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INTRODUCTION
Current management for patients with differentiated thyroid cancer includes near total thyroidectomy and radioactive iodine therapy followed by administration of supraphysiological doses of levothyroxine (L-T4). Because hyperthyroidism accelerates bone turnover and shortens the normal bone remodeling cycle [1,2], it was expected that suppressive L-T4 therapy for differentiated thyroid cancer might influence bone mineral density (BMD). Although longitudinal studies in patients with suppressive L-T4 therapy for differentiated thyroid cancer have reported conflicting data [3-12], the majority of investigators have concluded that recommended dose of L-T4 for postoperative therapy does not have negative effects on bone density [13]. However, the effects of suppressive L-T4 therapy on bone density in the Korean population have not been well defined. The aim of our study is to evaluate the impact of long-term suppressive therapy with L-T4 on BMD and bone turnover markers in Korean female patients who have undergone suppressive therapy for more than 10 years.
METHODS
Subjects
This cross-sectional study was conducted at a single center, Yonsei University Wonju College of Medicine, Korea. Ninety-four female subjects (range, 35-79 years) who underwent total or near total thyroidectomy and radioactive iodine therapy due to thyroid-differentiated carcinoma were enrolled in the study. We enrolled subjects from October 2009 to October 2010. Mean follow-up period was 12.17 ± 4.27 years (median, 12.00 years; range, 5-22 years) and 60.4% of enrolled subjects had been receiving L-thyroxine for more than 10 years. The mean dosage of L-thyroxine during the follow-up period was 160 µg (range, 25-200 µg/day). The percentage of subjects who were premenopausal was 66.7%. Patients with a history of vertebral or femoral fracture that were treated with agents that could interfere with bone metabolism, such as steroids and bisphosphonates, were excluded. To examine the effects of L-T4 on skeletal tissue, we analyzed BMD, bone turnover markers, and biochemical parameters from all subjects, who were divided into three groups by thyroid stimulating hormone (TSH) level (group 1 with TSH level ≤0.001 µIU/mL; group 2 with TSH level between 0.001 and 0.17 µIU/mL; group 3 with TSH level >0.17 µIU/mL) and four groups by quartile of free T4 level. Because most patient TSH levels were suppressed below 0.01 µIU/mL (61.4% of subjects), TSH level could not be grouped into tertiles. Instead, patients with TSH level above 0.01 µIU/mL were divided into two groups-upper 50% and lower 50%.
BMD and laboratory assays
BMD was measured at the lumbar spine (levels L2-4), femur neck, and trochanter by dual-energy radiographic absorptiometry (LUNAR prodigy, GE Healthcare, Little Chalfont, UK). T-score was defined as the number of standard deviations (SDs) between measured values and the mean for a control group from the general population matched for gender at 25-45 years of age. T-score ≤-2.5 SD at the lumbar spine, femur neck, or femur trochanter was defined as osteoporosis; T-score between -2.5 and -1.0 SD was defined as osteopenia; T-score ≥ -1.0 was defined as normal. A serum sample was taken from each participant without overnight fasting. We measured free T4 and TSH using the Centaur system (Siemens, Munich, Germany). For bone turnover markers, osteocalcin representative bone formation marker and C-telopeptides of type I collagen (CTX, Modular E170, Hoffmann-La Roche, Basel, Switzerland) representative bone resorption marker were measured.
Statistical analysis
Data were expressed as the mean ± SD. A one-way analysis of variance was used for the comparison of various anthropometric parameters, biochemical parameters, and BMD. The associations between the prevalence of osteoporosis or osteopenia and TSH and FT4 stratified groups were assessed using a chisquare test. The odds ratios were analyzed using logistic regression. All analyses were done using PASW ver. 18.0 (SPSS Inc., Chicago, IL, USA) and SAS ver. 9.2 (SAS Institute, Cary, NC, USA). A P-value <0.05 was considered significant.
