Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis | Endocrinology | JAMA | JAMA Network
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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.
Bassett  JH, Williams  GR.  Critical role of the hypothalamic-pituitary-thyroid axis in bone.  Bone. 2008;43(3):418-426.PubMedGoogle ScholarCrossref
3.
Bauer  DC, Ettinger  B, Nevitt  MC, Stone  KL; Study of Osteoporotic Fractures Research Group.  Risk for fracture in women with low serum levels of thyroid-stimulating hormone.  Ann Intern Med. 2001;134(7):561-568.PubMedGoogle ScholarCrossref
4.
Nicholls  JJ, Brassill  MJ, Williams  GR, Bassett  JH.  The skeletal consequences of thyrotoxicosis.  J Endocrinol. 2012;213(3):209-221.PubMedGoogle ScholarCrossref
5.
Flynn  RW, Bonellie  SR, Jung  RT, MacDonald  TM, Morris  AD, Leese  GP.  Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy.  J Clin Endocrinol Metab. 2010;95(1):186-193.PubMedGoogle ScholarCrossref
6.
Finigan  J, Greenfield  DM, Blumsohn  A,  et al.  Risk factors for vertebral and nonvertebral fracture over 10 years: a population-based study in women.  J Bone Miner Res.2008;23(1):75-85.PubMedGoogle ScholarCrossref
7.
Waring  AC, Harrison  S, Fink  HA,  et al.  A prospective study of thyroid function, bone loss, and fractures in older men: the MrOS study.  J Bone Miner Res.2013;28(3):472-479.PubMedGoogle ScholarCrossref
8.
Lee  JS, Buzková  P, Fink  HA,  et al.  Subclinical thyroid dysfunction and incident hip fracture in older adults.  Arch Intern Med. 2010;170(21):1876-1883.PubMedGoogle ScholarCrossref
9.
Wirth  CD, Blum  MR, da Costa  BR,  et al.  Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis.  Ann Intern Med. 2014;161(3):189-199.PubMedGoogle ScholarCrossref
10.
Simmonds  MC, Higgins  JP, Stewart  LA, Tierney  JF, Clarke  MJ, Thompson  SG.  Meta-analysis of individual patient data from randomized trials: a review of methods used in practice.  Clin Trials. 2005;2(3):209-217.PubMedGoogle ScholarCrossref
11.
Cardiovascular Health Study-National Heart, Lung, and Blood Institute.  The Cardiovascular Health Study.https://chs-nhlbi.org/. Accessed January 7, 2015.
12.
Rodondi  N, den Elzen  WP, Bauer  DC,  et al; Thyroid Studies Collaboration.  Subclinical hypothyroidism and the risk of coronary heart disease and mortality.  JAMA. 2010;304(12):1365-1374.PubMedGoogle ScholarCrossref
13.
BMJ Clinical Evidence.  Search filters (Medline cohort study filter): ClinicalEvidence website; 2013.http://clinicalevidence.bmj.com/x/set/static/ebm/learn/665076.html. Accessed May 5, 2015.
14.
Collet  TH, Gussekloo  J, Bauer  DC,  et al; Thyroid Studies Collaboration.  Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.  Arch Intern Med. 2012;172(10):799-809.PubMedGoogle ScholarCrossref
15.
Gencer  B, Collet  TH, Virgini  V,  et al; Thyroid Studies Collaboration.  Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.  Circulation. 2012;126(9):1040-1049.PubMedGoogle ScholarCrossref
16.
Collet  TH, Bauer  DC, Cappola  AR,  et al; Thyroid Studies Collaboration.  Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.  J Clin Endocrinol Metab. 2014;99(9):3353-3362.PubMedGoogle ScholarCrossref
17.
Riley  RD, Lambert  PC, Abo-Zaid  G.  Meta-analysis of individual participant data: rationale, conduct, and reporting.  BMJ. 2010;340:c221.PubMedGoogle ScholarCrossref
18.
Nanchen  D, Gussekloo  J, Westendorp  RG,  et al; PROSPER Group.  Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk.  J Clin Endocrinol Metab. 2012;97(3):852-861.PubMedGoogle ScholarCrossref
19.
Walsh  JP, Bremner  AP, Bulsara  MK,  et al.  Subclinical thyroid dysfunction as a risk factor for cardiovascular disease.  Arch Intern Med. 2005;165(21):2467-2472.PubMedGoogle ScholarCrossref
20.
Imaizumi  M, Akahoshi  M, Ichimaru  S,  et al.  Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism.  J Clin Endocrinol Metab. 2004;89(7):3365-3370.PubMedGoogle ScholarCrossref
21.
Ceresini  G, Ceda  GP, Lauretani  F,  et al.  Thyroid status and 6-year mortality in elderly people living in a mildly iodine-deficient area: the aging in the Chianti Area Study.  J Am Geriatr Soc. 2013;61(6):868-874.PubMedGoogle ScholarCrossref
22.
