Effect of Levothyroxine on Bone Health in Patients With Subclinical Hypothyroidism

Among patients aged 65 years and older with subclinical hypothyroidism, thyroid hormone replacement therapy with levothyroxine (LT4) had no significant effect on bone mass, bone geometry, and volumetric bone mineral density (BMD) compared with placebo, according to findings published in Bone

To assess the potential effect of LT4 on appendicular bone geometry and volumetric BMD, researchers performed a nested study within the Thyroid Hormone Replacement for Subclinical Hypothyroidism (TRUST) trial (ClinicalTrials.gov TRUST Thyroid trial NCT01660126 and Skeletal outcomes NCT02491008). In the TRUST trial, adults aged 65 and older with subclinical hypothyroidism were randomly assigned in a 1:1 fashion to receive either LT4 with dose titration or placebo with computerized mock titration. 

The researchers included data from 98 patients enrolled at a single TRUST site who had peripheral quantitative computed tomography performed at baseline and at follow-up visits at 1 or 2 years. The mean patient age was 73.9 years, 45.9% were women, and 12% had osteoporosis. Overall, 50 patients received LT4, and 48 received placebo. 

The primary outcomes were changes in the annual percentage of radius and tibia epiphysis and diaphysis bone geometry, measured as total and cortical cross-sectional area and cortical thickness, and of volumetric BMD, measured as bone mineral content and total, trabecular, and cortical volumetric BMD. 

The annual change in bone mineral content or volumetric BMD was similar between patients in the LT4 and placebo groups, and there was no significant difference in bone geometry or volumetric BMD changes at the diaphysis or epiphysis. There was a trend toward significance observed in regard to cortical BMD (P =.06), but no measurement found significant differences between the 2 patient groups. After adjustments for age, body mass index (BMI), and deleterious medications, no significant differences remained between the groups. 

The study was limited by a short follow-up period, a small sample size that prevented subgroup analyses regarding thyrotropin concentrations, and a lack of statistical adjustments for multiple outcomes.

The researchers concluded, “until long-term safety is ascertained, we suggest that physicians who wish to treat [subclinical hypothyroidism] in their older patients prescribe the lowest LT4 dose required to achieve a clinical response and keep [thyrotropin concentrations] within the reference range.”

Disclosure: One author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Büchi AE, Feller M, Netzer S, et al. Bone geometry in older adults with subclinical hypothyroidism upon levothyroxine therapy: a nested study within a randomized placebo controlled trial. Bone. Published online April 2, 2022. doi:10.1016/j.bone.2022.116404