Effect of Thyroid-Stimulating Hormone Suppression on Bone Mineral Density in Patients with Differentiated Thyroid Carcinoma: A Single Center Retrospective Study

Abstract

Background

This study evaluated the correlation between the degree and duration of thyroid-stimulating hormone (TSH) suppression and changes in bone mineral density (BMD) in patients who underwent surgery for differentiated thyroid carcinoma (DTC).

Methods

We included 65 women who underwent surgery for DTC and had at least two BMD measurements. Changes in BMD were statistically analyzed with a focus on postmenopausal women.

Results

The mean patient age was 52.2 years. During the follow-up period, 10 patients (15.4%) received osteoporosis treatment, and six (9.2%) experienced fractures. Analysis of 50 postmenopausal women revealed significant decreases in lumbar spine BMD (P=0.007), femoral neck BMD (P=0.008), and total hip BMD (P=0.010). Patients with TSH suppression <0.5 mU/L exhibited a 1.24%/y decrease in lumbar spine BMD, showing a marked reduction compared to a 0.33%/y decrease in BMD in the group with TSH ≥0.5 mU/L (P=0.025). Linear regression analysis comparing the duration of TSH suppression revealed a significant correlation with lumbar spine BMD (P<0.001). However, no correlation was observed between TSH suppression and decreased femoral neck BMD. Although not significant, the reduction in BMD in the lumbar spine was greater in the calcium and vitamin D non-supplementation group than in the supplementation group (1.31%/y vs. 0.71%/y; P=0.349).

Conclusions

Prolonged aggressive TSH suppression significantly affects lumbar spine BMD in patients with DTC. These findings highlight the need to balance TSH suppression with the risk of bone health deterioration, particularly in postmenopausal women.

GRAPHICAL ABSTRACT

INTRODUCTION

The incidence of thyroid cancer has been increasing globally.[1] Owing to advancements in treatment, the 5-year survival rate of patients with thyroid cancer in Asia has reached 95.3%.[2] Given its high prevalence and survival rates, the long-term management of patients with thyroid cancer has become a critical aspect of care. One of the key components of post-treatment management is thyroid-stimulating hormone (TSH) suppression therapy, which is widely used to reduce the risk of recurrence in patients with differentiated thyroid carcinoma (DTC). However, prolonged and excessive TSH suppression has been associated with increased risks of cardiovascular diseases, including arrhythmia and heart failure,[3,4] as well as adverse effects on bone health, such as osteoporosis and fractures.[5] Additionally, excessive TSH suppression has been linked to a decline in the quality of life and an increase in overall mortality.[4]

Thyroid hormones stimulate bone turnover in adults by increasing osteoclastic bone resorption.[6] Accordingly, a longstanding concern exists regarding the potential harm of TSH suppressive therapy in patients with DTC, particularly in postmenopausal women. Several studies have investigated the impact of TSH suppression on bone mineral density (BMD) in women; however, the results have been inconsistent, largely due to variations in study design, patient populations, and follow-up duration.[7] Although multiple studies and meta-analyses have demonstrated that chronic TSH suppression is generally safe in premenopausal women and men, it has been linked to reduced BMD, deterioration of bone microarchitecture, and a possible increase in fracture risk in postmenopausal women. [7,8] In response, the American Thyroid Association (ATA) recommends a risk-adapted approach that balances the benefits of recurrence prevention with the potential side effects, and the Korean Thyroid Association (KTA) similarly advises adjusting TSH targets based on individual disease risk after initial treatment.[9,10] Nevertheless, a lack of robust evidence exists to define the optimal level of TSH suppression across various risk groups, underscoring the need for further research to guide more precise and individualized management strategies.

This study explored changes in BMD in patients with DTC before treatment for osteoporosis. First, a comparative analysis was conducted between pre- and postmenopausal women to determine the differences in BMD reduction. Second, we assessed BMD reduction specifically in postmenopausal women according to the intensity of TSH suppression, duration of TSH suppression, and intake of calcium and vitamin D.

