The effects of TSH suppressive therapy on bone cannot be ignored because of the favorable prognosis and long survival of DTC patients [13]. However, there is no consensus about the effects of TSH suppressive therapy on BMD and fracture risk on account of heterogeneous study design (cross-sectional and longitudinal study), selected population, TSH suppressive level and duration, choice of outcome parameters, and so on. Here, we carried out a prospective cohort study that stratified the patients into three groups according to gender and menopausal status. DXA, as a gold standard for the diagnosis of osteoporosis, was used for the measurement of BMD in our study [14]. P1NP (bone formative marker) and β-CTX (bone resorptive marker) were used to evaluate BTMs, and they were recommended as reference BTMs by the International Osteoporosis Foundation (IOF) [15].
The effect of TSH suppressive therapy on BMD is the most controversial in postmenopausal women. In our study, there were no differences between postmenopausal DTC patients and controls in either BMD or BTMs both at 1-year and 2-year follow-up. The fracture risks calculated by FRAX were also similar between the two groups. These results suggested that short-term postoperative TSH suppressive therapy might not result in a deleterious effect on postmenopausal women. Consist with our results, Pei Zhang et al. reported that although postmenopausal women with 2-year postoperative TSH suppressive therapy (TSH<0.3 µIU/mL) showed a 1.9 % reduction in the LS-BMD, there was no significant difference in the LS-BMD between patients with TSH suppressive therapy (TSH<0.3 µIU/mL) and non-suppressed TSH patients (TSH>0.3 µIU/mL) after postoperative 6, 12, and 24 months [10]. In another 2-year longitudinal study including 23 postmenopausal patients with TSH suppressive therapy, no significant difference was observed in BMD at either baseline or follow-up compared with healthy controls [16].A recent meta-analysis including 17 cross-sectional studies reported that postmenopausal DTC patients receiving TSH suppressive therapy showed a significant decrease in LS-BMD, and a similar trend was seen in TH-BMD [17]. A large randomized controlled prospective cohort study by Sugitani et al. compared the T-score of the lumbar spine in 120 women receiving TSH suppressive therapy with those who did not receive TSH suppressive therapy. Those receiving TSH suppressive therapy had a significant deterioration of lumbar BMD from 1 year postoperatively, of which significant decreases in T-score within 1 year were seen in patients over 50 years old. The confounders such as menopause status, dietary calcium, vitamin D intake, physical exercise, and smoking were not evaluated in this study [6]. A retrospective cohort study including 273 postmenopausal women reported that a longer duration of TSH suppressive therapy was associated with decreased TBS rather than BMD [18]. Taken together, the results of TSH suppressive therapy on BMD in postmenopausal women are conflicting, but it is generally believed that TSH suppressive therapy has a negative effect on BMD. In this study, we failed to find an additional loss of BMD in postmenopausal DTC patients compared with controls, which might be related to the small sample size and short follow-up duration. Studies with a longer follow-up duration and a larger population are warranted. In premenopausal women, the FN-BMD in the DTC group was significantly higher than that in the control group at postoperative 1-year follow-up, a similar trend was observed in LS-BMD and TH-BMD. Therefore, our study suggested that TSH suppressive therapy had no adverse effects on BMD in premenopausal women. Two meta-analyses consistently reported FN-BMD and LS-BMD were significantly higher in patients with TSH suppressive therapy than in the control group [17, 19]. The safety of TSH suppressive therapy in premenopausal women might contribute to the protective role of estrogen. In our study, there was no significant difference in BMD between the male DTC patients and controls, which was in accordance with the results observed in previous studies. The majority of studies have shown that TSH suppressive therapy is safe in men [20]. Karner et al. conducted a 1-year cohort study of 9 men who had received TSH suppressive therapy for 8 years, and only mild bone loss was found in the distal radius. However, this study lacked a control group [5]. Another prospective cohort study which included the largest male sample size (n=28) showed LT4 therapy did not impair the BMD of patients compared with controls. The mean duration of LT4 therapy was 5.9 years and the mean follow-up duration was 1.1 years [7].
Up to date, only 2 studies evaluated risk fracture assessed by FRAX [21, 22]. Our results showed that, in postmenopausal women, MOF and HF were similar between DTC patients and controls, but in premenopausal women and men, MOF and HF in DTC patients were generally lower than those in the control group. These results suggested that postoperative 1-year TSH suppressive therapy did not increase the risk of fracture in patients on TSH suppressive therapy. A large population-based study revealed that both high and low dosage of levothyroxine treatment was associated with a higher risk for fractures in a J-shaped dose-dependent manner in post-thyroidectomy patients [23]. Another large cohort study also showed that DTC patients receiving levothyroxine have a higher risk of osteoporosis and osteoporotic fracture [24]. However, no fracture events were observed in overall participants during the period of the follow-up in this study, which might be limited to the small sample size and the short follow-up period.
