Result:

- Table 1. Comparison of characteristics between the group with

differentiated thyroid cancer (DTC) and the control group

In the table 1, the comparison data of 2 study groups is obtained, namely the DTC
subject and the control subject. On DTC subjects, serum TSH levels were lower
than controls, while serum levels for FT4, P1NP, CTX-1, and ALP were higher than
controls. Based on the significance value of p value <0.05, it was found that the p
value for each serum level of TSH, FT4, ALP, CTX-1, P1NP had a p-value of less
than 0.05 which indeed there was a significant difference between the study
groups, Significant differences were not found in serum FT3, iPTH, age, Ca, P,
vitamin D3, and Z-BMD scores between the two study groups because the p-value
was more than 0,05.

- Table 2. A comparison of the prevalence of low bone mineral density (BMD)

between subjects with differentiated thyroid cancer (DTC) and controls

The prevalence of low BMD was higher in the DTC group than in the control group. A
comparison of prevalence of low BMD between the two groups is shown in Table 2. The
prevalence of BMD patients in the DTC group and control group showed that 65 subject in
 the DCT group with low BMD 29 (44.62%) (n=65) while the control subject with low BMD
14 (28%) (n=50). Statistical for confidence interval : 1.083-5.345 and the odds ratio = 2.406

- Table 3.The relationship of serum thyroid hormone levels with Z-scores

of BMD and BTMs

Correlation analysis between serum thyroid hormone levels and Z-scores of BMD
and BTMs in the DTC group are shown in Table 3. Table 3 show that no obvious
associations between serum FT3, FT4, and TSH levels and Z-scores of BMD, iPTH,
P1NP, CTX-1, Ca, P, vitamin D3, and ALP in controls (P > 0,05). Similarly, there were no
significant associations between serum FT3, FT4 levels, and the above parameters in
the DTC group. Serum TSH levels were negatively associated with CTX-1 and ALP.
There were no associations of serum TSH levels with Z-scores of BMD and other
BTMs. So all of the characterized about relationship of serum thyroid hormone levels
with Z-scores of BMD and BTMs are not associated except ALP and CTX-1. ALP is an
enzyme that functions to help break down proteins in the body so this corelated with
TSH level and so CTX-1 which is a marker of bone resorption.

Table 3. Correlation coefficients (r values) between serum thyroid hormones levels and T-scores of
bone mineral density (BMD) and bone turnover markers (BTMs) in subjects with differentiated
thyroid cancer (DTC)

These results, in table 3 shown TSH level associated with ALP and CTX-1 (negatively)
but not with BMD. Low BMD level in premenopousal DTC woman who received long term
LT4 after thyroidectomy, long term LT4 was significantly risk factor decreased bone
strength, mainly by increasingly bone turnover marker (BTM) to a certain extent and
increased resorptive changes, but it is not osteoporosis. BTM is the process of
resorption followed by replacement by new bone with little change in shape, and it
occurs throughout a person's life. So there is great significance to evaluate the bone
metabolism status in premenopausal patients with thyroid cancer after receiving long-
term levothyroxine therapy, which can prevent osteopaenia or osteoporosis

- Table 4. Serum thyroid-stimulating hormone (TSH) levels in association with T-scores

of bone mineral density (BMD) and bone turnover markers (BTMs) using multivariate
logistic regression

The

significant difference was found in ALP which was 0.016 with a CI (convidence interval) of
0.998 – 6619, and in CTX-1 which was 0.023, with 0.953-3,728 CI (convidence interval).
The p-value at < 0.05 was considered statistically significant.

The aim of this study was to determine the impact of long-term TSH suppression treatment
on BMD and BTM of premenopausal women with thyroid cancer after total thyroidectomy.
In this study, iPTH, P1NP, CTX-1, Ca, P, vitamin D3, and ALP were selected as the BTM
evaluation index.

The effect of TSH suppressive therapy on BMD in premenopausal subjects undergoing

thyroidectomy is controversial. The majority of studies show no effect of TSH suppressive
therapy on BMD in premenopausal women and men. In this study, no change in BMD was
found in these premenopausal women on long-term TSH suppression therapy. The main
reason is because pre-menopausal women are not at high risk of decreased bone density due
to the effects of estrogen.

In premenopausal women with DTC who had received one year of TSH suppression
treatment, serum levels of P1NP, CTX-1, and ALP were higher than in TSH controls. In DTC
patients after thyroidectomy can induce subclinical hyperthyroidism, especially in the first
two years; Serum TSH level should be less than 0.1 mIU/L. Increased thyroid hormone can
stimulate bone turnover and bone resorption, resulting in decreased bone strength, damage to
bone structure, and an increased risk of fracture. In this study, increased serum levels of
P1NP, CTX-1, and ALP in DTC patients meant increased bone turnover and decreased bone
quality.

the prevalence of low BMD was higher among premenopausal DTC women receiving long-
term LT4 therapy. Osteoporosis is less common in premenopausal women than in
postmenopausal women. The main reason is the protective effect of estrogen in
premenopausal women who are less likely to develop osteoporosis. WHO and the
International Society for Clinical Densitometry (ISCD) recommend the use of a Z BMD
score rather than a T score in the diagnosis of low BMD, and the diagnosis of osteo porosis in
premenopausal women is only safe if there is a history of low fractures.

conflict of interest

that the risk of osteoporosis and fracture is increased in patients receiving TSH suppressive
therapy. They also found that high cumulative doses of levothyroxine were significantly
associated with an increased risk of osteoporosis and fractures. However, these conclusions
are all based on postmenopausal women.

Serum TSH levels were negatively associated with CTX-1 and ALP, but not with BMD. TSH
suppressive therapy increases bone turnover to some extent. The degree of inhibition of TSH
correlates with the rate of change in bone turnover. Previous data on dose suppression of le
vothyroxine therapy on bone mass and bone turnover in premenopausal women are limited.
However, several studies in hypothyroid premenopausal women on long-term levothyroxine
therapy have shown increased bone turnover and increased resorptive changes, but not
osteoporosis. Hyperthyroid patients also had significantly higher serum BTM concentrations
than euthyroid subjects, in relation to thyroid hormone excess and high bone turnover.
Therefore, it is very important to evaluate bone metabolic status in premenopausal patients
with thyroid cancer after receiving long-term levo thyroxine therapy, which can prevent
osteopenia or osteoporosis in the future through interventional treatment.

One of the limitations of our study is that the sample size is small. A larger cohort is needed
to investigate whether serum TSH levels in premenopausal women receiving long-term
levothyroxine treatment correlate with BMD and BTM. In different periods after thyroid
cancer surgery, there are different standards for the control of serum TSH levels. In addition,
despite clinical practice guidelines for the management of DTC, there are no
recommendations regarding rational serum TSH levels to prevent cancer recurrence and
improve survival. Therefore, in future studies, groups can be divided based on serum TSH
levels, so as to more accurately assess the impact of TSH inhibitory therapy on changes in
bone metabolism.