METHODS

1. Study subjects

This retrospective study analyzed patients who underwent thyroidectomy for DTC at Dankook University Hospital between 2013 and 2022. The initial cohort included 1,704 patients, of whom 101 underwent at least two BMD measurements during the follow-up period (Fig. 1). After excluding five patients with secondary causes of osteoporosis, hyperthyroidism (N=1), primary hyperparathyroidism (N=2), and long-term steroid therapy (N=2), a total of 96 patients underwent at least two BMD measurements (Fig. 1). To observe changes in BMD in women without osteoporosis treatment and to evaluate the significance of calcium and vitamin D supplementation, we additionally excluded six male patients, four patients with permanent hypoparathyroidism, and 21 patients who received treatment for osteoporosis immediately after the first BMD measurement. Therefore, 65 women were included in the final analysis, consisting of 50 post- and 15 premenopausal women. The study protocol conformed to the ethical guidelines of the World Medical Association Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Dankook University Hospital (IRB no. 2024-08-006).

Fig. 1.

Flowchart of the selection protocol for patients with differentiated thyroid carcinoma (DTC) in this study. BMD, bone mineral density.

2. Clinical data and TSH suppression parameter

Clinical data, including patient age, DTC type, surgery type, follow-up duration, levothyroxine dose, and calcium and vitamin D supplementation status, were extracted from electronic medical records. Serum 25-hydroxy-vitamin D levels measured during the observation period were also included. If multiple tests were performed, the last recorded value was used. Additionally, only patients who consistently consumed calcium and cholecalciferol supplements for at least one year were considered supplement users. The follow-up period of BMD measurement was defined as the time from the first BMD measurement to the last BMD measurement or the initiation of osteoporosis treatment. The BMD data obtained after the fracture occurred were not included in the analysis. To quantify TSH suppression exposure, patients were categorized into four groups based on the ATA and KTA guidelines: TSH <0.1 mU/L, 0.1≤TSH<0.5 mU/L, 0.5≤TSH≤2.0 mU/L, and >2.0 mU/L. In this study, all measured TSH values during the observation period were used to determine each patient’s TSH suppression category, and the degree of TSH suppression was generally consistent across measurements. The TSH value maintained for the longest duration was assigned as the representative TSH suppression category for each patient. The duration of exposure to each TSH category was recorded, and a TSH suppression intensity score was calculated using a weighting system, in which TSH levels of <0.1 mU/L, 0.1≤TSH<0.5 mU/L, 0.5≤TSH≤ 2.0 mU/L, and >2.0 mU/L was assigned weights of 4, 3, 2, and 1, respectively. The degree of TSH suppression was determined by multiplying the assigned weight by the duration of exposure in each category.

3. Statistical analysis

Normally and non-normally distributed variables are expressed as means±standard deviation and medians and interquartile ranges (25%–75%), respectively. Statistical analyses were conducted to assess the relationship between TSH suppression and BMD changes. Independent t-tests were used to compare mean values between two groups, whereas paired t-tests were used to assess pre- and post-BMD changes within the same group. Categorical variables were compared using the χ² test, and differences in BMD across three or more groups were analyzed using ANOVA. To evaluate the association between TSH suppression and changes in BMD, simple linear regression analysis was conducted. The regression coefficient (β) with its standard error (SE), co-efficient of determination (R²), and P-values were reported to assess the strength and significance of the relationships. All P values of less than 0.05 were considered to indicate statistical significance. Statistical analyses were performed using SPSS version 12.1 (SPSS Inc., Chicago, IL, USA).

RESULTS

1. Comparison between post- and premenopausal patients

A total of 65 women with a mean age of 52.2 years were included. Among them, 60 (92.3%) had classical papillary thyroid carcinoma (PTC), and 35 (53.8%) underwent total thyroidectomy. Levothyroxine therapy for TSH suppression was administered to 55 (84.6%) patients at a mean dose of 81 mcg/day. During the follow-up period, osteoporotic fractures occurred in six (9.2%) patients, most commonly at the wrist (4.6%), followed by the spine (1.5%) and hip (1.5%). In addition, 10 (15.4%) patients received treatment for osteoporosis after at least two BMD measurements, including bisphosphonates (9.2%), denosumab (3.1%), and selective estrogen receptor modulators (3.1%). Changes in BMD were analyzed only until the initiation of osteoporosis treatment. Additionally, 36 patients (55.4%) received calcium and vitamin D supplementation.