Hollowell  JG, Staehling  NW, Flanders  WD,  et al.  Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III).  J Clin Endocrinol Metab. 2002;87(2):489-499.PubMedGoogle ScholarCrossref
23.
Goichot  B, Sapin  R, Schlienger  JL.  Subclinical hyperthyroidism: considerations in defining the lower limit of the thyrotropin reference interval.  Clin Chem. 2009;55(3):420-424.PubMedGoogle ScholarCrossref
24.
Nevitt  MC, Ettinger  B, Black  DM,  et al.  The association of radiographically detected vertebral fractures with back pain and function: a prospective study.  Ann Intern Med. 1998;128(10):793-800.PubMedGoogle ScholarCrossref
25.
Helfand  M, Balshem  H.  Principles in Developing and Applying Guidance for Comparing Medical Interventions. Rockville, MD: Agency for Healthcare Research and Quality; 2008.
26.
Wells  GA, Shea  B, O’Connell  D,  et al.  The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed April 8, 2015.
27.
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188.PubMedGoogle ScholarCrossref
28.
Heinze  G, Schemper  M.  A solution to the problem of monotone likelihood in Cox regression.  Biometrics. 2001;57(1):114-119.PubMedGoogle ScholarCrossref
29.
da Costa  BR, Jüni  P.  Systematic reviews and meta-analyses of randomized trials: principles and pitfalls.  Eur Heart J. 2014;35(47):3336-3345.PubMedGoogle ScholarCrossref
30.
De Laet  C, Kanis  JA, Oden  A,  et al Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int.2005;16(11):1330-1338.PubMed
31.
Kanis  JA, Johnell  O, Oden  A,  et al Smoking and fracture risk: a meta-analysis. Osteoporos Int.2005;16(2):155-162.PubMed
32.
Drake  MT, Murad  MH, Mauck  KF,  et al.  Clinical review: risk factors for low bone mass-related fractures in men: a systematic review and meta-analysis.  J Clin Endocrinol Metab. 2012;97(6):1861-1870.PubMedGoogle ScholarCrossref
33.
Waring  AC, Arnold  AM, Newman  AB, Bùzková  P, Hirsch  C, Cappola  AR.  Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study.  J Clin Endocrinol Metab. 2012;97(11):3944-3950.PubMedGoogle ScholarCrossref
34.
Vittinghoff  E, Glidden  DV, Shiboski  S, McCulloch  CE.  Regression Methods in Biostatistics: Linear, Logistic, Survival, and Repeated Measures Models. New York, NY: Springer; 2005.
35.
Schoenfeld  D. Chi-squared goodness-of-fit tests for the proportional hazards regression model.  Biometrika.1980;67(1):145-153. doi: 10.1093/biomet/67.1.145.Google ScholarCrossref
36.
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634.PubMedGoogle ScholarCrossref
37.
Rodondi  N, Newman  AB, Vittinghoff  E,  et al.  Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death.  Arch Intern Med. 2005;165(21):2460-2466.PubMedGoogle ScholarCrossref
38.
Boekholdt  SM, Titan  SM, Wiersinga  WM,  et al.  Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study.  Clin Endocrinol (Oxf). 2010;72(3):404-410.PubMedGoogle ScholarCrossref
39.
Svare  A, Nilsen  TI, Åsvold  BO,  et al Does thyroid function influence fracture risk? prospective data from the HUNT2 study, Norway.  Eur J Endocrinol.2013;169(6):845-852.PubMedGoogle ScholarCrossref
40.
Gussekloo  J, van Exel  E, de Craen  AJ, Meinders  AE, Frölich  M, Westendorp  RG.  Thyroid status, disability and cognitive function, and survival in old age.  JAMA. 2004;292(21):2591-2599.PubMedGoogle ScholarCrossref
41.
Murphy  E, Glüer  CC, Reid  DM,  et al.  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.PubMedGoogle ScholarCrossref
42.
Hofman  A, Darwish Murad  S, van Duijn  CM,  et al.  The Rotterdam Study: 2014 objectives and design update.  Eur J Epidemiol. 2013;28(11):889-926.PubMedGoogle ScholarCrossref
43.
Fink  HA, Milavetz  DL, Palermo  L,  et al What proportion of incident radiographic vertebral deformities is clinically diagnosed and vice versa?  J Bone Miner Res.2005;20(7):1216-1222.PubMedGoogle ScholarCrossref
44.
Greenspan  SL, Greenspan  FS.  The effect of thyroid hormone on skeletal integrity.  Ann Intern Med. 1999;130(9):750-758.PubMedGoogle ScholarCrossref
45.
Schneider  R, Reiners  C.  The effect of levothyroxine therapy on bone mineral density: a systematic review of the literature.  Exp Clin Endocrinol Diabetes.2003;111(8):455-470.PubMedGoogle ScholarCrossref
46.
