Thyroid Function Tests in the Reference Range and Fracture: Individual Participant Analysis of Prospective Cohorts

doi:10.1210/jc.2017-00294

Meta-Analysis

. 2017 Aug 1;102(8):2719-2728.

doi: 10.1210/jc.2017-00294.

Thyroid Function Tests in the Reference Range and Fracture: Individual Participant Analysis of Prospective Cohorts

Carole E Aubert¹, Carmen Floriani¹, Douglas C Bauer², Bruno R da Costa^{3

4}, Daniel Segna¹, Manuel R Blum¹, Tinh-Hai Collet⁵, Howard A Fink^{6

7}, Anne R Cappola⁸, Lamprini Syrogiannouli³, Robin P Peeters⁹, Bjørn O Åsvold^{10

11}, Wendy P J den Elzen¹², Robert N Luben¹³, Alexandra P Bremner¹⁴, Apostolos Gogakos¹⁵, Richard Eastell¹⁶, Patricia M Kearney¹⁷, Mari Hoff^{10

18}, Erin Le Blanc¹⁹, Graziano Ceresini²⁰, Fernando Rivadeneira⁹, André G Uitterlinden⁹, Kay-Tee Khaw¹⁴, Arnulf Langhammer¹⁰, David J Stott²¹, Rudi G J Westendorp²², Luigi Ferrucci²³, Graham R Williams¹⁶, Jacobijn Gussekloo^{12

24}, John P Walsh^{25

26}, Drahomir Aujesky¹, Nicolas Rodondi^{1

3}; Thyroid Studies Collaboration

Affiliations

¹ Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.
² Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco, California 94143.
³ Institute of Primary Health Care (Berner Institut für Hausarztmedizin), University of Bern, 3012 Bern, Switzerland.
⁴ Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, 3010 Bern, Switzerland.
⁵ Service of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
⁶ Geriatric Research Education and Clinical Center, Veterans Affairs Health Care System, Minneapolis, Minnesota 55417.
⁷ Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455.
⁸ University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
⁹ Departments of Internal Medicine and Epidemiology, Erasmus University Rotterdam, 3062 Rotterdam, The Netherlands.
¹⁰ Department of Public Health and Nursing, Norges teknisk-naturvitenskapelige universitet, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
¹¹ Department of Endocrinology, St. Olav's Hospital, Trondheim University Hospital, N-7006 Trondheim, Norway.
¹² Leiden University Medical Center, Department of Clinical Chemistry and Laboratory Medicine, 2300 RC Leiden, The Netherlands.
¹³ Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0SR, United Kingdom.
¹⁴ School of Population Health, University of Western Australia, Crawley, Perth, Western Australia 6009, Australia.
¹⁵ Molecular Endocrinology Laboratory, Hammersmith Campus, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
¹⁶ Department of Oncology and Metabolism, University of Sheffield, Sheffield, South Yorkshire S10 2TN, United Kingdom.
¹⁷ Department of Epidemiology and Public Health, University College Cork, T12 PX46 Cork, Ireland.
¹⁸ Levanger Hospital, Nord-Trøndelag Hospital Trust, 7600 Levanger, Norway.
¹⁹ Center for Health Research NW, Kaiser Permanente, Portland, Oregon 97277.
²⁰ Department of Clinical and Experimental Medicine, Geriatric Endocrine Unit, University Hospital of Parma, 43126 Parma, Italy.
²¹ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G31 2ER, United Kingdom.
²² Department of Public Health, Center for Health Aging, University of Copenhagen, 1004 Copenhagen, Denmark.
²³ National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224.
²⁴ Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
²⁵ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia.
²⁶ School of Medicine and Pharmacology, University of Western Australia, Crawley, Perth, Western Australia 6009, Australia.

PMID: 28482002
PMCID: PMC6283437
DOI: 10.1210/jc.2017-00294

Meta-Analysis

Thyroid Function Tests in the Reference Range and Fracture: Individual Participant Analysis of Prospective Cohorts

Carole E Aubert et al. J Clin Endocrinol Metab. 2017.

. 2017 Aug 1;102(8):2719-2728.

doi: 10.1210/jc.2017-00294.

Authors

Affiliations

¹ Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.
² Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco, California 94143.
³ Institute of Primary Health Care (Berner Institut für Hausarztmedizin), University of Bern, 3012 Bern, Switzerland.
⁴ Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, 3010 Bern, Switzerland.
⁵ Service of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
⁶ Geriatric Research Education and Clinical Center, Veterans Affairs Health Care System, Minneapolis, Minnesota 55417.
⁷ Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455.
⁸ University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
⁹ Departments of Internal Medicine and Epidemiology, Erasmus University Rotterdam, 3062 Rotterdam, The Netherlands.
¹⁰ Department of Public Health and Nursing, Norges teknisk-naturvitenskapelige universitet, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
¹¹ Department of Endocrinology, St. Olav's Hospital, Trondheim University Hospital, N-7006 Trondheim, Norway.
¹² Leiden University Medical Center, Department of Clinical Chemistry and Laboratory Medicine, 2300 RC Leiden, The Netherlands.
¹³ Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0SR, United Kingdom.
¹⁴ School of Population Health, University of Western Australia, Crawley, Perth, Western Australia 6009, Australia.
¹⁵ Molecular Endocrinology Laboratory, Hammersmith Campus, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
¹⁶ Department of Oncology and Metabolism, University of Sheffield, Sheffield, South Yorkshire S10 2TN, United Kingdom.
¹⁷ Department of Epidemiology and Public Health, University College Cork, T12 PX46 Cork, Ireland.
¹⁸ Levanger Hospital, Nord-Trøndelag Hospital Trust, 7600 Levanger, Norway.
¹⁹ Center for Health Research NW, Kaiser Permanente, Portland, Oregon 97277.
²⁰ Department of Clinical and Experimental Medicine, Geriatric Endocrine Unit, University Hospital of Parma, 43126 Parma, Italy.
²¹ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G31 2ER, United Kingdom.
²² Department of Public Health, Center for Health Aging, University of Copenhagen, 1004 Copenhagen, Denmark.
²³ National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224.
²⁴ Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
²⁵ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia.
²⁶ School of Medicine and Pharmacology, University of Western Australia, Crawley, Perth, Western Australia 6009, Australia.