Several differences existed in the baseline characteristics between post- and premenopausal women. Postmenopausal women had a higher total thyroidectomy rate (62.3%) than premenopausal women (33.3%; P=0.010). Among postmenopausal women, 32 (64%) patients received calcium and vitamin D supplementation, which was higher than the proportion in premenopausal women (26.7%; P=0.017). The mean serum vitamin D level was also higher in postmenopausal women (28.9±9.0 ng/mL) compared to premenopausal women (14.0±2.9 ng/mL; P<0.001). During follow-up period, lumbar spine BMD decreased significantly in postmenopausal women (−0.89%/y), whereas premenopausal women exhibited minimal change (−0.04%/y; P=0.036). In contrast, BMD changes in the femoral neck and total hip were comparable between the groups (P= 0.431 and P=0.924, respectively) (Supplementary Table 1).

2. Characteristics according to the degree of TSH suppression in postmenopausal women

Among the 50 postmenopausal women, patients were categorized into four groups based on the degree of TSH suppression (Table 1). The group with TSH <0.1 mIU/L had the largest number of patients (N=23), whereas the group with TSH ≥2.0 mIU/L had the fewest (N=8). There were no significant differences among the groups in age, pathological subtype, follow-up duration, or baseline vitamin D levels. However, patients with more suppressed TSH levels were more likely to have undergone total thyroidectomy and received higher doses of levothyroxine. While the frequency of fractures and initiation of osteoporosis treatment did not differ significantly across groups, calcium and cholecalciferol supplementation were more commonly used in the more suppressed groups. Baseline BMD and T-scores were comparable among groups. At the beginning of the study, 10% of patients had osteoporosis, which increased to 28% over the course of the follow-up period (Table 1). A total of nine patients developed osteoporosis during follow- up, with no significant difference in incidence across TSH suppression groups. However, the mean time to osteoporosis diagnosis tended to vary: 59 months in the TSH <0.1 group, 44 months in the 0.1≤ TSH<0.5 group, 52.5 months in the 0.5≤TSH<2.0 group, and 75.5 months in the TSH ≥2.0 group, though these differences were not statistically significant.

Table 1.

Baseline characteristics of 50 postmenopausal patients with differentiated thyroid carcinoma who had serial bone mineral density measurement

