Effect of thyrotropin suppression therapy on bone microarchitecture in postoperative patients with differentiated thyroid cancer

Introduction

Differentiated thyroid cancer (DTC) accounts for more than 90% of thyroid malignancies, and its management strategy needs to follow the DATA framework (diagnosis, risk/benefit assessment, treatment decisions, and response assessment), in accordance with the latest guideline of the American Thyroid Association (1). The American Joint Committee on Cancer (AJCC) 8th edition staging system is essential for the development of treatment plans for active surveillance or immediate surgery (1,2). For patients who undergo surgical treatment, thyrotropin (TSH) suppression therapy is required after surgery, which refers to the use of thyroid hormone to suppress serum TSH concentrations below the normal range according to recurrence risk. This is commonly achieved by oral administration of superphysiological doses of levothyroxine (LT4) (3,4). The specific dosage of LT4 needs to be based on the disease risk stratification, and the aim of this strategy is to minimize the risk of recurrence by maintaining relatively low serum levels of TSH (1,5). Subclinical hyperthyroidism is defined as low levels of TSH accompanied by free thyroxine (FT4) and total or free triiodothyronine levels (T3 or FT3) within range (6,7). Prolonged iatrogenic subclinical hyperthyroidism also raises concerns about skeletal health, increasing the risk of bone loss and fracture (8-11).

Bone mineral density (BMD) is an effective indicator to measure bone health. Conventional dual-energy X-ray absorptiometry (DXA) is commonly utilized for evaluating areal bone mineral density (aBMD) and is considered the gold standard for diagnosing osteoporosis (12). A few studies have consistently demonstrated reduced aBMD in postmenopausal women with DTC following postoperative TSH suppression therapy, while findings regarding premenopausal women and male patients remain inconsistent (13,14). However, DXA comes with its limitation of failing to capture bone microstructural deterioration (15). High-resolution peripheral quantitative computed tomography (HR-pQCT) addresses this gap by providing three-dimensional quantification of trabecular and cortical microarchitecture, which are critical determinants of bone health evaluation (16,17). A prior cross-sectional observational study conducted in the non-Caucasian populations has indicated that prolonged TSH suppression in postoperative patients with DTC since childhood or adolescence may not have a significant negative impact on bone microarchitecture (18). The bone health of these patients in the Chinese population also requires great attention. This study leverages HR-pQCT to investigate the acute effects of active TSH suppression on bone microarchitecture as well as long-term skeletal sequelae in patients with prior TSH suppression history. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-552/rc).

Methods

Study design and subject selection

This cross-sectional study enrolled 70 adult patients in the Peking Union Medical College Hospital, Beijing, China, from August 2024 to June 2025 for assessment of bone geometry, microarchitecture and volumetric BMD (vBMD) by HR-pQCT. Among them, 67 patients with uniformly measured thyroid function at our institution were included for analysis and 3 cases were excluded due to inconsistent laboratory methodologies. None of the patients had osteomalacia, osteogenesis imperfecta, fibrous dysplasia of bone, Paget’s disease, hypopituitarism, Cushing’s syndrome, pheochromocytoma and paraganglioma, radius or tibia fractures, or had received corticosteroid treatment in the previous 6 months. Patients who had experienced postoperative hypoparathyroidism were excluded. Patients who had ever received anti-osteoporotic agents were excluded. After being provided with a detailed explanation of the study’s goals, all participants gave their written consent. Demographic, biochemical and pathological data were collected retrospectively through medical record review and clinical inquiry. HR-pQCT scans were conducted on control subjects who were matched in terms of age and gender with participants from a previous study which aimed to establish normative HR-pQCT reference data specific to the Chinese population (19). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Peking Union Medical College Hospital (No. K-6768) and informed consent was taken from all the patients.