PMID: 28482002
PMCID: PMC6283437
DOI: 10.1210/jc.2017-00294

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.

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Figures

**Figure 1.**
Risk of hip fracture according to TSH categories. Data on hip fractures were available for 12 studies (all except PROSPER).

**Figure 2.**
Risk of hip fracture per one SD increase in FT4, overall and stratified by sex, age, and duration of follow-up. The analysis stratified for sex was adjusted for age. All other analyses were adjusted for age (as a continuous variable) and sex. FT4 was measured in all studies but the Study of Osteoporotic Fractures (SOF) and the Health, Aging, and Body Composition (Health ABC) Study (FT4 not measured in participants with TSH within the reference range). Data on hip fractures were available for 10 studies with measured FT4 (all except PROSPER).

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References

1. Vestergaard P, Mosekilde L. Hyperthyroidism, bone mineral, and fracture risk—a meta-analysis. Thyroid. 2003;13(6):585–593. - PubMed
1. Blum MR, Bauer DC, Collet TH, Fink HA, Cappola AR, da Costa BR, Wirth CD, Peeters RP, Åsvold BO, den Elzen WP, Luben RN, Imaizumi M, Bremner AP, Gogakos A, Eastell R, Kearney PM, Strotmeyer ES, Wallace ER, Hoff M, Ceresini G, Rivadeneira F, Uitterlinden AG, Stott DJ, Westendorp RG, Khaw KT, Langhammer A, Ferrucci L, Gussekloo J, Williams GR, Walsh JP, Jüni P, Aujesky D, Rodondi N; Thyroid Studies Collaboration . Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA. 2015;313(20):2055–2065. - PMC - PubMed
1. Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev. 2016;37(2):135–187. - PMC - PubMed
1. Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid. 2006;16(4):375–380. - PubMed
1. Murphy E, Glüer CC, Reid DM, Felsenberg D, Roux C, Eastell R, Williams GR. Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women. J Clin Endocrinol Metab. 2010;95(7):3173–3181. - PubMed

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[1] Vestergaard P, Mosekilde L. Hyperthyroidism, bone mineral, and fracture risk—a meta-analysis. Thyroid. 2003;13(6):585–593. - PubMed

[2] Vestergaard P, Mosekilde L. Hyperthyroidism, bone mineral, and fracture risk—a meta-analysis. Thyroid. 2003;13(6):585–593. - PubMed

[3] Blum MR, Bauer DC, Collet TH, Fink HA, Cappola AR, da Costa BR, Wirth CD, Peeters RP, Åsvold BO, den Elzen WP, Luben RN, Imaizumi M, Bremner AP, Gogakos A, Eastell R, Kearney PM, Strotmeyer ES, Wallace ER, Hoff M, Ceresini G, Rivadeneira F, Uitterlinden AG, Stott DJ, Westendorp RG, Khaw KT, Langhammer A, Ferrucci L, Gussekloo J, Williams GR, Walsh JP, Jüni P, Aujesky D, Rodondi N; Thyroid Studies Collaboration . Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA. 2015;313(20):2055–2065. - PMC - PubMed

[4] Blum MR, Bauer DC, Collet TH, Fink HA, Cappola AR, da Costa BR, Wirth CD, Peeters RP, Åsvold BO, den Elzen WP, Luben RN, Imaizumi M, Bremner AP, Gogakos A, Eastell R, Kearney PM, Strotmeyer ES, Wallace ER, Hoff M, Ceresini G, Rivadeneira F, Uitterlinden AG, Stott DJ, Westendorp RG, Khaw KT, Langhammer A, Ferrucci L, Gussekloo J, Williams GR, Walsh JP, Jüni P, Aujesky D, Rodondi N; Thyroid Studies Collaboration . Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA. 2015;313(20):2055–2065. - PMC - PubMed

[5] Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev. 2016;37(2):135–187. - PMC - PubMed

[6] Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev. 2016;37(2):135–187. - PMC - PubMed

[7] Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid. 2006;16(4):375–380. - PubMed

[8] Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid. 2006;16(4):375–380. - PubMed

[9] Murphy E, Glüer CC, Reid DM, Felsenberg D, Roux C, Eastell R, Williams GR. Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women. J Clin Endocrinol Metab. 2010;95(7):3173–3181. - PubMed

[10] Murphy E, Glüer CC, Reid DM, Felsenberg D, Roux C, Eastell R, Williams GR. Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women. J Clin Endocrinol Metab. 2010;95(7):3173–3181. - PubMed

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Thyroid Function Tests in the Reference Range and Fracture: Individual Participant Analysis of Prospective Cohorts

Affiliations

Thyroid Function Tests in the Reference Range and Fracture: Individual Participant Analysis of Prospective Cohorts

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