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Persistent Increase in Bone Turnover in Graves’ Patients with Subclinical Hyperthyroidism

Division of Metabolism, Endocrinology and Molecular Medicine, Department of Internal Medicine, and First Department of Surgery (T.I.), Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan

Address all correspondence and requests for reprints to: Masaaki Inaba, M.D., Second Department of Internal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: m9837013{at}msic.med.osaka-cu.ac.jp

	Abstract

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Hyperthyroid patients exhibit accelerated bone loss by increased bone turnover, and normalization of thyroid function is associated with a significant attenuation of increased bone turnover, followed by an increase in bone mineral density. However, of patients with Graves’ disease (GD) maintained on antithyroid drug (ATD) treatment, some exhibit persistent suppression of TSH long after normalization of their serum free T₃ (FT₃) and free T₄ (FT₄) levels. The aim of this study was to examine whether bone metabolism is still enhanced in TSH-suppressed premenopausal GD patients with normal FT₃ and FT₄ levels after ATD therapy (n = 19) compared with that in TSH-normal premenopausal GD patients (n = 30), and to evaluate the relationship between serum TSH receptor antibody (TRAb), an indicator of disease activity of GD, and various biochemical markers of bone metabolism. No difference was found between the two groups in serum Ca, phosphorus, or intact PTH, or in urinary Ca excretion. Serum bone alkaline phosphatase (B-ALP), bone formation markers, and urinary excretions of pyridinoline (U-PYD) and deoxypyridinoline (U-DPD), which are bone resorption markers, were significantly higher in the TSH-suppression group than in the TSH-normal group (B-ALP, P < 0.05; U-PYD, P < 0.001; U-DPD, P < 0.001). For the group of all GD patients enrolled in this study, TSH, but neither FT₃ nor FT₄, exhibited a significant negative correlation with B-ALP (r = -0.300; P < 0.05), U-PYD (r = -0.389; P < 0.05), and U-DPD (r = -0.446; P < 0.05), whereas TRAb exhibited a highly positive and significant correlation with B-ALP (r = 0.566; P < 0.0001), U-PYD (r = 0.491; P < 0.001), and U-DPD (r = 0.549; P < 0.0001). Even in GD patients with normal TSH, serum TRAb was positively correlated with B-ALP (r = 0.638; P < 0.001), U-PYD (r = 0.638; P < 0.001), and U-DPD (r = 0.641; P < 0.001). In conclusion, it is important to achieve normal TSH levels during ATD therapy to normalize bone turnover. TRAb was not only a useful marker for GD activity, but was also a very sensitive marker for bone metabolism in GD patients during ATD treatment.

	Introduction

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THYROID HORMONE exerts its effect on osteoblasts via nuclear receptors to stimulate osteoclastic bone resorption (1, 2, 3); hyperthyroidism is thus one of the major causes of secondary osteoporosis (4). Previous studies clearly demonstrated that hyperthyroid patients exhibited increases in both osteoclastic and osteoblastic activities, with a predominance of bone resorption, resulting in a decrease in bone mineral density (BMD) (5, 6), and that normalization of thyroid function was associated with an increase in lumbar spine BMD, which was preceded by significant attenuation of increased bone turnover (7).

However, discrepancy exists in the results of studies to determine whether antithyroid drugs (ATD) can completely normalize bone metabolism (8, 9). Of Graves’ disease (GD) patients maintained on ATD treatment, some have exhibited persistent suppression of TSH long after their serum free T₃ (FT₃) and free T₄ (FT₄) levels were normalized by treatment with ATD; these patients are in a so-called subclinical hyperthyroid state (10). Therefore, one explanation for the discrepancy in the findings of previous reports may be the presence or absence of TSH suppression. GD patients whose serum TSH remains suppressed often have elevated levels of serum TSH receptor antibody (TRAb), an indicator of disease activity of GD.

These considerations prompted us to examine whether bone metabolism is still enhanced in TSH-suppressed GD patients even after normalization of FT₃ and FT₄ by ATD therapy and to evaluate the relationship between serum TRAb and various biochemical markers of bone metabolism.

