Skeletal Effects of Levothyroxine for Subclinical Hypothyroidism in Older Adults: A TRUST Randomized Trial Nested Study.

Elena Gonzalez Rodriguez,Douglas C Bauer,Simon Mooijaart,Axel L Löwe,Nicolas Rodondi,David J Stott,Cinzia Del Giovane,Rudi G J Westendorp,Patricia M Kearney,Daniel Aeberli,Jacobijn Gussekloo,Martin Feller,Diana Van Heemst,Tinh-Hai Collet,Manuel R Blum,Mirah Stuber,Didier Hans,Nicolien A Van Vliet

doi:10.1210/clinem/dgz058

Abstract

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. 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. 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. 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. 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. 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. Over 1-year levothyroxine had no effect on bone health in older adults with SHypo. ClinicalTrial.gov NCT01660126 and NCT02491008.

Highlights

The prevalence of subclinical hypothyroidism (SHypo), defined as an elevated thyrotropin (TSH) level with free thyroxine (FT4) within the reference range, increases with age, reaching >10% in men over 65 years and up to 21% in women ≥75 years [1, 2]
Studies have found no association between SHypo and bone mineral density a (BMD) changes [11, 12]; a meta-analysis of individual participant data found no association between SHypo and fracture risk [10]
We found similar results for Trabecular Bone Score (TBS) both in adjusted analyses, and independently of the included vertebrae

Summary

Introduction

The prevalence of subclinical hypothyroidism (SHypo), defined as an elevated thyrotropin (TSH) level with free thyroxine (FT4) within the reference range, increases with age, reaching >10% in men over 65 years and up to 21% in women ≥75 years [1, 2]. Increasing evidence suggests that treating SHypo with levothyroxine (LT4) does not confer clinical benefit [3, 4]. Studies have found no association between SHypo and bone mineral density a (BMD) changes [11, 12]; a meta-analysis of individual participant data found no association between SHypo and fracture risk [10]. One RCT analyzed bone turnover markers (BTMs) which increased p transiently at 24 weeks in the LT4-treated group (between 7.7% for alkaline phosphatase, and 29.9% for e sCTX), during a 48 weeks treatment with LT4 [16]. No study has analyzed the effect of levothyroxine c substitution on Trabecular Bone Score, a textural index that evaluates pixel gray-level variations in the Ac lumbar spine DXA image and provides an indirect index of trabecular microarchitecture, independent of bone density [17]

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