Characteristics	Total (N=50)	Group 1: TSH<0.1 mIU/L (N=23)	Group 2: 0.1 mIU/L≤ TSH<0.5 mIU/L (N=9)	Group 3: 0.5 mIU/L≤ TSH<2.0 mIU/L (N=10)	Group 4: TSH≥2.0 mIU/L (N=8)	P b),c),d),e),f),g)
Age at diagnosis (yr)	56.1±7.29	56.0±6.91	57.8±9.00	55.6±7.66	55.0±6.93	0.879
Pathological subtype						0.646
Classical PTC	45 (90.0)	20 (87.0)	8 (88.9)	9 (90.0)	8 (100.0)
Follicular variant PTC	2 (4.0)	2 (8.7)	0 (0.0)	0 (0.0)	0 (0.0)
Aggressive subtype PTC	2 (4.0)	0 (0.0)	1 (11.1)	1 (10.0)	0 (0.0)
Follicular thyroid carcinoma	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Poor differentiated thyroid carcinoma	1 (2.0)	1 (4.3)	0 (0.0)	0 (0.0)	0 (0.0)
Surgery						<0.01
Hemithyroidectomy	18 (36.0)	0 (0.0)	4 (44.4)	7 (70.0)	7 (87.5)
Total thyroidectomy	32 (64.0)	23 (100.0)	5 (55.6)	3 (30.0)	1 (12.5)
Use of levothyroxine	44 (88.0)	23 (100.0)	9 (100.0)	6 (60.0)	6 (75.0)	0.004
Dose of levothyroxine (mcg/day)	88.8±46.0	112.0±19.7	116.7±37.5	83.3±30.3	52.1±30.0	<0.01c),d),f)
Duration of BMD follow-up (mon)a)	44.1±29.2	48.3±30.9	26.7±20.8	40.1±23.3	56.5±33.5	0.148b)
25(OH)D level (ng/mL)	28.9±9.0	30.2±9.2	29.4±11.5	26.0±7.8	26.0±5.4	0.740
Fracture	5 (10.0)	0 (0.0)	2 (22.2)	2 (20.0)	1 (12.5)	0.396
Spine	1 (2.0)	0 (0.0)	1 (11.1)	0 (0.0)	0 (0.0)
Hip	1 (2.0)	0 (0.0)	1 (11.1)	0 (0.0)	0 (0.0)
Wrist	2 (4.0)	0 (0.0)	0 (0.0)	1 (10.0)	1 (12.5)
Other	1 (2.0)	0 (0.0)	0 (0.0)	1 (10.0)	0 (0.0)
Medication of osteoporosis	10 (20.0)	3 (13.0)	4 (44.4)	1 (10.0)	2 (25.0)	0.046
Oral/IV bisphosphonate	6 (12.0)	1 (4.3)	2 (22.2)	1 (10.0)	2 (25.0)
Denosumab	2 (4.0)	0 (0.0)	2 (22.2)	0 (0.0)	0 (0.0)
SERM	2 (4.0)	2 (8.7)	0 (0.0)	0 (0.0)	0 (0.0)
Calcium and vitamin D replacement						0.006
None	18 (36.0)	6 (26.1)	2 (22.2)	5 (50.0)	5 (62.5)
Calcium 100 mg/500 mg + cholecalciferol 1,000 IU	32 (64.0)	17 (73.9)	7 (77.8)	5 (50.0)	3 (37.5)
BMD (g/cm2)
Lumbar spine	0.917±0.136	0.932±0.129	0.881±0.175	0.960±0.117	0.862±0.126	0.370
Femoral neck	0.690±0.087	0.684±0.093	0.654±0.065	0.726±0.099	0.720±0.073	0.317
Total hip	0.809±0.099	0.798±0.105	0.769±0.081	0.834±0.090	0.861±0.090	0.250
T-score
Lumbar spine	−0.83±1.18	−0.72±1.11	−1.08±1.50	−0.54±1.16	−1.24±1.10	0.558
Femoral neck	−1.02±0.82	−1.11±0.87	−1.41±0.61	−0.71±0.94	−0.78±0.68	0.308
Total hip	−0.34±0.85	−0.45±0.92	−0.71±0.72	−0.15±0.78	−0.09±0.77	0.253
Osteopenia/osteoporosis
Initial status	23 (46.0)/5 (10.0)	11 (47.8)/2 (8.7)	4 (44.4)/2 (22.2)	4 (40.0)/0 (0.0)	4 (50.0)/1 (12.5)	0.750
Follow-up	20 (40.0)/14 (28.0)	11 (47.8)/5 (21.7)	4 (44.4)/4 (44.4)	2 (20.0)/2 (20.0)	3 (37.5)/3 (37.5)	0.330

The data is presented as mean±standard deviation or N (%). Bold values indicate statistical significance (P<0.05).

^a)Duration of follow-up between the first and last bone mineral density (BMD) measurement or the initiation of osteoporosis treatment.

^b)P<0.05 between group 1 and 2,

^c)P<0.05 between group 1 and 3,

^d)P<0.05 between group 1 and 4,

^e)P<0.05 between group 2 and 3,

^f)P<0.05 between group 2 and 4,

^g)P<0.05 between group 3 and 4 (post-hoc analysis).

TSH, thyroid-stimulating hormone; PTC, papillary thyroid carcinoma; 25(OH)D, 25-hydroxy-vitamin D; IV, intravenous; SERM, selective estrogen receptor modulator.

3. Changes in BMD in postmenopausal women

The changes in BMD during the follow-up period in postmenopausal women are shown in Table 2. Lumbar spine BMD showed a significant annual decrease of 0.0077±0.0194 g/cm² per year (0.89%) (P=0.007). Similarly, BMD of the femoral neck decreased by 0.0067±0.0266 g/cm² per year (0.81%) (P=0.008), and total hip BMD decreased by 0.0063±0.0163 g/cm² per year (0.67%) (P=0.010). Changes in T-scores in each site followed a pattern similar to that of BMD.

Table 2.

