Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

Manuel R Blum; Douglas C Bauer; Tinh-Hai Collet; Howard A Fink; Anne R Cappola; Bruno R da Costa; Christina D Wirth; Robin P Peeters; Bjørn O Åsvold; Wendy P J den Elzen; Robert N Luben; Misa Imaizumi; Alexandra P Bremner; Apostolos Gogakos; Richard Eastell; Patricia M Kearney; Elsa S Strotmeyer; Erin R Wallace; Mari Hoff; Graziano Ceresini; Fernando Rivadeneira; André G Uitterlinden; David J Stott; Rudi G J Westendorp; Kay-Tee Khaw; Arnuf Langhammer; Luigi Ferrucci; Jacobijn Gussekloo; Graham R Williams; John P Walsh; Peter Jüni; Drahomir Aujesky; Nicolas Rodondi; Thyroid Studies Collaboration

doi:10.1001/jama.2015.5161

Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

Manuel R Blum, Douglas C Bauer, Tinh-Hai Collet, Howard A Fink, Anne R Cappola, Bruno R da Costa, Christina D Wirth, Robin P Peeters, Bjørn O Åsvold, Wendy P J den Elzen, Robert N Luben, Misa Imaizumi, Alexandra P Bremner, Apostolos Gogakos, Richard Eastell, Patricia M Kearney, Elsa S Strotmeyer, Erin R Wallace, Mari Hoff, Graziano CeresiniFernando Rivadeneira, André G Uitterlinden, David J Stott, Rudi G J Westendorp, Kay-Tee Khaw, Arnuf Langhammer, Luigi Ferrucci, Jacobijn Gussekloo, Graham R Williams, John P Walsh, Peter Jüni, Drahomir Aujesky, Nicolas Rodondi, Thyroid Studies Collaboration

155 Citations (Scopus)

Abstract

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant datawere obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid functionwere defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcomewas hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age-and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidismwas 1.36 for hip fracture (95%CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56 471); for any fracture, HRwas 1.28 (95%CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HRwas 1.16 (95%CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for spine fracture, HRwas 1.51 (95%CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20 328). Lower TSHwas associated with higher fracture rates: for TSH of less than0.10 mIU/L, HRwas 1.61 for hip fracture (95%CI, 1.21-2.15; 47 events in 510participants); for any fracture, HRwas 1.98 (95%CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HRwas 1.61 (95%CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HRwas 3.57 (95%CI, 1.88-6.78; 8 events in 162 participants). Riskswere similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users)was associated with HRs of 1.52 (95%CI, 1.19-1.93) for hip fracture, 1.42 (95%CI, 1.16-1.74) for any fracture, and 1.74 (95%CI, 1.01-2.99) for spine fracture.No associationwas found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidismwas associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Original language	English
Journal	J A M A: The Journal of the American Medical Association
Volume	313
Issue number	20
Pages (from-to)	2055-65
Number of pages	11
ISSN	0098-7484
DOIs	https://doi.org/10.1001/jama.2015.5161
Publication status	Published - 26 May 2015

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Blum, M. R., Bauer, D. C., Collet, T-H., Fink, H. A., Cappola, A. R., da Costa, B. R., Wirth, C. D., Peeters, R. P., Åsvold, B. O., den Elzen, W. P. J., Luben, R. N., Imaizumi, M., Bremner, A. P., Gogakos, A., Eastell, R., Kearney, P. M., Strotmeyer, E. S., Wallace, E. R., Hoff, M., ... Thyroid Studies Collaboration (2015). Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis. J A M A: The Journal of the American Medical Association, 313(20), 2055-65. https://doi.org/10.1001/jama.2015.5161

Blum, MR, Bauer, DC, Collet, T-H, Fink, HA, Cappola, AR, da Costa, BR, Wirth, CD, Peeters, RP, Åsvold, BO, den Elzen, WPJ, 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, RGJ, Khaw, K-T, Langhammer, A, Ferrucci, L, Gussekloo, J, Williams, GR, Walsh, JP, Jüni, P, Aujesky, D, Rodondi, N & Thyroid Studies Collaboration 2015, 'Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis', J A M A: The Journal of the American Medical Association, vol. 313, no. 20, pp. 2055-65. https://doi.org/10.1001/jama.2015.5161

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title = "Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis",

abstract = "IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant datawere obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid functionwere defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcomewas hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age-and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidismwas 1.36 for hip fracture (95%CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56 471); for any fracture, HRwas 1.28 (95%CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HRwas 1.16 (95%CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for spine fracture, HRwas 1.51 (95%CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20 328). Lower TSHwas associated with higher fracture rates: for TSH of less than0.10 mIU/L, HRwas 1.61 for hip fracture (95%CI, 1.21-2.15; 47 events in 510participants); for any fracture, HRwas 1.98 (95%CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HRwas 1.61 (95%CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HRwas 3.57 (95%CI, 1.88-6.78; 8 events in 162 participants). Riskswere similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users)was associated with HRs of 1.52 (95%CI, 1.19-1.93) for hip fracture, 1.42 (95%CI, 1.16-1.74) for any fracture, and 1.74 (95%CI, 1.01-2.99) for spine fracture.No associationwas found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidismwas associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Female, Fractures, Bone, Hip Fractures, Humans, Hyperthyroidism, Hypothyroidism, Male, Middle Aged, Risk Factors, Spinal Fractures, Thyrotropin, Young Adult",

