Skeletal Effects of Levothyroxine for Subclinical Hypothyroidism in Older Adults: A TRUST Randomized Trial Nested Study
Open accessAbstract
Context: Both thyroid dysfunction and levothyroxine (LT4) therapy have been associated with bone loss, but studies on the effect of LT4 for subclinical hypothyroidism (SHypo) on bone yielded conflicting results. Objective: To assess the effect of LT4 treatment on bone mineral density (BMD), Trabecular Bone Score (TBS), and bone turnover markers (BTMs) in older adults with SHypo. Design and Intervention: Planned nested substudy of the double-blind placebo-controlled TRUST trial. Participants with SHypo were randomized to LT4 with dose titration versus placebo with computerized mock titration. Setting and Participants: 196 community-dwelling adults over 65 years enrolled at the Swiss TRUST sites had baseline and 1-year follow-up bone examinations; 4 participants withdrew due to adverse events not related to treatment. Main Outcome Measures: One-year percentage changes of BMD, TBS, and 2 serum BTMs (serum CTX-1 [sCTX] and procollagen type 1 N-terminal polypeptide [P1NP]). Student’s t-test for unadjusted analyses and linear regression adjusted for clinical center and sex were performed. Results: Mean age was 74.3 years ± 5.7, 45.4% were women, and 19.6% were osteoporotic. The unadjusted 1-year change in lumbar spine BMD was similar between LT4 (+0.8%) and placebo-treated groups (–0.6%; between-groups difference +1.4%: 95% confidence interval [CI] –0.1 to 2.9, P = .059). Likewise, there were no between-group differences in 1-year change in TBS (–1.3%: 95% CI –3.1 to 0.6, P = .19), total hip BMD (–0.2%: 95% CI –1.1 to 0.1, P = .61), or BTMs levels (sCTX +24.1%: 95% CI –7.9 to 56.2, P = .14), or after adjustment for clinical centers and sex. Conclusions: Over 1-year levothyroxine had no effect on bone health in older adults with SHypo. Registration: ClinicalTrial.gov NCT01660126 and NCT02491008
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The effects of LT4 treatment on bone for hypothyroid patients remain controversial.
“However, the effects of levothyroxine (LT4) treatment on bone for hypothyroid patients remain controversial.”
From Effects of levothyroxine therapy on bone and mineral metabolism in hypothyroidism: a systematic review and meta-analysis (2025) · cites this paper as [21]
The introduction says evidence on LT4’s effects on bone is scarce and conflicting, and the Discussion describes conflicting results from earlier trials. Those statements concern subclinical hypothyroidism; the cited paper does not establish the same uncertainty for hypothyroid patients generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredLT4 replacement doses do not impact bone metabolism biomarkers.
“It has been indicated in previous studies [17, 21] that LT4 replacement doses do not impact bone metabolism biomarkers.”
From Effects of levothyroxine therapy on bone and mineral metabolism in hypothyroidism: a systematic review and meta-analysis (2025) · cites this paper as [21]
The Results report no statistically significant difference in bone turnover markers between LT4 and placebo after one year. The citing sentence states this as a general absence of impact, whereas the study tested one-year treatment in community-dwelling adults aged 65 or older with subclinical hypothyroidism. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOther studies have failed to determine changes in BMD and bone metabolism in patients with hypothyroidism receiving LT4 replacement therapy.
“Conversely, other studies [20–22] have failed to determine changes in BMD and bone metabolism in patients with hypothyroidism receiving LT4 replacement therapy.”
From Effects of levothyroxine therapy on bone and mineral metabolism in hypothyroidism: a systematic review and meta-analysis (2025) · cites this paper as [21]
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- Authors
- Gonzalez Rodriguez, E., Stuber, M., Del Giovane, C., Feller, M., Collet, T.-H., Löwe, A. L., Blum, M. R., van Vliet, N. A., van Heemst, D., Kearney, P. M., Gussekloo, J., Mooijaart, S., Westendorp, R. G. J., Stott, D. J., Aeberli, D., Bauer, D. C., Hans, D., & Rodondi, N.
- Affiliations
- Center of Bone Diseases, Rheumatology Unit, Bone and Joint Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- University of Bern (CH)
- Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
- Centre Hospitalier Universitaire Vaudois (CH)
- Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
- University College Cork (IE)
- Leiden University Medical Center (NL)
- University of Copenhagen (DK)
- University of Glasgow (GB)
- University Hospital of Bern (CH)
- University of California, San Francisco (US)
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2019-11-08
- Volume
- 105
- Issue
- 1
- Pages
- 336-343
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2985284104
- Cited by
- 33
- References
- 8
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 3
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (acceptedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- BORIS (University Library Bern) (submittedVersion, other-oa)
- IRIS (submittedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- European Union (FP7-HEALTH-2011)
- Swiss National Science Foundation (320030-150025, 320030-172676, PZ00P3-167826)
- Swiss Heart Foundation
- Velux Stiftung (974a)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Keywords
- levothyroxine, subclinical hypothyroidism, bone mineral density, trabecular bone score, bone turnover markers, older adults, osteoporosis, TRUST trial, dose titration, lumbar spine, hip bone density, C-terminal telopeptide of type I collagen, P1NP, bone loss, thyroid hormone replacement, community-dwelling older adults, osteopenia, osteomalacia
- MeSH terms
- Aged, Aged, 80 and over, Bone and Bones, Double-Blind Method, Female, Humans, Hypothyroidism, Male, Osteoporosis, Switzerland, Thyroxine, Bone Density, Bone Remodeling, Age of Onset, Hormone Replacement Therapy, Asymptomatic Diseases
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