Changes in bone mineral density in postmenopausal women according to intensity of thyroid-stimulating hormone suppression

BMD (g/cm2)	Initial	Follow-up	P	Annual BMD changes (g/cm2/yr [%/yr])	TSH<0.5 mIU/L (N=32)	TSH≥0.5 mIU/L (N=18)	P
Lumbar spine	0.917±0.136	0.887±0.127	0.007	−0.0077±0.0194 (−0.89)	−0.0119±0.0204 (−1.24)	−0.0021±0.0151 (−0.33)	0.025
Femoral neck	0.690±0.087	0.666±0.096	0.008	−0.0067±0.0266 (−0.81)	−0.0056±0.0292 (−0.86)	−0.0082±0.0228 (−0.92)	0.763
Total hip	0.809±0.099	0.792±0.098	0.010	−0.0063±0.0163 (−0.67)	−0.0064±0.0162 (−0.68)	−0.0061±0.0170 (−0.55)	0.946
T-score
Lumbar spine	−0.83±1.18	−1.05±1.11	0.008	-	-	-	-
Femoral neck	−1.06±0.82	−1.29±0.90	0.008	-	-	-	-
Total hip	−0.36±0.86	−0.52±0.84	0.010	-	-	-	-

The data is presented as mean±standard deviation. Bold values indicate statistical significance (P<0.05).

BMD, bone mineral density; TSH, thyroid-stimulating hormone.

1) Changes in BMD according to intensity of TSH suppression

The annual rate of BMD change according to the degree of TSH suppression was further analyzed (Supplementary Table 2). Lumbar spine BMD showed a greater reduction with stronger TSH suppression. Specifically, the 0.1≤TSH <0.5 group exhibited a 1.52% annual decrease, while the TSH ≥2.0 group showed a minimal reduction of only 0.01%, which was statistically significant (P<0.05). In contrast, no significant differences in BMD were observed at the femoral neck or total hip sites across TSH suppression levels.

Given the observed differences at a TSH threshold of 0.5 mIU/L, we compared BMD changes between the TSH <0.5 and TSH ≥0.5 groups (Table 2). In the TSH <0.5 group, lumbar spine BMD decreased by 1.24% per year, whereas the TSH ≥0.5 group showed a smaller annual decrease of 0.33%, which was statistically significant (P=0.025). However, no significant differences were found in the femoral neck or total hip BMD between the two groups (Table 2).

2) Changes in BMD according to the duration of TSH suppression

A linear regression analysis evaluating the correlation between TSH suppression duration and BMD reduction demonstrated a significant positive correlation between lumbar spine BMD and TSH suppression duration (β=0.002, R²= 0.363, P<0.001; Fig. 2A). In contrast, the BMD of the femur neck and total hip exhibited no significant correlation with the duration of TSH suppression (P=0.129 and P=0.846, respectively; Fig. 2B, C).

Fig. 2.

Correlation of the duration of thyroid-stimulating hormone (TSH) suppression and decline in bone mineral density (BMD). (A) Correlation of the duration of TSH suppression and the decline in lumbar spine BMD. (B) Correlation of the duration of TSH suppression and the decline in femoral neck BMD. (C) Correlation of the duration of TSH and the decline in total hip BMD. SE, standard error.

3) Changes in BMD according to the degree of TSH suppression

The degree of TSH suppression was determined by multiplying the assigned weight (1–4) of each TSH suppression category by the duration of exposure. A linear regression analysis evaluating the correlation between the degree of TSH suppression and BMD reduction demonstrated a significant positive correlation in terms of lumbar spine BMD (β=0.003, R²=0.112, P=0.018; Fig. 3A). In contrast, the BMD of the femoral neck and total hip exhibited no significant correlation with the degree of TSH suppression (P=0.575 and P=0.855, respectively; Fig. 3B, C).

Fig. 3.

Correlation of the degree of thyroid-stimulating hormone (TSH) suppression and decline in bone mineral density (BMD). (A) Correlation of the duration of TSH suppression and the decline in lumbar spine BMD. (B) Correlation of the duration of TSH suppression and the decline in femoral neck BMD. (C) Correlation of the duration of TSH and the decline in total hip BMD. SE, standard error.

4. Effect of calcium and vitamin D supplementation on BMD in postmenopausal women

To assess the impact of calcium and vitamin D supplementation, patients were divided into two groups: those who received no supplementation and those who received 100 mg or 500 mg of calcium+1,000 IU cholecalciferol. At baseline, the BMD of the lumbar spine was significantly higher in the no supplementation group (0.980±0.106 g/cm²) compared with that in the Ca/VitD supplementation group (0.882±0.140 g/cm²; P=0.008), whereas no significant difference existed in terms of femur neck and total hip (Table 3). At the end of the follow-up, the BMD of the lumbar spine, femoral neck, and total hip showed no significant differences between the groups. When comparing the changes (Table 3, Fig. 4), the lumbar spine BMD reduction was 5.61% in the no supplementation group, whereas the Ca/VitD supplementation groups exhibited a smaller reduction (2.38%), although this difference was not significant (P=0.120). Similarly, reductions in the femoral neck and total hip BMD were more pronounced in the non-supplementation group, although the differences were less marked than those observed in the lumbar spine.