author = "Blum, {Manuel R} and Bauer, {Douglas C} and Tinh-Hai Collet and Fink, {Howard A} and Cappola, {Anne R} and {da Costa}, {Bruno R} and Wirth, {Christina D} and Peeters, {Robin P} and {\AA}svold, {Bj{\o}rn O} and {den Elzen}, {Wendy P J} and Luben, {Robert N} and Misa Imaizumi and Bremner, {Alexandra P} and Apostolos Gogakos and Richard Eastell and Kearney, {Patricia M} and Strotmeyer, {Elsa S} and Wallace, {Erin R} and Mari Hoff and Graziano Ceresini and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G} and Stott, {David J} and Westendorp, {Rudi G J} and Kay-Tee Khaw and Arnuf Langhammer and Luigi Ferrucci and Jacobijn Gussekloo and Williams, {Graham R} and Walsh, {John P} and Peter J{\"u}ni and Drahomir Aujesky and Nicolas Rodondi and {Thyroid Studies Collaboration}",

year = "2015",

month = may,

day = "26",

doi = "10.1001/jama.2015.5161",

language = "English",

volume = "313",

pages = "2055--65",

journal = "J A M A: The Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "20",

}

TY - JOUR

T1 - Subclinical Thyroid Dysfunction and Fracture Risk

T2 - A Meta-analysis

AU - Blum, Manuel R

AU - Bauer, Douglas C

AU - Collet, Tinh-Hai

AU - Fink, Howard A

AU - Cappola, Anne R

AU - da Costa, Bruno R

AU - Wirth, Christina D

AU - Peeters, Robin P

AU - Åsvold, Bjørn O

AU - den Elzen, Wendy P J

AU - Luben, Robert N

AU - Imaizumi, Misa

AU - Bremner, Alexandra P

AU - Gogakos, Apostolos

AU - Eastell, Richard

AU - Kearney, Patricia M

AU - Strotmeyer, Elsa S

AU - Wallace, Erin R

AU - Hoff, Mari

AU - Ceresini, Graziano

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G

AU - Stott, David J

AU - Westendorp, Rudi G J

AU - Khaw, Kay-Tee

AU - Langhammer, Arnuf

AU - Ferrucci, Luigi

AU - Gussekloo, Jacobijn

AU - Williams, Graham R

AU - Walsh, John P

AU - Jüni, Peter

AU - Aujesky, Drahomir

AU - Rodondi, Nicolas

AU - Thyroid Studies Collaboration

PY - 2015/5/26

Y1 - 2015/5/26

N2 - IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant datawere obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid functionwere defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcomewas hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age-and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidismwas 1.36 for hip fracture (95%CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56 471); for any fracture, HRwas 1.28 (95%CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HRwas 1.16 (95%CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for spine fracture, HRwas 1.51 (95%CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20 328). Lower TSHwas associated with higher fracture rates: for TSH of less than0.10 mIU/L, HRwas 1.61 for hip fracture (95%CI, 1.21-2.15; 47 events in 510participants); for any fracture, HRwas 1.98 (95%CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HRwas 1.61 (95%CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HRwas 3.57 (95%CI, 1.88-6.78; 8 events in 162 participants). Riskswere similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users)was associated with HRs of 1.52 (95%CI, 1.19-1.93) for hip fracture, 1.42 (95%CI, 1.16-1.74) for any fracture, and 1.74 (95%CI, 1.01-2.99) for spine fracture.No associationwas found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidismwas associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

AB - IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant datawere obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid functionwere defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcomewas hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age-and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidismwas 1.36 for hip fracture (95%CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56 471); for any fracture, HRwas 1.28 (95%CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HRwas 1.16 (95%CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for spine fracture, HRwas 1.51 (95%CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20 328). Lower TSHwas associated with higher fracture rates: for TSH of less than0.10 mIU/L, HRwas 1.61 for hip fracture (95%CI, 1.21-2.15; 47 events in 510participants); for any fracture, HRwas 1.98 (95%CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HRwas 1.61 (95%CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HRwas 3.57 (95%CI, 1.88-6.78; 8 events in 162 participants). Riskswere similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users)was associated with HRs of 1.52 (95%CI, 1.19-1.93) for hip fracture, 1.42 (95%CI, 1.16-1.74) for any fracture, and 1.74 (95%CI, 1.01-2.99) for spine fracture.No associationwas found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidismwas associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Female

KW - Fractures, Bone

KW - Hip Fractures

KW - Humans

KW - Hyperthyroidism

KW - Hypothyroidism

KW - Male

KW - Middle Aged

KW - Risk Factors

KW - Spinal Fractures

KW - Thyrotropin

KW - Young Adult

U2 - 10.1001/jama.2015.5161

DO - 10.1001/jama.2015.5161

M3 - Journal article

C2 - 26010634

SN - 0098-7484

VL - 313

SP - 2055

EP - 2065

JO - J A M A: The Journal of the American Medical Association

JF - J A M A: The Journal of the American Medical Association

IS - 20

ER -

Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

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