Journal of Bone and Mineral Metabolism

, Volume 36, Issue 2, pp 209–220 | Cite as

RETRACTED ARTICLE: The relationship between subclinical thyroid dysfunction and the risk of fracture or low bone mineral density: a systematic review and meta-analysis of cohort studies

  • Ruifei Yang
  • Liang Yao
  • Yuan Fang
  • Jing Sun
  • Tiankang Guo
  • Kehu YangEmail author
  • Limin TianEmail author
Original Article


Our aim was to assess the risk of fractures or low bone mineral density (BMD) associated with subclinical thyroid dysfunction among cohorts. We systematically searched Medline (via PubMed), EMBASE, Cochrane Library, Web of Science, CENTRAL and SinoMed up to 31 July 2016 to identify cohort studies which have analyzed associations between subclinical thyroid dysfunction and fracture or BMD. A total of 19 population-based cohorts including 79,368 participants with relationships between subclinical thyroid dysfunction and fractures or BMD were identified as eligible for this meta-analysis. Subclinical hypothyroidism was associated with relative risks (RRs) of 1.34 (95% confidence interval [CI] 1.14, 1.58; I 2 = 32%) for hip fracture, 1.27 (95% CI 1.02, 1.58; I 2 = 51.9%) for any location of fracture, and 1.25 (95% CI 1.04, 1.50) for forearm fracture. Subclinical hyperthyroidism was associated with RRs of 1.71 (95% CI 1.06, 2.76; I 2 = 0.0%) for spine fracture, 1.20 (95% CI 1.03, 1.39; I 2 = 0.0%) for non-spine fracture, 1.44 (95% CI 1.21, 1.71; I 2 = 0.0%) for hip fracture, and 1.38 (95% CI 1.21, 1.58; I 2 = 0.0%) for any location of fracture. Subgroup analysis was conducted according to whether thyroid/anti-thyroid drug users were excluded or not and the results were similar. The change in BMD at the hip (weighted mean difference [WMD] = −0.060, 95% CI −0.116, −0.004; I 2 = 0.0%) and femoral neck (WMD = −0.046, 95% CI −0.077, −0.015; I 2 = 0.0%) was significantly decreased in the subclinical hyperthyroidism group compared with the euthyroidism groups in females. We failed to find any associations between the change in BMD and subclinical hypothyroidism. The overall quality of evidence was low in all outcomes. Subclinical hyperthyroidism and subclinical hypothyroidism were associated with an increased risk of fractures. Although subclinical hyperthyroidism was related to reduced BMD, no evidence could prove a definite association between subclinical hypothyroidism and the risk of low BMD.


Subclinical hypothyroidism Subclinical hyperthyroidism Fracture Bone mineral density 



The authors thank the Tian JH, Bai ZG and Yang KH (Evidence Based Medicine Center of Lanzhou University) for their help and support with the methodology and meta-processing.

Author contributions

LT conceived and designed the experiments; RY performed the experiments; RY, YF, and JS analyzed the data; RY wrote the paper; and LT, K-HY, and LY offered suggestions.