	Subjects and Methods

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Patients

Forty-nine premenopausal patients with GD were enrolled in this study after informed consent was obtained from each. The diagnosis of GD was established by the presence of symptoms and signs of hyperthyroidism, a diffuse goiter, or elevated FT₃ and FT₄ with decreased TSH concentrations in serum with increased thyroid uptake of iodine 123 before initiation of ATD treatment. All patients had been maintained within the normal range of FT₃ and FT₄ (4.0 pmol/L < FT₃ < 6.6 pmol/L; 10.3 pmol/L < FT₄ < 23.2 pmol/L) under treatment with antithyroid drug therapy of less than 5 mg/day thiamazole or 50 mg/day propylthiouracil. Patients were divided into two groups on the basis of their serum TSH level as follows: a TSH-normal group (n = 30) with normal FT₃ and FT₄ levels and serum TSH within the normal range (0.4 mU/L TSH < 4.0 mU/L), and a TSH-suppression group (n = 19) whose serum TSH remained suppressed (<0.4 mU/L) for at least 10 months even after their serum FT₃ and FT₄ levels had been normalized (the former group averaged 18.6 ± 1.8 months, the latter group averaged 13.4 ± 2.5 months). No patient had a history of hepatic or renal disorders, alcoholism, or other major medical conditions or had taken any medications that might affect calcium (Ca) metabolism.

Blood and urine samples

Blood and urine samples were drawn after an overnight fast and were kept frozen at -20 C until assayed for determination of biochemical markers.

Thyroid function

FT₃, FT₄, and TSH were measured using commercially available kits. TRAb was measured by RRA using a commercial kit (Baxter, Tokyo, Japan) (11).

Biochemical parameters for Ca metabolism

Biochemical markers for Ca metabolism were determined essentially as we previously reported (12, 13). Briefly, Ca, phosphorus, and creatinine (Cre) were measured in serum and urine using standard laboratory methods. Serum intact PTH was measured by an immunoradiometric assay (Allegro Intact PTH, Nichols Institute Diagnostics, San Juan, Capistrano, CA) (14). This assay measures only the active intact PTH and not degradation products resulting from cleavage of PTH inside or outside of the parathyroid gland (15). The intraassay coefficient of variation (CV) and the interassay CV for intact PTH were 4.8% and 9.3%, respectively. As bone resorption markers, urinary excretions of pyridinoline (U-PYD) and deoxypyridinoline (U-DPD) were determined by high performance liquid chromatography (16, 17). U-PYD and U-DPD were corrected for urinary Cre measured by the automatic analyzer. The intra- and interassay CVs for U-PYD were 2.7% and 9.1%, respectively; those for U-DPD were 7.5% and 10.1%, respectively. Serum osteocalcin (OC) and bone alkaline phosphatase (B-ALP) were measured as bone formation markers. OC was measured by an immunoradiometric assay kit (Mitsubishi Kagaku, Tokyo, Japan), and B-ALP by an enzyme immunoassay kit (ALKPHASE-B, Metra Biosystem, Mountain View, CA) (18). The intra- and interassay CVs for OC were 6.8% and 8.5%, respectively, and those for B-ALP were 2.2% and 3.1%, respectively.

Normal ranges for premenopausal women were determined to be 0.17–0.41 µkat/L for serum B-ALP and 0.52–2.12 nmol/L for serum OC in 60 and 48 healthy premenopausal women (mean ± SD age, 40.2 ± 11.5 and 39.1 ± 13.5 yr, respectively). Normal ranges of 13.84–46.32 nmol/mmol Cre for U-PYD and 1.88–5.60 nmol/mmol Cre for U-DPD were determined in 35 healthy premenopausal women (mean age, 41.8 ± 10.2 yr).

Statistical analysis

Results are expressed as the mean ± SD unless otherwise indicated. Differences between groups were analyzed using the Mann-Whitney U test for assessment of mean values. Correlation coefficients were calculated by simple regression analysis. P < 0.05 was considered significant. Statistical analysis was performed with the StatView software program (Abacus Concepts, Berkeley, CA).

	Results

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Clinical characteristics of GD patients in the TSH-suppression and TSH-normal groups

Table 1 shows patient profiles and clinical characteristics in the TSH-suppression and TSH-normal groups. Serum levels of FT₃, FT₄, and lipids, including total cholesterol, triglyceride, and high density lipoprotein cholesterol, which are metabolic markers of thyroid function, did not differ significantly between the two groups. However, serum TSH was significantly lower in the TSH-suppression group, which had a serum TRAb level significantly higher than the TSH-normal group. Concerning biochemical parameters of Ca metabolism, there were no differences between the two groups in serum Ca, phosphorus, or intact PTH or in urinary Ca excretion.