Measurement of thyroid parameters

Thyroid function indicators, including serum TSH, FT4, and FT3, were assessed using the Direct chemiluminescence method (ADVIA Centaur, Siemens). The reference ranges were as follows: TSH 0.38–4.34 µIU/mL, FT4 0.81–1.89 ng/dL, FT3 1.80–4.10 pg/mL.

Commonly used indicators for assessing central thyroid hormone sensitivity included the thyrotropin thyroxine resistance index (TT4RI), thyroid-stimulating hormone index (TSHI), thyroid feedback quantile-based index (TFQI), which quantified the feedback loop of HPT axis (20). A higher value of these indicators represented a greater extent of impaired thyroid hormone sensitivity. The calculation methods for these indicators were detailed as follows:

TT4RI=FT4(pmol/L)∗TSH(mIU/L)[1]

TSHI=lnTSH(mIU/L)+0.1345∗FT4(pmol/L)[2]

TFQI=cdfFT4−(1−cdfTSH)[3]

HR-pQCT scans

The patients and controls included in the study underwent scanning of the non-dominant distal radius and distal tibia using an HR-pQCT system (Xtreme CTII, Scanco Medical AG, Brüttisellen, Switzerland). A standardized scan protocol was used, with the scan region positioned 9.0 mm (radius) and 22.0 mm (tibia) proximal to the respective articular surfaces. This protocol involved acquiring 168 contiguous axial slices per site at an isotropic voxel resolution of 61 µm. Image acquisition and reconstruction were performed according to manufacturer guidelines, with automated contouring algorithms used to delineate cortical and trabecular compartments. Manual adjustments were made by a trained operator to ensure anatomical accuracy (21).

The quality of images was thoroughly evaluated using a standardized 5-point grading system. Datasets with scores below grade 3 were excluded to reduce potential artifacts. The following parameters were directly calculated and automatically reported: (I) vBMD including total density (Tt.vBMD, mgHA/cm³), trabecular density (Tb.vBMD, mgHA/cm³), and cortical density (Ct.vBMD, mgHA/cm³); (II) geometric properties such as total cross-sectional area (Tt.Ar, mm²), trabecular area (Tb.Ar, mm²), and cortical area (Ct.Ar, mm²); (III) trabecular microarchitectural indices like trabecular bone volume fraction (Tb.BV/TV), trabecular number (Tb.N, mm⁻¹), trabecular thickness (Tb.Th, mm), trabecular separation (Tb.Sp, mm), and inhomogeneity of trabecular network (Tb.1/N.SD, mm); (IV) cortical metrics including cortical thickness (Ct.Th, mm), cortical porosity (Ct.Po, %), and cortical perimeter (Ct.Pm, mm) (17).

Statistical analysis

The normality of variable distribution was assessed through normality plots and the Shapiro-Wilk test. Continuous variables that followed a normal distribution were presented as means ± standard deviation (SD), while those that did not follow a normal distribution were represented as median (interquartile range). To compare differences between two groups for normally distributed continuous data, an independent sample t-test was conducted. For non-normally distributed continuous data, a Mann-Whitney U test was utilized. Categorical variables were reported as absolute numbers (percentage, %) and analyzed using either Pearson chi-squared or Fisher’s exact test. The relationship between thyroid function parameters and HR-pQCT indices was explored using Spearman analysis. A two-tailed P value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS statistics version 23.0 (SPSS Inc., Chicago, IL, USA).