Compliance wih ethical standards

Conflict of interest



  1. 1.
    Cummings SR, Bates D, Black DM (2002) Clinical use of bone densitometry: scientific review. JAMA 288:1889–1897CrossRefGoogle Scholar
  2. 2.
    Kanis JA, Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, Oden A, Zethraeus N, Pfleger B, Khaltaev N (2005) Assessment of fracture risk. Osteoporos Int 16:581–589CrossRefGoogle Scholar
  3. 3.
    Vadiveloo T, Donnan PT, Cochrane L, Leese GP (2011) The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab 96:1344–1351CrossRefGoogle Scholar
  4. 4.
    National Osteoporosis Foundation (2002). America’s bone Health: the state of osteoporosis and low bone mass in our nation. National Osteoporosis Foundation, Washington, DCGoogle Scholar
  5. 5.
    Vestergaard P, Mosekilde L (2003) Hyperthyroidism, bone mineral and fracture risk−a meta-analysis. Thyroid 13:585–593CrossRefGoogle Scholar
  6. 6.
    National Guideline C (2014) Management and prevention of osteoporosis. Agency for Healthcare Research and Quality (AHRQ), Rockville, MD.
  7. 7.
    Ahmed LA, Schirmer H, Berntsen GK, Fonnebo V, Joakimsen RM (2006) Features of the metabolic syndrome and the risk of non-vertebral fractures: the Tromso study. Osteoporos Int 17:426–432CrossRefGoogle Scholar
  8. 8.
    Vestergaard P, Mosekilde L (2002) Fractures in patients with hyperthyroidism and hypothyroidism: a nationwide follow-up study in 16,249 patients. Thyroid 12:411–419CrossRefGoogle Scholar
  9. 9.
    Biondi B, Cooper DS (2008) The clinical significance of subclinical thyroid dysfunction. Endocr Rev 29:76–131CrossRefGoogle Scholar
  10. 10.
    Vadiveloo T, Donnan PT, Cochrane L, Leese GP (2011) The Thyroid Epidemiology, Audit, and Research Study (TEARS): the natural history of endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab 96:E1–E8CrossRefGoogle Scholar
  11. 11.
    Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, Tracy RP, Ladenson PW (2006) Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 295:1033–1041CrossRefGoogle Scholar
  12. 12.
    Waring AC, Arnold AM, Newman AB, Buzkova P, Hirsch C, Cappola AR (2012) Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. J Clin Endocrinol Metab 97:3944–3950CrossRefGoogle Scholar
  13. 13.
    Lee WY, Oh KW, Rhee EJ, Jung CH, Kim SW, Yun EJ, Tae HJ, Baek KH, Kang MI, Choi MG, Yoo HJ, Park SW (2006) Relationship between subclinical thyroid dysfunction and femoral neck bone mineral density in women. Arch Med Res 37:511–516CrossRefGoogle Scholar
  14. 14.
    Nagata M, Suzuki A, Sekiguchi S, Ono Y, Nishiwaki-Yasuda K, Itoi T, Yamamoto S, Imamura S, Katoh T, Hayakawa N, Oda N, Hashimoto S, Itoh M (2007) Subclinical hypothyroidism is related to lower heel QUS in postmenopausal women. Endocr J 54:625–630CrossRefGoogle Scholar
  15. 15.
    Saler T, Ahbab S, Sağlam ZA, Keşkek ŞÖ, Kurnaz S (2014) Endogenous subclinical hyperthyroidism may not lead to bone loss in premenopausal women. Hippokratia 18:240–244PubMedPubMedCentralGoogle Scholar
  16. 16.
    Furlan AD, Malmivaara A, Chou R, Maher CG, Deyo RA, Schoene M, Bronfort G, van Tulder MW, Editorial Board of the Cochrane Back, Neck Group (2015) 2015 updated method guideline for systematic reviews in the Cochrane Back and Neck Group. Spine (Phila Pa 1976) 40:1660–1673CrossRefGoogle Scholar
  17. 17.
    Zhang YJ (2009) Clinical analysis of clinical and subclinical hyperthyroidism in patients with bone mineral density. Neimeng Med J 4:434–437Google Scholar
  18. 18.
    Svare A, Nilsen TI, Asvold BO, Forsmo S, Schei B, Bjøro T, Langhammer A (2013) Does thyroid function influence fracture risk? Prospective data from the HUNT2 study, Norway. Eur J Endocrinol 169:845–852CrossRefGoogle Scholar
  19. 19.
    Bertoli A, Fusco A, Andreoli A, Magnani A, Tulli A, Lauro D, De Lorenzo A (2002) Effect of subclinical hypothyroidism and obesity on whole-body and regional bone mineral content. Horm Res 57:79–84PubMedGoogle Scholar
  20. 20.
    Waring AC, Harrison S, Fink HA, Samuels MH, Cawthon PM, Zmuda JM, Orwoll ES, Bauer DC, Osteoporotic Fractures in Men (MrOS) Study (2013) A prospective study of thyroid function, bone loss, and fractures in older men: the MrOS study. J Bone Miner Res 28:472–479CrossRefGoogle Scholar
  21. 21.
    Grimnes G, Emaus N, Joakimsen RM, Figenschau Y, Jorde R (2008) The relationship between serum TSH and bone mineral density in men and postmenopausal women: the Tromso study. Thyroid 18:1147–1155CrossRefGoogle Scholar
  22. 22.
    Finigan J, Greenfield DM, Blumsohn A, Hannon RA, Peel NF, Jiang G, Eastell R (2008) Risk factors for vertebral and nonvertebral fracture over 10 years: a population-based study in women. J Bone Miner Res 23:5–85Google Scholar
  23. 23.
    Bauer DC, Ettinger B, Nevitt MC, Stone KL, Study of Osteoporotic Fractures Research G (2001) Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med 134:561–568CrossRefGoogle Scholar
  24. 24.
    Garin MC, Arnold AM, Lee JS, Robbins J, Cappola AR (2014) Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: the cardiovascular health study. J Clin Endocrinol Metab 99:2657–2664CrossRefGoogle Scholar
  25. 25.