RESULTS
The clinical characteristics of the subjects are summarized in Table 1. Mean duration of LT4 treatment was 15.0 ± 5.7 years, and mean L-T4 dose was 125.27 ± 38.81 µg/day (range, 25-200 µg/day). Because most patient TSH levels were suppressed below 0.01 µU/mL, the subjects of group 1 defined by TSH ≤0.001 µIU/mL represented 61.17% of participants. The subjects of group 2 defined by TSH >0.001 to ≤0.17 µIU/mL and group 3 defined by TSH >0.17 µIU/mL accounted for 17% and 21% of patients, respectively. Mean BMD contents and T-scores for each group divided by TSH level did not differ significantly among groups (Table 2). Also, bone turnover markers and prevalence of osteoporosis and osteopenia were not different among groups (Table 2). For grouping by FT4 level, all subjects were divided into FT4 quartiles. The subjects of Q1, Q2, Q3, and Q4 were defined by FT4 ≤1.44 ng/dL, FT4 >1.44 through ≤1.63 ng/dL, FT4 >1.63 through ≤1.86 ng/dL, and FT4 >1.86 ng/dL, respectively. The relationship between BMD and prevalence of osteoporosis and osteopenia also did not show any differences among the four FT4 groups (Table 3). No differences existed between BMD and bone turnover markers among groups according to FT4 and TSH levels when subgroup analysis was performed according to state of menopause (data not shown). The odds ratios for risk of osteoporosis and osteopenia in groups 2 and 3 were not significant when compared to the reference group (group 1) (Table 4). The odds ratios for risk of osteoporosis and osteopenia in Q2, Q3, and Q4 by FT4 were not significantly larger than the reference group (Q 1) (Table 4). Also, the prevalence of osteoporosis and osteopenia was not different among groups (Table 4).
DISCUSSION
Although overt endogenous hyperthyroidism is known to be an important risk factor of osteoporosis, osteopenia, and osteoporotic fracture [14-17], the clinical outcome of patients with subclinical hyperthyroidism, mild thyrotoxicosis associated with treatment of levothyroxine for hypothyroidism, or suppression therapy after thyroid cancer remains unclear [3-8,18,19].
Abe et al. [20] reported that the TSH receptor is expressed in osteoblasts and osteoclasts. Also, TSH treatment could suppress bone turnover and prevent bone loss [20,21]. Two other in vitro studies reported that increased thyroid hormone-not decreased TSH level-induced bone loss [22,23]. Subsequently, although composited results also exist [24], the roles of thyroid hormone and TSH on BMD have been emphasized by clinicians.
Patients with differentiated thyroid cancer have been treated with a supraphysiological dose of levothyroxine for inhibition of tumor recurrence and metastasis after total or near total thyroidectomy. Clinical studies regarding the relationship between levothyroxine treatment and bone turnover markers or BMD do not show consistent results. Thus, the effect of high dose levothyroxine on bone metabolism remains controversial.
There have been no data about levothyroxine or BMD reported from patients with differentiated thyroid cancer in Korea. In our data, the prevalence of osteoporosis and osteopenia were not different between patients with different TSH suppression and different levels of FT4. Also, BMD and bone turnover markers were not different among the patient groups. However, the prevalence of osteoporosis and osteopenia did not show consistent change according to increase of TSH or decrease of FT4 level. Although we expected that the prevalence of osteoporosis and osteopenia would decrease incrementally according to TSH level, the results were contrary to our expectation. This may be due to the number of subjects: because a large number of patients were treated with levothyroxine up to TSH level < 0.003 µIU/mL, the number of subjects with high TSH level and low FT4 level was relatively small. Therefore, the prevalence of osteoporosis and osteopenia among subjects with high TSH level and low FT4 level may seem improbably high. Because the purpose of TSH suppression is prevention of tumor recurrence, we attempted to suppress the TSH level below the undetectable level. But, for patients with old age, comorbid condition, or reduced adherence to medication due to thyrotoxic symptoms, we suppressed the TSH level to 0.1-2.0 µIU/mL. So, the majority of the subjects showed TSH levels of <0.003 µIU/mL.
The limitations of our study include small sample size and the fact that all participants were enrolled at a single center. Also, we could not analyze daily calcium intake or exercise-both known to be influencing factors for osteoporosis and osteopenia. Finally, because we performed a cross-sectional study, we could not obtain the initial BMD and other markers that was the another limitation of our study. So, further prospective studies are needed.
In conclusion, we suggest that the degree of TSH suppression in thyroid cancer patients is not directly related to bone health, and long-term treatment with levothyroxine can be safely used in patients with total or subtotal thyroidectomy after thyroid cancer.
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