Results

Basic characteristics

A total of 67 postoperative patients with DTC were initially enrolled (Figure 1). The cohort was stratified into active TSH suppression group (n=35) and TSH-normalized group (n=32). The former group included patients with TSH below the reference range currently, and the latter included patients currently in euthyroid state. Both groups demonstrated comparable demographic and clinical profiles as summarized in Table 1. Patients in the active TSH suppression group were relatively younger than TSH-normalized group (median 40.0 vs. 44.5 years, P=0.004). Each group had 5 male patients. Although no significant differences in height, patients in the active TSH suppression group showed lower weight (median 60.0 vs. 70.0 kg, P=0.047) and body mass index (BMI) (median 22.41 vs. 26.72 kg/m², P=0.01). As for surgical characteristics, 16 patients in the active TSH suppression group and 9 patients in the TSH-normalized group experienced total thyroidectomy. The diagnosis of DTC was supported by histopathological evidence, and most patients in both groups were evaluated as AJCC stage I (88.57% vs. 93.75%, P=0.46). As for the risk stratification according to the latest guidelines, 4 patients in the active TSH suppression group and 13 patients in the TSH-normalized group were evaluated as low-risk of recurrence (11.43% vs. 40.63%, P=0.006). Not only the AJCC stage but also the risk stratification would influence the extent of TSH suppression therapy. Currently, both LT4 daily dose (median 107.14 vs. 100.00 µg/day, P=0.02) and LT4 weight-based dose (median 1.79 vs. 1.35 µg/kg/day, P<0.001) were significantly higher in active TSH suppression group, aligning with therapeutic targets. Suppressed TSH levels (median 0.09 vs. 1.24 µIU/mL, P<0.001) with comparable values of FT4 (mean 1.61 vs. 1.43 ng/dL, P=0.001) and FT3 (median 3.33 vs. 3.07 pg/mL, P=0.001) were found in the active TSH suppression group. As for thyroid hormone sensitivity indices, although the levels of TT4RI and TSHI were significantly lower in the active TSH suppression group, the levels of TFQI showed no intergroup divergence.

Figure 1 The composition of enrolled postoperative patients with DTC. DTC, differentiated thyroid cancer; TSH, thyrotropin.

Bone microarchitecture in patients with DTC under TSH suppression

Comparisons of bone microarchitecture measured by HR-pQCT between patients with DTC under TSH suppression (n=35) and controls (n=35) were shown in Table 2. These controls were matched by age and gender, respectively. At the distal radius, patients with DTC under TSH suppression were found to have decreased Tt.vBMD (median 313.55 vs. 351.73 mgHA/cm³, P=0.01), Tb.Ar (median 260.10 vs. 240.50 mm², P=0.046), Ct.Ar (median 53.70 vs. 60.70 mm², P=0.006), and Ct.Th (mean 0.99 vs. 1.14 mm, P=0.002). No significant differences were observed between the 2 groups at the distal tibia. In the subgroup analysis stratified by gender, the comparisons in HR-pQCT indices between patients with DTC under TSH suppression and controls were analyzed (Figure 2). Female patients with DTC under TSH suppression were found to have decreased Tt.vBMD (−9.5%, mean 306.90 vs. 351.11 mgHA/cm³, P=0.01), Tb.Ar (+5.8%, mean 199.80 vs. 176.21 mm², P=0.03), Ct.Ar (−10.5%, mean 53.24 vs. 60.46 mm², P=0.001), Tb.Th (−2.8%, mean 0.222 vs. 0.230 mm, P=0.02), and Ct.Th (−11.5%, mean 0.96 vs. 1.13 mm, P=0.002) at the distal radius. At the distal tibia, increased Tb.BV/TV was shown in female patients with DTC under TSH suppression (+4.4%, median 0.231 vs. 0.211, P=0.044), and no significant differences of other bone microarchitecture indices were observed between the 2 groups. Mild damage to bone microarchitecture mainly occurred in the distal radius, specifically shown in Table S1. Comparing female patients in the active TSH suppression group and those in the TSH-normalized group, the bone microarchitecture was generally similar (Figure 3). The number of male patients was limited. Compared with male patients of the similar age, there was no significant difference in bone microarchitecture between patients in the active TSH suppression group and those in the TSH-normalized group (Figure 4).