Table 3.

Changes in bone mineral density according to supplement of calcium and cholecalciferol

BMD (g/cm2)	Lumbar spine		P	Femoral neck		P	Total hip		P
	None (N=18)	Ca+VitD (N=32)		None (N=18)	Ca+VitD (N=32)		None (N=18)	Ca+VitD (N=32)
Baseline	0.980±0.106	0.882±0.140	0.008	0.707±0.080	0.687±0.091	0.380	0.829±0.069	0.804±0.110	0.494
Follow-up	0.925±0.107	0.866±0.135	0.096	0.674±0.099	0.664±0.097	0.745	0.814±0.087	0.783±0.110	0.323
Annual change (g/cm2/yr [%/yr])	−0.0111±0.0186 (−1.31)	−0.0058±0.0198 (−0.71)	0.349	0.0094±0.0176 (−0.90)	−0.0053±0.0301 (−0.66)	0.590	−0.0088±0.0187 (−0.69)	−0.0051±0.0153 (−0.65)	0.535

The data is presented as mean±standard deviation.

BMD, bone mineral density; Ca, calcium; VitD, vitamin D.

Fig. 4.

Changes in bone mineral density (BMD) according to supplement of calcium (Ca) and cholecalciferol. VitD, vitamin D.

DISCUSSION

This study confirmed that BMD loss was more prominent in postmenopausal than in premenopausal women with DTC who were undergoing TSH suppression therapy. Furthermore, BMD reduction was primarily observed in the lumbar spine and was associated with greater TSH suppression intensity and longer suppression duration. In addition, although not statistically significant, the group that received calcium and vitamin D supplementation showed a slower decline in BMD, with this trend being more prominent in the lumbar spine. These findings provide valuable insights into the long-term management of thyroid cancer, particularly in postmenopausal populations.

These results have several notable clinical implications. In postmenopausal women with a low risk of thyroid cancer recurrence, balancing the benefits and risks of TSH suppression is crucial; however, in some cases, avoiding TSH suppression may be necessary. For moderate-risk patients, where the benefits of TSH suppression remain unclear, a less aggressive suppression strategy should be considered, avoiding full suppression (TSH <0.1 mIU/L). Additionally, because prolonged TSH suppression is associated with greater BMD loss, reducing the duration of TSH suppression should also be considered. However, further studies are required to establish the optimal duration of suppression. Although not statistically significant, calcium and vitamin D supplementation appeared to mitigate BMD loss, suggesting that routine supplementation should be recommended for postmenopausal women undergoing TSH suppression therapy, provided no adverse effects are observed. Furthermore, comprehensive bone health management, including regular BMD monitoring, fracture prevention education, exercise, and pharmacological interventions such as antiresorptive therapy, should be considered when necessary.

Our findings are consistent with those of previous studies, indicating that TSH suppression therapy has a more pronounced effect on BMD in postmenopausal women than in premenopausal women or men.[11] A meta-analysis of observational studies reported that BMD was significantly decreased in postmenopausal women with thyroid cancer, whereas premenopausal women showed an increase in BMD, and men exhibited no significant changes. [8,12] Similarly, in this study, after 44 months of follow-up, postmenopausal women experienced a 0.89%/y reduction in lumbar spine BMD, whereas premenopausal women had only a 0.04%/y change. This suggests that estrogen deficiency-related bone remodeling alterations in postmenopausal women may interact with subclinical hyperthyroidism to exacerbate bone loss.[13] Therefore, postmenopausal women with thyroid cancer should be considered a high-risk group for TSH suppression-related osteoporosis.

