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Original Studies |
Second Division of Endocrinology and Metabolism, Alexandra Hospital, Athens 115 28, Greece
Address all correspondence and requests for reprints to: Dr. Peter D. Papapetrou, Second Division of Endocrinology and Metabolism, Bas. Sofias and K. Lourou Street, Alexandra Hospital, Athens 115 28, Greece.
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Abstract |
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Mean serum calcium and phosphorus were both slightly above the normal mean at week 0 and decreased significantly (by 10% and 24%, respectively) during treatment. Fasting urinary calcium was 236 ± 4 (mean ± SEM) mg/g creatinine, and the fractional excretion of Ca was 2.0 ± 0.33% before treatment; both fell significantly to minimums of 61 ± 20 mg/g and 0.6 ± 0.16%, respectively. Urinary phosphorus was 282 ± 60 mg/g creatinine, and the fractional excretion of phosphorus was 3.3 ± 0.6% before treatment; both increased significantly to 452 ± 40 mg/g and 8.4 ± 1.0%, respectively, during treatment. The z-scores were calculated from the mean and SD of the respective control groups. The z-score of urinary N-telopeptides of type I collagen (U.NTx) was 9.3 ± 1.3 at week 0 and declined exponentially, but failed to normalize after 1 yr of antithyroid treatment. The serum alkaline phosphatase (ALP) z-score was initially 2.2 ± 0.2, increased to 6.0 ± 1.0 at week 6, and declined slowly there after to 1.0 ± 1.1 at week 54. The serum osteocalcin (OC) z-score showed a temporal pattern similar to that of ALP. It was initially 2.2 ± 0.2, increased to 4.0 ± 0.6 at week 6, and later declined slowly to 0.7 ± 0.5 at week 54. The failure of the markers of bone turnover to normalize after 1 yr of therapy indicates an on-going high rate of bone turnover despite the attained euthyroidism. The uncoupling index (UI = z-score of U.NTx minus z-score of OC) was 7.1 ± 1.2 before treatment, indicating unbalanced bone turnover in favor of bone resorption, and fell close to zero at week 30 of treatment. Pretreatment plasma PTH was suppressed slightly to 2.17 ± 0.47 pmol/L and rose significantly during treatment, reaching a plateau of 5.27 ± 0.78 at week 12. In all postmenopausal women PTH increased above the upper limit of normal (6.84 pmol/L). Pretreatment serum 25-hydroxyvitamin D was normal and remained unchanged during treatment, whereas 1,25-dihydroxyvitamin D was initially subnormal and rose to normal level after treatment. There was a significant positive linear correlation between PTH and U.NTx after week 12. PTH was also significantly correlated with ALP, but not with OC. ALP and OC were significantly correlated. A significant positive correlation was found between T3 and U.NTx, and a negative correlation was found between T3 and each of the formation markers (ALP and OC) over the 0- to 12-week interval. The latter correlations and the very high pretreatment UI indicate some inhibitory effect of the high thyroid hormone levels on the osteoblasts. The marked and sustained elevation of PTH, more pronounced in the postmenopausal women, during the first year of treatment of hyperthyroidism seems to play a pivotal role in maintaining a relatively high rate of bone turnover despite euthyroidism, and in the conservation of calcium by reducing renal calcium excretion and increasing calcium absorption (via 1,25-dihydroxyvitamin D). It may also account in part for the additional rise of the bone formation markers by an anabolic effect on the osteoblasts. Endogenous PTH may be important in the restoration of bone mineral density of treated hyperthyroid patients.