Figure 2 Comparisons of percentage difference in the mean of bone microarchitecture parameters between patients with DTC under TSH suppression and healthy controls. (A) Female; (B) male. *, P<0.05. Ct.Ar, cortical bone area; Ct.Pm, cortical perimeter; Ct.Po, cortical porosity; Ct.Th, cortical thickness; Ct.vBMD, cortical volume bone mineral density; DTC, differentiated thyroid cancer; Tb.1/N.SD, inhomogeneity of trabecular network; Tb.Ar, trabecular bone area; Tb.BV/TV, trabecular bone volume to total volume ratio; Tb.N, trabecular number; Tb.Sp, trabecular separation; Tb.Th, trabecular thickness; Tb.vBMD, trabecular volume bone mineral density; TSH, thyrotropin; Tt.Ar, total bone area; Tt.vBMD, total volume bone mineral density.

Figure 3 Comparison of bone microarchitecture in female patients with DTC under TSH suppression (A-F) and female patients with DTC in euthyroid state currently (G-L). 3D visualization of cortical bone and trabecular bone in female patients with DTC under TSH suppression at the distal radius (A-C) and at the distal tibia (D-F), as well as female patients with DTC in euthyroid state currently at the distal radius (G-I) and at the distal tibia (J-L). DTC, differentiated thyroid cancer; TSH, thyrotropin.

Figure 4 Comparison of bone microarchitecture in male patients with DTC under TSH suppression (A-F) and male patients with DTC in euthyroid state currently (G-L). 3D visualization of cortical bone and trabecular bone in male patients with DTC under TSH suppression at the distal radius (A-C) and at the distal tibia (D-F), as well as male patients with DTC in euthyroid state currently at the distal radius (G-I) and at the distal tibia (J-L). DTC, differentiated thyroid cancer; TSH, thyrotropin.

Analysis for HR-pQCT comparisons in postmenopausal patients

A total of 15 postmenopausal women who underwent thyroid surgery were confirmed to have DTC, among whom 5 postmenopausal women were under TSH suppression currently and 10 postmenopausal women were in euthyroid state currently though they had experienced a period of subclinical hyperthyroidism after surgery. Data of 50 postmenopausal women collected from previous epidemiological surveys were used as controls for comparison of bone microarchitecture measured by HR-pQCT. At the distal radius, postmenopausal women under TSH suppression had decreased Ct.vBMD (median 881.60 vs. 942.30 mgHA/cm³, P=0.002), Ct.Ar (mean 47.64 vs. 58.53 mm², P=0.005) and Ct.Th (median 0.87 vs. 1.05 mm, P=0.01), and the group of postmenopausal women with DTC who were in euthyroid state currently had lower Ct.vBMD (median 907.60 vs. 942.30 mgHA/cm³, P=0.007) than the group of controls. At the distal tibia, only lower Ct.vBMD (median 809.70 vs. 867.32 mgHA/cm³, P=0.047) were found in postmenopausal women under TSH suppression. The comparisons of bone microarchitecture among different groups were shown in Figure 5, and the specific outcomes were shown in Table S2. The bone microarchitecture of postmenopausal women with DTC under TSH suppression was worse than those in euthyroid state. However, due to the small sample size, these differences did not reach statistical significance.

Figure 5 Associations between cortical microarchitecture indices and age in patients with DTC under TSH suppression (purple square, n=5), patients with DTC in euthyroid state (blue triangle, n=10) and controls (gray circle, n=50). (A) Radius-Ct.vBMD; (B) Radius-Ct.Th; (C) Tibia-Ct.vBMD. Ct.Th, cortical thickness; Ct.vBMD, cortical volume bone mineral density; DTC, differentiated thyroid cancer; TSH, thyrotropin.

Changes in bone microarchitecture along with the indicators of thyroid function

In the group of patients with DTC under TSH suppression (n=35), the comparisons of bone microarchitecture parameters assessed by HR-pQCT along with the levels of TSH, TT4RI, TSHI and TFQI after adjustment for age, gender and BMI are shown in Table 3. None of the indicators of bone microarchitecture had relationships with TSH and thyroid hormone sensitivity at both distal radius and tibia.