Barrett-Connor  E, Weiss  TW, McHorney  CA, Miller  PD, Siris  ES.  Predictors of falls among postmenopausal women: results from the National Osteoporosis Risk Assessment (NORA).  Osteoporos Int.2009;20(5):715-722.PubMedGoogle ScholarCrossref
47.
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.PubMedGoogle ScholarCrossref
48.
Turner  MR, Camacho  X, Fischer  HD,  et al.  Levothyroxine dose and risk of fractures in older adults: nested case-control study.  BMJ. 2011;342:d2238.PubMedGoogle ScholarCrossref
49.
Egger  M, Davey Smith  G, Altman  DG.  Systematic Reviews in Health Care: Meta-analysis in Context. 2nd ed. London, England: BMJ Publishing Group; 2001.
50.
Altman  DG.  Systematic reviews of evaluations of prognostic variables.  BMJ. 2001;323(7306):224-228.PubMedGoogle ScholarCrossref
51.
Walsh  JP, Bremner  AP, Feddema  P, Leedman  PJ, Brown  SJ, O’Leary  P.  Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques.  J Clin Endocrinol Metab. 2010;95(3):1095-1104.PubMedGoogle ScholarCrossref
52.
Meyerovitch  J, Rotman-Pikielny  P, Sherf  M, Battat  E, Levy  Y, Surks  MI.  Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians.  Arch Intern Med. 2007;167(14):1533-1538.PubMedGoogle ScholarCrossref
53.
Rosario  PW.  Natural history of subclinical hyperthyroidism in elderly patients with TSH between 0.1 and 0.4 mIU/l: a prospective study.  Clin Endocrinol (Oxf). 2010;72(5):685-688.PubMedGoogle ScholarCrossref
54.
Parle  JV, Franklyn  JA, Cross  KW, Jones  SC, Sheppard  MC.  Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom.  Clin Endocrinol (Oxf). 1991;34(1):77-83.PubMedGoogle ScholarCrossref
55.
Bahn  RS, Burch  HB, Cooper  DS,  et al Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists.  Thyroid.2011;21(6):593-646. doi:10.1089/thy.2010.0417.Google ScholarCrossref
56.
Meier  C, Beat  M, Guglielmetti  M, Christ-Crain  M, Staub  JJ, Kraenzlin  M.  Restoration of euthyroidism accelerates bone turnover in patients with subclinical hypothyroidism: a randomized controlled trial.  Osteoporos Int.2004;15(3):209-216.PubMedGoogle ScholarCrossref
57.
Yönem  O, Dökmetaş  HS, Aslan  SM, Erselcan  T.  Is antithyroid treatment really relevant for young patients with subclinical hyperthyroidism?  Endocr J. 2002;49(3):307-314.PubMedGoogle ScholarCrossref
58.
Buscemi  S, Verga  S, Cottone  S,  et al.  Favorable clinical heart and bone effects of anti-thyroid drug therapy in endogenous subclinical hyperthyroidism.  J Endocrinol Invest. 2007;30(3):230-235.PubMedGoogle ScholarCrossref
59.
Ross  DS.  Bone density is not reduced during the short-term administration of levothyroxine to postmenopausal women with subclinical hypothyroidism: a randomized, prospective study.  Am J Med. 1993;95(4):385-388.PubMedGoogle ScholarCrossref
Original Investigation
May 26, 2015

Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

Author Affiliations
  • 1Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland
  • 2Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco
  • 3Service of Endocrinology, Diabetes and Metabolism, University Hospital of Lausanne, Lausanne, Switzerland
  • 4Department of Medicine, University of Minnesota School of Medicine, Minneapolis
  • 5Geriatric Research Education and Clinical Center, VA Medical Center, Minneapolis, Minnesota
  • 6University of Pennsylvania School of Medicine, Philadelphia
  • 7Associate Editor, JAMA
  • 8Department of Physical Therapy, Nicole Wertheim College of Nursing and Health Science, Florida International University, Miami
  • 9Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
  • 10Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
  • 11Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway
  • 12Department of Endocrinology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
  • 13Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
  • 14Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 15Radiation Effects Research Foundation, Nagasaki, Japan
  • 16School of Population Health, University of Western Australia, Crawley, WA, Australia
  • 17Department of Medicine, Imperial College London, London, United Kingdom
  • 18Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom
  • 19Department of Epidemiology and Public Health, University College Cork, Cork, Ireland
  • 20Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 21Cardiovascular Health Research Unit, University of Washington, Seattle
  • 22Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
  • 23Department of Clinical and Experimental Medicine, Geriatric Endocrine Unit, University Hospital of Parma, Parma, Italy
  • 24Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom
  • 25Department of Public Health, University of Copenhagen, Copenhagen, Denmark
  • 26National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • 27School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia
  • 28Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
  • 29Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
JAMA. 2015;313(20):2055-2065. doi:10.1001/jama.2015.5161
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 data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were 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 outcome was 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 euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56 471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20 328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were 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 association was found between subclinical hypothyroidism and fracture risk.

Conclusions and Relevance  Subclinical hyperthyroidism was 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.

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