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Introduction |
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After treatment of hyperthyroidism, serum calcium falls (5, 11), sometimes enough to cause tetany (11, 12, 13). This hypocalcemia is ascribed to the healing of the metabolic bone disease and increased calcium deposition to bone, although in some cases published in the older literature it cannot be excluded that the hypocalcemia was due partly to postoperative damage of the parathyroid glands (11). Cook et al. (14) demonstrated that calcium and phosphorus balance was negative during the hyperthyroid status and was converted to positive soon after euthyroidism was attained. Mosekilde et al. (5, 11) studied the effect of antithyroid treatment on calcium and phosphorus metabolism in hyperthyroidism and observed that the initially very high urinary hydroxyproline level fell rapidly, whereas the initially high serum ALP level increased farther to a maximum after 8 weeks of antithyroid treatment. Serum calcium and the 24-h urinary calcium excretion decreased. These findings were suggestive of decreased bone resorption and increased bone formation with deposition of bone mineral after antithyroid treatment. Cooper et al. (7) showed that the rise of serum ALP observed after treatment of hyperthyroidism is due mainly to the bone isoenzyme. Recently, Siddiqi et al. (10) also observed a fall of the bone resorption markers Upyr and Udpd and a farther rise of the bone formation markers B-ALP and OC during treatment of hyperthyroid patients with antithyroid drugs.
In the present work we studied the effects of treatment of hyperthyroidism with antithyroid drugs on some novel biochemical markers of bone and mineral metabolism in an attempt to contribute to the elucidation of the mechanism by which the catabolic status of bone associated with the hyperthyroid phase is converted to anabolic bone status characterized by increased deposition of mineral into bone early after euthyroidism is attained.
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Subjects and Methods |
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Thirteen patients (11 women, aged 20–72 yr, of whom 7 were postmenopausal, and 2 men, 37 and 50 yr old) with newly diagnosed overt hyperthyroidism were included in the study. Patients with mild disease or diagnosed early after relapse of thyrotoxicosis were excluded. None of the patients was a tobacco or alcohol abuser, and the postmenopausal women had not received hormone replacement therapy or any other treatment for osteoporosis in the past. Throughout the period of the study the patients were not taking any other medication apart from the antithyroid drug. Their daily calcium intake, estimated from the daily consumption of diary products, was 400 mg for 1 woman, 700 mg for 6 patients, and more than 1000 mg for 6 patients. All of the patients had Graves’ disease. After the initial examination (week 0), treatment with methimazole (10 mg, three times daily) was initiated, and the dose was tapered later. A few patients needed small doses of T4 to avoid hypothyroidism. The patients were examined every 6 weeks between 0900–1000 h, and fasting blood samples and fasting double voided urine samples were obtained. The patients were followed up for a period of 48- 54 weeks (2 patients for 36 weeks) during antithyroid treatment. Normal ranges were established in our laboratory from control groups of healthy euthyroid women (58 premenopausal and 66 postmenopausal). Informed consent was obtained from the patients who participated in the study, which was approved by the scientific committee of the hospital.
Methods
Evaluation of thyroid function was based on serum total
T4 and T3 measured by RIA
(Amersham Pharmacia Biotech, Aylesbury, UK), TSH measured
by a third generation chemiluminescence assay, and free
T4 (FT4) by
chemiluminescence assay (Nichols Institute Diagnostics,
San Juan Capistrano, CA). Calcium, phosphorus, creatinine, ALP, and
-glutamyl transpeptidase (GGT) were measured by autoanalyzer using
standard laboratory methods. Serum calcium was corrected for total
serum proteins using the McLean-Hastings nomogram. The fractional
excretion of calcium and phosphorus was calculated using the formula:
% fractional excretion of Ca (FECa) = [(urinary Ca x
plasma creatinine)/(PCa x UCr)] x 100; only the filtered 60%
of the total serum calcium concentration was used for the calculations.
