title: Subclinical thyroid dysfunction and fracture risk: a meta-analysis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
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authors.forename: Douglas C
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authors.affiliation: Service of Endocrinology, Diabetes and Metabolism, University Hospital of Lausanne, Lausanne, Switzerland.
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authors.lastname: Collet
authors.affiliation: Department of Medicine, University of Minnesota School of Medicine, Minneapolis5Geriatric Research Education and Clinical Center, VA Medical Center, Minneapolis, Minnesota.
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authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia7Associate Editor, JAMA.
authors.forename: Anne R
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authors.affiliation: Department of Physical Therapy, Nicole Wertheim College of Nursing and Health Science, Florida International University, Miami.
authors.forename: Bruno R
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authors.affiliation: Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Christina D
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authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands10Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Robin P
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authors.lastname: Peeters
authors.affiliation: Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway12Department of Endocrinology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
authors.forename: Bjørn O
authors.initials: BO
authors.lastname: Åsvold
authors.affiliation: Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Wendy P J
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authors.lastname: den Elzen
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Robert N
authors.initials: RN
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authors.affiliation: Radiation Effects Research Foundation, Nagasaki, Japan.
authors.forename: Misa
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authors.affiliation: School of Population Health, University of Western Australia, Crawley, WA, Australia.
authors.forename: Alexandra P
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authors.lastname: Bremner
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Apostolos
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authors.affiliation: Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom.
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authors.lastname: Eastell
authors.affiliation: Department of Epidemiology and Public Health, University College Cork, Cork, Ireland.
authors.forename: Patricia M
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authors.lastname: Kearney
authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle.
authors.forename: Erin R
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authors.affiliation: Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway22Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
authors.forename: Mari
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authors.lastname: Hoff
authors.affiliation: Department of Clinical and Experimental Medicine, Geriatric Endocrine Unit, University Hospital of Parma, Parma, Italy.
authors.forename: Graziano
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authors.lastname: Ceresini
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands10Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Fernando
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authors.lastname: Rivadeneira
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands10Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
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authors.lastname: Uitterlinden
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom.
authors.forename: David J
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authors.lastname: Stott
authors.affiliation: Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Arnuf
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authors.lastname: Langhammer
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: Luigi
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authors.lastname: Ferrucci
authors.affiliation: Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jacobijn
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authors.lastname: Gussekloo
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Williams
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia28Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
authors.forename: Peter
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authors.lastname: Jüni
authors.affiliation: Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Drahomir
authors.initials: D
authors.lastname: Aujesky
authors.affiliation: Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Nicolas
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D050723:Fractures, Bone / Q000209:etiology*; D006620:Hip Fractures / Q000209:etiology*; D006801:Humans; D006980:Hyperthyroidism / Q000150:complications*; D007037:Hypothyroidism / Q000150:complications*; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D016103:Spinal Fractures / Q000209:etiology; D013972:Thyrotropin / Q000097:blood; D055815:Young Adult
chemical_list: D013972:Thyrotropin