Discussion

This study revealed that the state of subclinical hyperthyroidism caused by TSH suppression therapy was associated with inferior bone microarchitecture for patients with DTC after surgery. They held decreased total bone volume and thinner cortical bone at the distal radius compared with controls, and this significant difference persisted in the subgroup of female patients. However, no differences were observed in bone microarchitecture of distal tibia. In postmenopausal patients, those undergoing TSH suppression therapy had decreased cortical bone volume and lower cortical thickness at the distal radius, and decreased cortical bone volume at the distal tibia.

Bone deterioration caused by excessive thyroid hormone exposure is primarily attributed to the relatively increased bone resorption resulting from a state of high bone turnover (22,23). Untreated hyperthyroidism manifests as significant bone loss (24). However, the skeletal effects of subclinical hyperthyroidism remain controversial. A few studies utilized DXA to evaluate the impact of postoperative TSH suppression therapy in patients with DTC on the skeleton, but showed different results. Some of them indicated that TSH suppression therapy in patients with DTC did not cause significant differences in BMD (25-28). However, a meta-analysis by Ku et al. revealed that lumbar spine BMD in postmenopausal patients who received suppression for more than 5 years was significantly lower than that in patients with short-term suppression (13). Both the surgery itself and postoperative treatment have a certain impact on patients’ postoperative quality of life (29). Pałyga et al. pointed out that recurrence was rare in patients with DTC, and the meta-analysis from Gubbi et al. indicated that TSH suppression therapy in intermediate- and high-risk DTC probably did not improve survival outcomes, but might instead increase the risk of cardiac and skeletal complications (30-32). The latest guideline also endorsed more conservative management strategies for low-risk DTC, such as considering active surveillance over immediate surgery and implementing a relatively relaxed, risk-adjusted protocol for postoperative TSH suppression therapy (1). Therefore, the specific implementation plan for TSH suppression therapy required a balance between preventing recurrence and mitigating the hazards of subclinical hyperthyroidism.

This controversy is partly due to the limitations of detection methods, which may be related to the insufficient sensitivity of BMD itself. At this point, the value of bone microarchitecture assessment becomes prominent. A previous histomorphometric analysis confirmed that iliac crest biopsies from 22 patients with thyrotoxicosis showed increased cortical porosity, mainly affecting cortical bone, while cortical bone structure improved after 4 months of antithyroid drug treatment (33). Bone biopsy allows direct observation of various subtle changes in the skeleton, enabling early detection of various signs of osteoporosis and quantitative analysis of bone tissue (34). However, bone biopsy is ultimately an invasive examination. With advancements in monitor equipment, bone microstructure detection can also be achieved through non-invasive means. The trabecular bone score (TBS) is a structural index derived from DXA images that reflects bone microarchitecture and assists in the prediction of fractures (35). It can help identifying individuals with normal BMD but impaired bone microstructure. Several studies indicated that patients with DTC who had undergone long-term TSH suppression held lower TBS, although their BMD might be normal (36-38). Hawkins Carranza et al. conducted a long-term follow-up and found that postmenopausal women with DTC undergoing TSH suppression therapy after surgery had a slight decrease of BMD but a significant decrease of TBS, and they had a gradual decline in overall bone health as the duration of TSH suppression therapy extended, regardless of the baseline levels of BMD (39). Schneider et al. reported a risk of reduced total bone volume at the distal radius measured by pQCT in premenopausal women with DTC under TSH suppression therapy (40). Tournis et al. also used pQCT to investigate the effect of TSH suppression therapy on bone health in patients with DTC and indicated that it led to significant trabecular bone loss as well as thinner cortical region in postmenopausal women mainly at the radius, while they did not find any relationship between the duration of disease and any deficits in bone microarchitecture (41).

