Background: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. Objective: To investigate the association between subclinical thyroid dysfunction and bone loss. Methods: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946–2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45–4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50–19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. Results: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = −0.18 (95% CI: −0.34, −0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = −0.14 (95% CI: −0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: −0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = −0.59; [95% CI: −0.99, −0.19]) and total hip region (%ΔBMD = −0.46 [95% CI: −1.05, −0.13]). In contrast, SHypo was not associated with bone loss at any site. Conclusion: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.
Bibliographical noteFunding Information:
Financial support: This work was supported by grants from the Swiss National Science Foundation (SNSF 320030-150025 and 320030-172676 to Prof. Rodondi). Dr. Collet’s research is supported by grants from the Swiss National Science Foundation (P3SMP3-155318, PZ00P3-167826). Cardiovascular Health Study (CHS): This research was supported by contracts HHSN2682012000 36C, HHSN268200800007C, N01HC55222, N01H C85079, N01HC85080, N01HC85081, N01HC85 082, N01HC85083, N01HC85086 and grant U01 HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. Health, Aging and Body Composition (Health ABC) study: The Health, Aging and Body Composition study is supported by contracts N01-AG-6-2101, N01-AG-6-2103 and N01-AG-6-2106 from the National Institute on Aging; grant R01-AG028050 from the National Institute on Aging; grant R01-NR012459 from the National Institute of Nursing Research; and by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Osteoporotic Fractures in Men (MrOS) Study: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS) and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160 and UL1 TR000128. Osteoporosis and Ultrasound Study (OPUS) is supported by Sanofi-Aventis, Eli Lilly, Novartis, Pfizer, Proctor and Gamble Pharmaceuticals and Roche. Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, the Netherlands; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Dutch Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Sheffield Study is funded by Arthritis Research United Kingdom.
Dr. Rodondi and Dr. Gussekloo report funding for a randomized controlled trial on subclinical hypothyroidism (TRUST trial) from the European Commission FP7-HEALTH-2011, Specific Programme ‘Cooperation’ – Theme ‘Health’ Investigator-driven clinical trials for therapeutic interventions in elderly populations (Proposal No: 278148-2). Dr. Peeters reports lecture and/or advisory board fees from Genzyme B.V., EISAI, IPSEN and Goodlife Fertility; and grant support from Veracyte, all outside of the submitted work. Dr. Eastell reports grants and personal fees from Amgen, grants from Department of Health, grants from AstraZeneca, grants, personal fees and nonfinancial support from Immunodiagnostic Systems, grants from ARUK/MRC Centre for Excellence in Musculoskeletal Ageing Research, grants from National Institute for Health Research, grants from MRC/AZ Mechanisms of Diseases Call, grants from MRC, grants and personal fees from Alexion, grants and other from National Osteoporosis Society, grants, personal fees and other from Roche, personal fees and other from Eli Lilly, other from European Calcified Tissue Society, other from IOF CSA, other from IBMS, other from ASBMR, personal fees from D-STAR, personal fees from GSK Nutrition, outside the submitted work; Dr Robbins reports funding from NHLBI during the conduct of the study. Dr Collet reports grants from Swiss National Science foundation during the conduct of the study.
- bone density
- bone loss
- prospective studies
- thyroid disease