LS-BMD in the male and postmenopausal controls, BMD at all sites in premenopausal controls significantly decreased at the 1-year follow-up compared to the baseline, while no significant change was observed within DTC patients. The male and premenopausal controls had a higher risk of fracture than DTC patients, which might partially account for their reduction of BMD. We further investigated lifestyles consisting of sleep and exercise between DTC patients and controls, only in the premenopausal women group, there was a significant difference in sleep time between the two groups. The number of subjects with sleep duration less than 7 hours was significantly higher in the premenopausal controls than the DTC patients (40.6 % vs. 6.3 %). A previous study showed decreased sleep duration closely associated with lower BMD, especially in middle-aged and elderly women [25]. Patients with cancer are usually told to rest and exercise properly, take a balanced diet, and avoid fatigue when they leave the hospital. Due to the possible negative effects of TSH suppressive therapy on bone, patients with DTC are also recommended to eat foods rich in calcium and ensure adequate sun exposure. Thus, DTC patients might adopt a healthier lifestyle compared to controls, which might be beneficial for bone health. Further researches can be carried out to explore whether lifestyle intervention can increase the BMD and reduce fracture risk of patients with long-term TSH suppressive therapy.
BTMs did not differ between male DTC patients and controls at baseline and at 1-year follow-up. At baseline, P1NP in premenopausal DTC patients was significantly lower than that in controls, the same was true at 1-year follow-up. However, P1NP was significantly increased at 1-year follow-up compared to baseline within the premenopausal DTC group. In vitro studies have demonstrated that thyroid hormone enhances expression and synthesis of the osteoblast differentiation markers collagen I, osteocalcin, and ALP in osteoblasts [26, 27]. The increased P1NP level might result from the action of mildly excess thyroid hormone. On the other hand, estrogen may provide some protection against bone loss and counteracts the resorptive effects of excess thyroid hormones in premenopausal patients with levothyroxine therapy [28]. The change of BTMs might provide an explanation for the higher BMD observed in premenopausal DTC patients than controls in this study, as well as in the above-mentioned meta-analyses [17, 19]. The change of β-CTX was significantly different between postmenopausal DTC patients and controls, with a reduction in DTC patients and an increase in controls. One possible explanation for the reduction of β-CTX is the aforementioned healthier lifestyle adopted by cancer patients. A longitudinal study by Schneider et al. including 28 men and 46 women with a 7.2-year TSH suppressive duration showed that both bone formation (PICP) and resorption (ICTP) serum markers generally decreased in DTC patients and healthy controls after 1.1-year follow-up, moreover, female DTC patients had significantly greater ICTP decreases than controls [7]. A cross-sectional study by Tournis et al. found that β-CTX in postmenopausal DTC patients was significantly higher than that in the control group, but no difference in P1NP. No difference in BTMs was found in premenopausal women [29]. Another cross-sectional study by Heijckmann reported ICTP levels were significantly higher in DTC patients than that in age-matched controls, PINP levels were not different [30]. In the research by Duan Bin Hong et al., the ALP, CTX-1, and P1NP of premenopausal DTC patients were significantly higher than that of the control group [11]. An early cross-sectional study by Kung et al. found that on thyroxine treatment for a mean period of 12.2 years, bone formation index (ALP, osteocalcin) and bone resorption index (urinary hydroxyproline) in postmenopausal DTC patients were higher than those in the control group [31]. Taken together, previous studies showed inconsistent results of BTMs, longitudinal studies with a longer duration of follow-up are necessary. In the multivariate regression analysis, P1NP and β-CTX were found to be negatively associated with FN-BMD. Therefore, FN-BMD might be more sensitive to the changes in BTMs.
The key strength of this study is that it is a prospective controlled cohort study and the data of this field in China was scarce. Both BMD and BTMs were evaluated in our study. Our study has several limitations. First, the sample size in each group was small. To avoid the difference between groups caused by sampling error, age, gender, and BMI were carefully matched between groups in our study. Second, the duration of follow-up was short and prolonged follow-up should be further investigated. Third, some factors associated with bone health were not thoroughly investigated, such as demographic characteristics (education, income), dietary habits, and so on.
In conclusion, our prospective controlled cohort study indicated that postoperative 1-year TSH suppressive therapy did not have detrimental effects on BMD and BTMs in men, premenopausal, and postmenopausal DTC patients. The postoperative 2-year TSH suppressive therapy did not lead to additional loss of bone mass in postmenopausal DTC patients.