HR-pQCT quantifies bone microstructural parameters of the radius and tibia, simulating the effects of bone biopsy to detect early microstructural changes in bones that are not identifiable by traditional methods, offering a new perspective on analyzing bone health (42). Vinther et al. found that the trends of changes in serum bone turnover markers and alterations in bone microarchitecture assessed by HR-pQCT in individuals with thyroid dysfunction can be jointly utilized to evaluate changes in bone metabolism (43). Moser et al. analyzed the HR-pQCT indices of patients with hypothyroidism who had been treated with LT4 for a long time, and pointed out that the bone microarchitecture of individuals who were well-substituted with LT4 would not be significantly affected (44). Mendonça Monteiro de Barros et al. conducted a study using HR-pQCT to measure the bone microarchitecture of patients with DTC who initiated TSH suppression therapy during adolescence, and did not find any bone microarchitectural damage (18). Our study included a broader range of patients across different age groups and examined them based on gender and age categories. We compared patients currently experiencing subclinical hyperthyroidism with those who had undergone TSH suppression therapy and were currently euthyroid, providing a more comprehensive assessment of the effects of TSH suppression therapy on bone health in patients with DTC after surgery. Our findings showed that TSH suppression therapy had a site-specific impact on bone health in postoperative patients with DTC, with active TSH suppression consistently associated with decreased cortical thickness at the distal radius, regardless of age or gender. Although other parameters indicating bone microarchitectural deterioration were also observed, including total vBMD, cortical vBMD, trabecular thickness, and various geometric properties, subclinical hyperthyroidism appeared to manifest as early cortical thinning before affecting trabecular bone. The slightly higher trabecular bone volume fraction at the distal tibia in female patients suggested less deterioration in trabecular bone compared to the cortical region, consistent with previous research using pQCT or bone biopsies (33,41). Most parameters of bone microarchitecture did not significantly differ between patients and controls in our study, supporting the trend in recent years to decrease the degree of TSH suppression therapy in postoperative DTC patients to minimize cardiovascular and skeletal complications (45).

To the best of our knowledge, this is the first study to investigate bone microarchitecture through HR-pQCT in postoperative patients with DTC under TSH suppression therapy in the Chinese population. The clinical utility of HR-pQCT is further highlighted by its ability to detect microstructural deficits that are invisible to DXA. Previous studies have shown normal aBMD in DXA examinations of patients with DTC undergoing postoperative TSH suppression therapy. However, HR-pQCT can reveal damage to bone microarchitecture, making it possible to identify the risk of skeletal deterioration in cases of subclinical hyperthyroidism. Several limitations should be noted in this study. Firstly, the cross-sectional design limits our ability to establish definite causal relationships, temporal progression, or recovery after the relaxation of TSH suppression. Secondly, the results of this single-center study should be interpreted cautiously in terms of their generalizability. The patient cohort, management strategies, and clinical expertise at our tertiary referral center may differ significantly from those in general community practice or other regions with varying healthcare resources. Thirdly, due to the lack of information on fracture incidence or validated fracture risk assessment scores, the severity of clinical risk can only be inferred from observed changes in bone microstructure. Furthermore, a longitudinal study could provide more robust evidence of the impact of surgery on bone microarchitecture over time. Future research involving a more diverse study population and utilizing longitudinal data collection methods could help address these limitations.

Conclusions

In conclusion, this study indicated bone microarchitectural deterioration, especially the cortical thickness of distal radius, in patients with DTC under postoperative TSH suppression therapy. Future research will be necessary to track changes in HR-pQCT at different time points during the period of subclinical hyperthyroidism to capture the dynamic transformation of bone and provide evidence for relevant preventive action.

Acknowledgments

The authors extend their thanks to the cooperation of all the participants and administrators in this study. The authors would like to thank Beiqi Yan, a native English-speaker who is majoring in medicine, for her help in polishing this paper.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-552/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-552/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-552/prf

Funding: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2021-I2M-1-001); Preferred Research Foundation for the Returned Overseas Scholars from Ministry of Human Resources and Social Security of China (Key Category) (2014).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-552/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Peking Union Medical College Hospital (No. K-6768) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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