Cross-linked N-telopeptides of type I collagen (U.NTx) were measured in
urine using an enzyme-linked immunosorbent assay (Osteomark,
Ostex International, Inc., Seattle, WA) and were
expressed as nanomoles of bone collagen equivalents (BCE) per L/mmol/L
creatinine.The sensitivity of the assay was 5.0 nmol/L BCE, the
intraassay coefficients of variation (CVs) were 5.1% and 2.7%, and
the interassay CVs were 10.8% and 7.2% at the 35.3 and 66.7 nmol/L
BCE/mmol/L creatinine levels, respectively. Human OC (both intact and
its large N-terminal midregion fragment) was measured in serum using a
two-site immunoradiometric assay (Nichols Institute Diagnostics). Sera were stored at -80 C until assayed for OC no
more than 3 weeks after the blood withdrawal. The sensitivity of the
assay was 0.04 ng/mL; the intraassay CVs were 4.9% and 3.5%, and the
interassay CVs were 6.2% and 5% at the 1.5 and 12.0 ng/mL levels,
respectively. Plasma intact PTH-(1–84) was measured by a two-site
immunoradiometric assay (Nichols Institute Diagnostics)
with a sensitivity of 0.2 pmol/L; the intra- and interassay CVs of two
quality control pools with mean values of 3.5 and 29.4 pmol/L were
3.2% and 2.8%, and 4.6% and 4%, respectively.
The z-scores of the markers U.NTx, OC, and ALP were calculated from the mean and SD of the respective control groups and an uncoupling index was derived as a measure of the balance between bone resorption and bone formation (15). The uncoupling index was the z-score for the resorption marker U.NTx minus the z-score for the formation marker OC (15).
25-Hydroxyvitamin D (25OHD)was measured in alcohol serum extracts by a competitive protein binding assay (Nichols Institute Diagnostics), and 1,25-dihydroxyvitamin D [1,25-(OH)2D] was measured by RIA in immunoextracted serum (Nichols Institute Diagnostics) from six unselected patients from whom sufficient serum was available.
Statistical analysis
The results of all variables are reported as the mean ± SEM. The significance of the differences of the values between week 0 and each subsequent time was evaluated by the Wilcoxon signed rank sum test for paired groups. Differences in the means of variables between two groups were evaluated by t test. Statistical significance was considered a two-tailed test value of P < 0.05. The statistical analysis, including linear correlations between variables and curve fitting, were performed using Prism software (GraphPad Software, Inc., San Diego, CA).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Pretreatment serum
T3 was 6.5 ± 0.7 nmol/L (normal, 0.8–2.8),
fell to 2.1 ± 0.2 within 6 weeks, and remained normal there after
(Fig. 1B). Serum calcium was 2.41 ± 0.05 mmol/L (slightly above
the mean normal of 2.30) before therapy; it fell significantly
(P = 0.003) to a nadir of 2.17 ± 0.05 (10% fall)
12 weeks after the beginning of treatment and rose gradually thereafter
to nearly pretreatment levels (Fig. 2A).
Serum phosphorus was 1.32 ± 0.08 mmol/L initially (higher than
the average mean normal of 1.15), and it fell significantly
(P = 0.015) to a plateau of approximately 1.1 ±
0.03 (24% fall) at week 12 of treatment (Fig. 2B). Before commencing
antithyroid treatment, plasma PTH was suppressed to a low normal level
(2.17 ± 0.47 pmol/L) compared to the mean normal level of 3.95
and rose significantly to 5.27 ± 0.78 (P =
0.00025) at week 12 of treatment, remaining thereafter at a plateau
level (Fig. 2C). U.NTx was 275.5 ± 38.7 nmol/L BCE/mmol
creatinine before treatment, an 8-fold increase compared to the mean
normal value of 35.0 in young women; it fell steeply to 180.6 ±
18.6 (P = 0.0025) within 6 weeks after starting
treatment and gradually thereafter, without reaching normal levels a
year after the start of the antithyroid treatment (Fig. 2E). A
one-phase exponential decay equation could be fitted
