Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts

Carole E. Aubert; Carmen Floriani; Douglas C. Bauer; Bruno R. da Costa; Daniel Segna; Manuel R. Blum; Tinh-Hai Collet; Howard A. Fink; Anne R. Cappola; Lamprini Syrogiannouli; Robin P. Peeters; Bjørn Olav Åsvold; Wendy P. J. den Elzen; Robert N. Luben; Alexandra P. Bremner; Apostolos Gogakos; Richard Eastell; Patricia M. Kearney; Mari Hoff; Erin Le Blanc; Graziano Ceresini; Fernando Rivadeneira; André G. Uitterlinden; Kay-Tee Khaw; Arnulf Langhammer; David J. Stott; Rudi G. J. Westendorp; Luigi Ferrucci; Graham R. Williams; Jacobijn Gussekloo; John P. Walsh; Drahomir Aujesky; Nicolas Rodondi; Thyroid Studies Collaboration

doi:10.1210/jc.2017-00294

Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts

Carole E. Aubert, Carmen Floriani, Douglas C. Bauer, Bruno R. da Costa, Daniel Segna, Manuel R. Blum, Tinh-Hai Collet, Howard A. Fink, Anne R. Cappola, Lamprini Syrogiannouli, Robin P. Peeters, Bjørn Olav Åsvold, Wendy P. J. den Elzen, Robert N. Luben, Alexandra P. Bremner, Apostolos Gogakos, Richard Eastell, Patricia M. Kearney, Mari Hoff, Erin Le BlancGraziano Ceresini, Fernando Rivadeneira, André G. Uitterlinden, Kay-Tee Khaw, Arnulf Langhammer, David J. Stott, Rudi G. J. Westendorp, Luigi Ferrucci, Graham R. Williams, Jacobijn Gussekloo, John P. Walsh, Drahomir Aujesky, Nicolas Rodondi, Thyroid Studies Collaboration

18 Citations (Scopus)

Abstract

Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

Original language	English
Journal	The Journal of clinical endocrinology and metabolism
Volume	102
Issue number	8
Pages (from-to)	2719–2728
Number of pages	10
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2017-00294
Publication status	Published - 1 Aug 2017

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Journal Article

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Aubert, C. E., Floriani, C., Bauer, D. C., da Costa, B. R., Segna, D., Blum, M. R., Collet, T.-H., Fink, H. A., Cappola, A. R., Syrogiannouli, L., Peeters, R. P., Åsvold, B. O., den Elzen, W. P. J., Luben, R. N., Bremner, A. P., Gogakos, A., Eastell, R., Kearney, P. M., Hoff, M., ... Thyroid Studies Collaboration (2017). Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts. The Journal of clinical endocrinology and metabolism, 102(8), 2719–2728. https://doi.org/10.1210/jc.2017-00294

Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts. / Aubert, Carole E.; Floriani, Carmen; Bauer, Douglas C. et al.
In: The Journal of clinical endocrinology and metabolism, Vol. 102, No. 8, 01.08.2017, p. 2719–2728.

Research output: Contribution to journal › Journal article › Research › peer-review

Aubert, CE, Floriani, C, Bauer, DC, da Costa, BR, Segna, D, Blum, MR, Collet, T-H, Fink, HA, Cappola, AR, Syrogiannouli, L, Peeters, RP, Åsvold, BO, den Elzen, WPJ, Luben, RN, Bremner, AP, Gogakos, A, Eastell, R, Kearney, PM, Hoff, M, Le Blanc, E, Ceresini, G, Rivadeneira, F, Uitterlinden, AG, Khaw, K-T, Langhammer, A, Stott, DJ, Westendorp, RGJ, Ferrucci, L, Williams, GR, Gussekloo, J, Walsh, JP, Aujesky, D, Rodondi, N & Thyroid Studies Collaboration 2017, 'Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts', The Journal of clinical endocrinology and metabolism, vol. 102, no. 8, pp. 2719–2728. https://doi.org/10.1210/jc.2017-00294

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title = "Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts",

abstract = "Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.",

keywords = "Journal Article",

author = "Aubert, {Carole E.} and Carmen Floriani and Bauer, {Douglas C.} and {da Costa}, {Bruno R.} and Daniel Segna and Blum, {Manuel R.} and Tinh-Hai Collet and Fink, {Howard A.} and Cappola, {Anne R.} and Lamprini Syrogiannouli and Peeters, {Robin P.} and {\AA}svold, {Bj{\o}rn Olav} and {den Elzen}, {Wendy P. J.} and Luben, {Robert N.} and Bremner, {Alexandra P.} and Apostolos Gogakos and Richard Eastell and Kearney, {Patricia M.} and Mari Hoff and {Le Blanc}, Erin and Graziano Ceresini and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G.} and Kay-Tee Khaw and Arnulf Langhammer and Stott, {David J.} and Westendorp, {Rudi G. J.} and Luigi Ferrucci and Williams, {Graham R.} and Jacobijn Gussekloo and Walsh, {John P.} and Drahomir Aujesky and Nicolas Rodondi and {Thyroid Studies Collaboration}",

year = "2017",

month = aug,

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doi = "10.1210/jc.2017-00294",

language = "English",

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journal = "The Journal of clinical endocrinology and metabolism",

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TY - JOUR

T1 - Thyroid function tests in the reference range and fracture

T2 - Individual participant analysis of prospective cohorts

AU - Aubert, Carole E.

AU - Floriani, Carmen

AU - Bauer, Douglas C.

AU - da Costa, Bruno R.

AU - Segna, Daniel

AU - Blum, Manuel R.

AU - Collet, Tinh-Hai

AU - Fink, Howard A.

AU - Cappola, Anne R.

AU - Syrogiannouli, Lamprini

AU - Peeters, Robin P.

AU - Åsvold, Bjørn Olav

AU - den Elzen, Wendy P. J.

AU - Luben, Robert N.

AU - Bremner, Alexandra P.

AU - Gogakos, Apostolos

AU - Eastell, Richard

AU - Kearney, Patricia M.

AU - Hoff, Mari

AU - Le Blanc, Erin

AU - Ceresini, Graziano

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G.

AU - Khaw, Kay-Tee

AU - Langhammer, Arnulf

AU - Stott, David J.

AU - Westendorp, Rudi G. J.

AU - Ferrucci, Luigi

AU - Williams, Graham R.

AU - Gussekloo, Jacobijn

AU - Walsh, John P.

AU - Aujesky, Drahomir

AU - Rodondi, Nicolas

AU - Thyroid Studies Collaboration

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

AB - Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

KW - Journal Article

U2 - 10.1210/jc.2017-00294

DO - 10.1210/jc.2017-00294

M3 - Journal article

C2 - 28482002

SN - 0021-972X

VL - 102

SP - 2719

EP - 2728

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 8

ER -

Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts

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