Concerning bone formation markers, serum B-ALP in the TSH-suppression group was 0.39 ± 0.27 µkat/L, which was significantly higher than the respective value of 0.24 ± 0.08 µkat/L in the TSH-normal group (P < 0.05). However, serum OC did not differ significantly between the two groups (0.94 ± 0.38 vs. 0.85 ± 0.40 nmol/L; P = 0.4358; Fig. 1). Concerning bone resorption markers, U-PYD and U-DPD in the TSH-suppression group were 32.73 ± 10.66 and 6.56 ± 2.05 nmol/mmol Cre, respectively. These values were significantly greater than the respective values of 23.28 ± 7.50 and 4.58 ± 1.42 nmol/mmol Cre in the TSH-normal group (U-PYD/Cre, P < 0.001; U-DPD/Cre, P < 0.001; Fig. 2).

View larger version (34K): [in this window] [in a new window]   Figure 1. Serum levels of B-ALP (A) and OC (B) in the TSH-suppression group (n = 19) and the TSH-normal group (n = 30). Horizontal lines indicate the geometric mean value for each group. The shaded area indicates the normal reference range. The difference between the TSH-suppression group and the TSH-normal group was statistically significant for B-ALP (P < 0.05), but not for OC (P = 0.4358). ns, Not significant.

View larger version (31K): [in this window] [in a new window]   Figure 2. Levels of U-PYD and U-DPD in the TSH-suppression group (n = 19) and the TSH-normal group (n = 30). U-PYD and U-DPD excretions were corrected for urinary Cre. Horizontal lines indicate the geometric mean value for each group. The shaded area indicates the normal reference range. The difference in means of U-PYD and U-DPD between the TSH-suppression group and the TSH-normal group were statistically significant (U-PYD, P < 0.001; U-DPD, P < 0.001).

For the group of all GD patients (n = 49), B-ALP, U-PYD, and U-DPD were significantly correlated in a negative manner with TSH (Fig. 3), but not with serum FT₃ or FT₄, when serum samples with TSH levels below the detection limit (0.005 mU/L) were regarded as having TSH levels equivalent to 0.005 mU/L. There were significant negative correlations between TSH and B-ALP (r = -0.300; P = 0.0361), U-PYD (r = -0.389; P = 0.0058), and U-DPD (r = -0.446; P = 0.0013). Neither FT₃ nor FT₄ was correlated with various bone markers; FT₃ did not correlate with B-ALP (r = 0.137; P = 0.3392), OC (r = 0.125; P = 0.3809), U-PYD (r = 0.184; P = 0.2045), or U-DPD (r = 0.183; P = 0.2081), nor did FT₄ correlate with B-ALP (r = -0.037; P = 0.1410), OC (r = 0.007; P = 0.9607), U-PYD (r = -0.152; P = 0.2962), or U-DPD (r = -0.199; P = 0.2119). Serum OC did not correlate significantly with TSH (r = -0.061; P = 0.6684).

View larger version (10K): [in this window] [in a new window]   Figure 3. Negative correlations of serum TSH with B-ALP (A), U-PYD (B), and U-DPD (C) for the group of all GD patients enrolled in this study (n = 49). Serum samples with TSH levels below the detection limit (0.005 mU/L) were regarded as having TSH levels equivalent to 0.005 mU/L. Serum TSH did correlate significantly in a negative manner with B-ALP (A; r = -0.300, P = 0.0361), U-PYD (B; r = -0.389, P = 0.0058), or U-DPD (C; r = -0.446, P = 0.0013).

For the group of all GD patients (n = 49), there were significant positive correlations between TRAb and B-ALP (r = 0.566; P < 0.0001), U-PYD (r = 0.491; P = 0.0003), and U-DPD (r = 0.549; P < 0.0001; Fig. 4), whereas serum TRAb was not significantly correlated with serum OC (r = 0.154; P = 0.2945).

View larger version (11K): [in this window] [in a new window]   Figure 4. Positive correlations of serum TRAb with B-ALP (A), U-PYD(B), and U-DPD (C) for the group of all GD patients enrolled in this study (n = 49). TRAb exhibited a significant positive correlation with B-ALP (A; r = 0.566, P < 0.0001), U-PYD (B; r = 0.491, P = 0.0003), and U-DPD (C; r = 0.549, P < 0.0001).

Even in GD patients with serum TSH within normal ranges (n = 30), TRAb retained significant and positive correlations with B-ALP (r = 0.638; P = 0.0002), U-PYD (r = 0.638; P = 0.0002), and U-DPD (r = 0.641; P = 0.0001; Fig. 5). Neither serum TSH, FT₃, nor FT₄ was correlated with any marker of bone metabolism (data not shown).