(r2 = 0.32) to the declining U.NTx values:
y = span x e-K x
x + plateau, where span is 166.3, K is
0.07697, and the plateau value is 97.95. The U.NTx values were
transformed to z-scores, taking into account the menopausal status of
the patients and the corresponding normal ranges (Table 1). Again, a 9-fold increase in the
z-score of U.NTx before treatment was noted, which fell similarly, but
remained higher than normal, throughout the year of antithyroid
treatment (Table 1). A similar equation was also a best fit
(r2 = 0.38) for the z-score of U.NTx, where span
is 6.77, K is 0.09, and the plateau value is 0.66. Serum ALP was
84.8 ± 8.0 IU/L (slightly above the upper limit of normal range
of 25–80) before therapy and increased significantly by 67%
(P = 0.0003), reaching a peak of 140.5 ± 13.7 at
week 12 of treatment; subsequently it declined slowly, reaching the
pretreatment level at about week 30 (Fig. 2G). The pretreatment z-score
of ALP was 2.2 ± 0.6 and increased to 6.0 ± 1.0 (a rise of
172%) at weeks 6–12 of treatment, declining slowly thereafter to the
pretreatment levels (Table 1). To ensure that high values of ALP were
not due to liver injury, GGT was measured along with ALP in every serum
specimen and was always normal. Serum OC was initially 10.6 ± 0.6
ng/mL, above the upper limit of normal for young women (1.9–8.7), and
rose significantly by 34% (P = 0.004) at week 6 of
treatment, subsequently falling gradually to nearly pretreatment levels
(Fig. 3A) The OC values were transformed to a z-score considering the
different normal range of postmenopausal women (2.9–11.7) in this
laboratory (Table 1). Again, the pretreatment z-score of OC (2.2
± 0.2) increased significantly (P = 0.004) to 4.0
± 0.6 (by 82%) at week 6 and later declined gradually to levels that
remained above normal throughout the year of antithyroid therapy. Thus,
the normalized levels of the two formation markers were elevated to a
similar degree before treatment, and their temporal patterns of change
were also similar (Table 1). The uncoupling index was 7.1 ± 1.2
before the start of treatment, decreased significantly
(P = 0.001) and steeply within the first 6 weeks of
antithyroid treatment, and reached a value close to zero (0.5–0.2)
from about week 30 of treatment on (Table 1). The morning fasting
urinary calcium/creatinine (Ca/Cr) ratio (milligrams/milligrams) was
0.24 ± 0.04 before treatment and fell significantly
(P = 0.0007) to 0.06 ± 0.02 at week 12 (Fig. 3C). Similarly, the morning fasting
fractional excretion of calcium decreased significantly from a
pretreatment value of 1.99 ± 0.33% (P = 0.002)
to 0.65 ± 0.16% at week 12 (Fig. 3D). The morning fasting
urinary phosphorus/creatinine (Pi/Cr) ratio (milligrams/milligrams)
increased significantly from a pretreatment value of 0.28 ± 0.06
(P = 0.04) to 0.45 ± 0.04 at week 12 (Fig. 3E);
similarly, the morning fasting fractional excretion of phosphorus
increased significantly from a pretreatment value of 3.35 ±
0.58% (P = 0.005) to 8.43 ± 1.0%, reaching a
plateau at week 12 (Fig. 3F). The pretreatment serum level of
1,25-(OH)2D was 34.0 ± 14.2 pmol/L, below
the lower limit of the normal range of 43.2–148.8, and increased
significantly (P = 0.05) to 70.0 ± 7.6 at week
12, whereas the pretreatment serum level of 25OHD was 39.8 ± 4.1
nmol/L, in the low normal range of 23–113, and remained unchanged
during 36 weeks of antithyroid treatment (Fig. 3, G and H).
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). The z-score of U.NTx was
significantly higher in the PREM group at weeks 0 and 6, and values
were similar thereafter (Fig. 2F). The z-score of ALP was significantly
higher in the POSTM patients on several occasions between 0–54 weeks
(Fig. 2H), whereas the z-score of OC displayed a reverse pattern
compared to ALP on several occasions (Fig. 3B).
