366	0.826	5.809	1.425	153.832	1.619	1.454	6.391
P值	0.751	0.359	0.354	0.003	0.185	<0.001	0.104	0.198	<0.001

指标	模型1		模型2		模型3
指标	OR（95%CI）	P值	OR（95%CI）	P值	OR（95%CI）	P值
TFQI	6.442（5.669~7.325）	<0.001	6.264（5.444~7.524）	<0.001	6.612（5.793~8.192）	<0.001
TSHI	1.432（0.880~2.331）	0.171	0.951（0.540~1.675）	0.875	1.020（0.567~1.834）	0.976
TT4RI	1.011（0.933~1.028）	0.226	0.995（0.975~1.016）	0.657	0.999（0.978~1.021）	0.925
FT₃/FT₄	0.004（0.001~0.008）	<0.001	0.154（0.001~2.191）	0.622	0.541（0.001~9.588）	0.589

指标	模型1		模型2		模型3
指标	OR（95%CI）	P值	OR（95%CI）	P值	OR（95%CI）	P值
TFQI	6.442（5.669~7.325）	<0.001	6.264（5.444~7.524）	<0.001	6.612（5.793~8.192）	<0.001
TSHI	1.432（0.880~2.331）	0.171	0.951（0.540~1.675）	0.875	1.020（0.567~1.834）	0.976
TT4RI	1.011（0.933~1.028）	0.226	0.995（0.975~1.016）	0.657	0.999（0.978~1.021）	0.925
FT₃/FT₄	0.004（0.001~0.008）	<0.001	0.154（0.001~2.191）	0.622	0.541（0.001~9.588）	0.589