This study also confirmed a meaningful association between both the intensity and duration of TSH suppression and BMD loss, which is generally in line with previous findings. A longitudinal study conducted in the United States, involving 537 patients with low- to intermediate-risk thyroid cancer over a six-year period, found that osteoporosis developed in 3.9% of patients, with a 3.5-fold higher risk in those whose TSH was suppressed to ≤0.4 mIU/L.[14] Similarly, a meta-analysis of 16 studies evaluating BMD in thyroid cancer patients showed that significant BMD loss was only observed in those with TSH <0.1 mIU/L (standardized mean difference [SMD], −0.55; 95% confidence interval [CI], −0.99 to −0.10; I²=75.8%).[15] However, some studies have reported conflicting results. For instance, a Korean study involving 100 postmenopausal women found no direct association between TSH suppression and BMD reduction,[16] although its relatively short observation period (12–18 months) may limit the strength of its conclusions. Another study that followed 36 postmenopausal women over a mean period of 4.02 years also found no significant difference in BMD between the TSH-suppressed and control groups.[17] Furthermore, meta-analytic data showed that TSH levels between 0.1 and 0.49 mIU/L did not significantly affect BMD (SMD, −0.50; 95% CI, −1.07 to 0.07; I²=84.9%). Despite these discrepancies, our findings support the notion that TSH suppression (TSH <0.5 mIU/L), particularly when prolonged, is associated with significant lumbar spine BMD loss in postmenopausal women. These results highlight the importance of a balanced approach to TSH suppression, emphasizing caution in applying aggressive suppression strategies in this high-risk population.

Another key finding of this study was that BMD loss was predominantly observed in the lumbar spine with no significant changes in femoral neck BMD. This finding is consistent with previous research and may be explained by physiological differences between trabecular and cortical bones. TSH suppression-induced subclinical hyperthyroidism accelerates bone remodeling, leading to increased bone resorption, reduced mineralization, lower BMD and a higher fracture risk.[18] The lumbar spine consists primarily of trabecular bone, which is more metabolically active and, therefore, more susceptible to changes in bone turnover, whereas the femoral neck has a higher proportion of cortical bone, making it less responsive to metabolic changes.[15] Additionally, postmenopausal estrogen deficiency predominantly affects the trabecular bone, further accelerating lumbar spine BMD loss.[19] The combined effects of estrogen deficiency and TSH suppression therapy likely explain why the lumbar spine BMD reduction was more pronounced than the femoral neck BMD reduction in our study. Furthermore, the lumbar spine BMD tended to decline more rapidly, whereas femoral neck BMD changes occurred more gradually,[20] suggesting that longer observation periods may be necessary to detect femoral neck changes.

The results of this study indicated that calcium and vitamin D supplementation may help mitigate BMD loss in postmenopausal women with TSH suppression. Although limited research has addressed this issue, a study by Mazziotti et al. [21] which analyzed 179 postmenopausal women reported that those receiving both vitamin D and calcium supplementation had a lower incidence of vertebral fractures. In our study, although statistical significance was not reached, the group receiving calcium and cholecalciferol for an average of 58.9±34.1 months exhibited less lumbar spine and femoral neck BMD loss than the nonsupplemented group. Given the multifactorial nature of BMD reduction, proving the protective effects of supplementation is challenging; however, our findings suggest that postmenopausal women requiring long-term TSH suppression should consider routine calcium and vitamin D supplementation.

This study had several limitations. Because this was a single-center study, the sample size was relatively small, limiting subgroup analyses. Longer studies are needed to evaluate the long-term effects of levothyroxine therapy on BMD. In addition, the retrospective study design prevented definitive causal conclusions, and some potential confounding variables may not have been fully controlled. In addition, this study did not include bone microarchitecture analysis or bone turnover markers, which could provide deeper insights into the effects of TSH suppression on bone metabolism. Furthermore, because only women were included, the findings may not be applicable to male patients with thyroid cancer. Despite these limitations, our study has several strengths. Unlike previous studies that primarily compared TSH-suppressed patients with healthy controls, this study quantitatively assessed TSH suppression intensity and duration as cumulative exposure variables, thereby offering clinically relevant insights into appropriate TSH suppression strategies.

In conclusion, this study confirms that TSH suppression therapy poses a significant risk of BMD loss, particularly in postmenopausal women, and that both TSH suppression intensity and duration are associated with lumbar spine BMD reduction. These findings suggest that patients with low-risk PTC should avoid excessive TSH suppression, and even in high-risk patients, individualized TSH targets should be considered based on patient age and baseline BMD. Additionally, in patients requiring prolonged TSH suppression, regular BMD monitoring and osteoporosis prevention strategies, including calcium and vitamin D supplementation, should be implemented to mitigate bone loss.