View larger version (10K): [in this window] [in a new window]   Figure 5. Correlations of serum TRAb with B-ALP (A), U-PYD (B), and U-DPD (C) in GD patients when the patients were restricted to those having normal TSH levels (n = 30). TRAb exhibited a significant positive correlation with B-ALP (A; r = 0.638, P = 0.0002), U-PYD (B; r = 0.638, P = 0.0002), and U-DPD (C; r = 0.641, P = 0.0001).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

To our knowledge, only a few studies conducted to date have focused on the effect of a subclinical hyperthyroid state on bone metabolism. Recently, it was reported that subclinical hyperthyroid patients with nodular goiter, in whom serum TSH was suppressed, exhibited accelerated bone loss about 2%/yr, although their thyroid function was estimated only by free T₃ and T₄ indexes (total T₃ and T₄ multiplied by T₃ uptake) (23). Therefore, it has not been determined whether bone turnover is actually affected in this clinical state in which serum FT₃ and FT₄ levels are within the normal range.

In our cross-sectional studies using GD patients, serum TSH had been kept suppressed and normal for at least 10 months in the TSH-suppression and TSH-normal groups, respectively, after normalization of FT₃ and FT₄. Therefore, the bone metabolic state of these patients appeared to be stable. B-ALP, U-PYD, and U-DPD were still significantly higher in the TSH-suppression group than in the TSH-normal group, strongly suggesting a high bone turnover state in the former group. However, as bone metabolic parameters did not exhibit significant correlations with serum FT₃ or FT₄, except for negative correlations with TSH, it appeared that the higher bone turnover in the TSH-suppression group may have resulted not only from subclinical hyperthyroidism, but also from some other mechanism. Serum TRAb, which was also significantly higher in the TSH-suppression group than in the TSH-normal group, exhibited a significant positive correlation with bone metabolic parameters, including B-ALP, U-PYD, and U-DPD. It was previously reported that serum TRAb was significantly correlated with serum OC in hyperthyroid GD patients (24). However, as in hyperthyroid GD patients serum TRAb correlated with serum levels of FT₃ and FT₄, the correlation with serum OC appeared to result from hyperthyroidism, reflected by an increase in serum TRAb. In our cross-sectional study, bone metabolic markers, including B-ALP, U-PYD, and U-DPD, were more strongly correlated with TRAb than with TSH. Even in GD patients with normal TSH, TRAb exhibited significant positive correlations with serum B-ALP, U-PYD, and U-DPD, further supporting the clinical usefulness of TRAb as a marker of bone metabolism in GD patients. As TRAb correlated with neither FT₃ nor FT₄ in the present study (data not shown), and TRAb exhibited close correlations with biochemical parameters of bone metabolism, suggesting that TRAb might directly affect bone metabolism independently of thyroid function. Supportive of this idea is the recent report (25) demonstrating that osteoblasts possess functional TSH receptors. Therefore, it may be possible that the abnormal bone metabolism in GD may be partially explained by the interaction of TRAb with TSH receptors in osteoblasts.

As differences between the TSH-suppression group and the TSH-normal group did not reach statistical significance for serum total cholesterol, triglyceride, and high density lipoprotein cholesterol levels, which are clinically useful metabolic markers of thyroid function, it is possible that bone metabolic markers are more sensitive than serum lipid levels in detecting subtle increase in thyroid function. As the thyroid function of GD patients enrolled in this study had been kept stable for at least 10 months in those patients when bone metabolism became stable, the possibility of differences in time-course changes between serum lipid and bone parameters after normalization of thyroid function appeared to be negated. Alternatively, if TRAb exerts its effects directly on bone metabolism, but not on lipid metabolism, it is reasonable that biochemical bone parameters, but not serum lipid, exhibited a significant change in the TSH-suppression group.

In summary, GD patients who exhibited normal FT₃ and FT₄ levels with maintenance of serum TSH suppression long after ATD treatment exhibited a significant increase in bone turnover. As a persistent increase in bone turnover is responsible for accelerated bone loss (19, 20, 21, 22), TSH-suppressed GD patients may have increased risk for secondary osteoporosis. Although further study is needed to elucidate the significance of a slight increase in bone turnover in those patients on the rate of bone loss, it still appears important to achieve normal TSH levels during treatment for GD patients to normalize their bone metabolism.

Received November 30, 1999.

Revised April 20, 2000.

Accepted July 3, 2000.

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