Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis | Endocrinology | JAMA | JAMA Network
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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

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.