    Lee JS, Buzková P, Fink HA, Vu J, Carbone L, Chen Z, Cauley J, Bauer DC, Cappola AR, Robbins J. (2010) Subclinical thyroid dysfunction and incident hip fracture in older adults. Arch Intern Med 170:1876–1883CrossRefGoogle Scholar
  26. 26.
    Boekholdt SM, Titan SM, Wiersinga WM, Chatterjee K, Basart DC, Luben R, Wareham NJ, Khaw KT (2010) Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study. Clin Endocrinol 72:404–410CrossRefGoogle Scholar
  27. 27.
    Hofman A, Darwish Murad S, van Duijn CM, Franco OH, Goedegebure A, Ikram MA, Klaver CC, Nijsten TE, Peeters RP, Stricker BH, Tiemeier HW,Uitterlinden AG, Vernooij MW (2013) The Rotterdam Study: 2014 objectives and design update. Eur J Epidemiol 28:889–926CrossRefGoogle Scholar
  28. 28.
    Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, Bauer DC (2005) Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 165:2460–2466CrossRefGoogle Scholar
  29. 29.
    Nanchen D, Gussekloo J, Westendorp RG, Stott DJ, Jukema JW, Trompet S, Ford I, Welsh P, Sattar N, Macfarlane PW, Mooijaart SP, Rodondi N, de Craen AJ, PROSPER Group (2012) Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk. J Clin Endocrinol Metab 97:852–861CrossRefGoogle Scholar
  30. 30.
    Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P, Michelangeli V (2005) Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 165:2467–2472CrossRefGoogle Scholar
  31. 31.
    Murphy E, Glüer CC, Reid DM, Felsenberg D, Roux C, Eastell R, Williams GR (2010) 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 95:3173–3181CrossRefGoogle Scholar
  32. 32.
    Ceresini G, Ceda GP, Lauretani F, Maggio M, Usberti E, Marina M, Bandinelli S, Guralnik JM, Valenti G, Ferrucci L (2013) 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 61:868–874CrossRefGoogle Scholar
  33. 33.
    Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG (2004) Thyroid status, disability and cognitive function, and survival in old age. JAMA 292:2591–2599CrossRefGoogle Scholar
  34. 34.
    Cooper DS, Biondi B (2012) Subclinical thyroid disease. Lancet 379:1142–1154CrossRefGoogle Scholar
  35. 35.
    Mendonça Monteiro de Barros G, Madeira M, Vieira Neto L, de Paula Paranhos Neto F, Carvalho Mendonça LM, Corrêa Barbosa Lima I, Corbo R, Fleiuss Farias ML (2016) Bone mineral density and bone microarchitecture after long-term suppressive levothyroxine treatment of differentiated thyroid carcinoma in young adult patients. J Bone Miner Metab 34:417–421CrossRefGoogle Scholar
  36. 36.
    Baliram R, Sun L, Cao J, Li J, Latif R, Huber AK, Yuen T, Blair HC, Zaidi M, Davies TF (2012) Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling. J Clin Investig 122:3737–3741CrossRefGoogle Scholar
  37. 37.
    Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS (2006) The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid 16:375–380CrossRefGoogle Scholar
  38. 38.
    Faber J, Galloe AM (1994) Changes in bone mass during prolonged subclinical hyperthyroidism due to l-thyroxine treatment: a meta-analysis. Eur J Endocrinol 130:350–356CrossRefGoogle Scholar
  39. 39.
    Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY (1996) Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 81:4278–4289PubMedGoogle Scholar
  40. 40.
    Toft AD (2001) Clinical practice. Subclinical hyperthyroidism. N Engl J Med 345:512–516CrossRefGoogle Scholar
  41. 41.
    Biondi B, Palmieri EA, Klain M, Schlumberger M, Filetti S, Lombardi G (2005) Subclinical hyperthyroidism: clinical features and treatment options. Eur J Endocrinol 152:1–9CrossRefGoogle Scholar
  42. 42.
    Bassett JH, Williams AJ, Murphy E, Boyde A, Howell PG, Swinhoe R, Archanco M, Flamant F, Samarut J, Costagliola S, Vassart G, Weiss RE, Refetoff S, Williams GR (2008) A lack of thyroid hormones rather than excess thyrotropin causes abnormal skeletal development in hypothyroidism. Mol Endocrinol 22:501–512CrossRefGoogle Scholar
  43. 43.
    Barrett-Connor E, Weiss TW, McHorney CA, Miller PD, Siris ES (2009) Predictors of falls among postmenopausal women: results from the National Osteoporosis Risk Assessment (NORA). Osteoporos Int 20:715–722CrossRefGoogle Scholar
  44. 44.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) Group. JAMA 283:2008–2012CrossRefGoogle Scholar
  45. 45.
    Vestergaard P, Rejnmark L, Mosekilde L (2005) Influence of hyper- and hypothyroidism, and the effects of treatment with antithyroid drugs and levothyroxine on fracture risk. Calcif Tissue Int 77:139–144CrossRefGoogle Scholar
  46. 46.
    Ko YJ, Kim JY, Lee J, Song HJ, Kim JY, Choi NK, Park BJ (2014) Levothyroxine dose and fracture risk according to the osteoporosis status in elderly women. J Prev Med Public Health 47:6–46CrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan 2017

Authors and Affiliations

  1. 1.Department of EndocrinologyThe Gansu Provincial HospitalLanzhouPeople’s Republic of China
  2. 2.Institution of Clinical Research and Evidence Based MedicineThe Gansu Provincial HospitalLanzhouPeople’s Republic of China
  3. 3.Department of General SurgeryThe Gansu Provincial HospitalLanzhouPeople’s Republic of China
  4. 4.Evidence Based Medicine Center, School of Basic Medical SciencesLanzhou UniversityLanzhouPeople’s Republic of China

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