There was a significant, although weak, negative linear correlation
between serum calcium and PTH over the 0- to 12-week interval (r =
-0.37; P = 0.02). A significant positive linear
correlation was found between plasma PTH and U.NTx for the time period
12–54 weeks (r = 0.55; P < 0.0001), whereas
these two parameters were not correlated over the 0- to 12-week period.
Serum T3 was also significantly positively
correlated with U.NTx between 0–12 weeks (r = 0.36;
P = 0.016) as well as from 12–54 weeks (r = 0.34;
P = 0.005). For the period from 12–54 weeks a
significant multiple linear regression of U.NTx on both plasma PTH and
serum T3 was found (r = 0.61; F =
19.41; P < 0.0001); thus, 37% of the total variation
of U.NTx was explained by both PTH and T3
(
28% due to PTH and 10% due to T3). Serum
FT4 was not significantly correlated with U.NTx.
A significant negative linear correlation was found between plasma PTH
and the FECa (r = -0.37; P = 0.0011) as well as
between PTH and the Ca/Cr ratio (r = -0.42; P =
0.0002) over the entire period of follow-up (0- 48 weeks), whereas
there was a positive correlation between plasma PTH and the FEPi
(r = 0.50; P < 0.0001; Fig. 3D) as well as
between PTH and the Pi/Cr ratio (r = 0.49; P <
0.0001) over the same period of time. Plasma PTH and ALP were
significantly correlated (r = 0.44; P < 0.0001).
ALP was also correlated with OC (r = 0.53; P <
0.0001) during the period from 0–54 weeks. However, there was no
correlation between plasma PTH and OC. A significant negative linear
correlation was found between serum FT4 and ALP
(r = -0.46; P = 0.003), serum
T3 and ALP (r = -0.60; P <
0.0001), and T3 and OC (r = -0.27;
P = 0.05) for the interval between 0–12 weeks.
Bone mineral density (BMD) was measured using dual energy x-ray absortiometry only at the end of the follow-up period of 1 yr of antithyroid treatment. The z-score of the BMD of the spinal column (L2–L4) was 0.27 ± 1.12 (mean ± SD), and that of the femoral neck was 0.34 ± 0.78. None of the patients had severe osteopenia, as the lowest z-score noted was -1.3 in two patients. The z-score of BMD was calculated using the mean and SD of the BMD of a control population of Greek extraction.
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Discussion |
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The bone formation markers ALP and OC were both slightly above the normal euthyroid range at week 0, and both increased significantly more with treatment. These results for ALP agree with the findings of other investigations (5, 6, 7, 9, 10, 11). However, there is a controversy concerning the behavior of OC early during antithyroid treatment. The increase in OC that we found mainly in the premenopausal women was also observed by Siddiqi et al. (10) in a similar premenopausal group, whereas other investigators (9, 17) did not observe a rise in OC during treatment. In our patients the two formation markers, ALP and OC, were significantly correlated, and their z-scores were similar before treatment and displayed similar temporal patterns. The positive correlation between PTH and ALP that we found may represent a direct anabolic effect of PTH on the osteoblasts or may be an indirect result of the coupling, as a correlation between PTH and U.NTx was also found for the interval between 12–54 weeks. The lack of correlation between PTH and OC may be due to distinct, albeit unknown, functions of the two formation markers. The negative correlation between T3 and ALP or OC during the first 12 weeks of treatment (in contrast with the positive correlation between T3 and U.NTx during this time interval) implies that the high thyroid hormone levels during the hyperthyroid phase exert some inhibitory effect on the osteoblasts in accordance with the theory of Eriksen (18). This researcher summarized the effects of thyrotoxicosis on bone remodeling as follows. In the hyperthyroid status the initiation rate of new remodeling cycles is significantly increased. However, the total work performed by resorptive cells (i.e. the final resorption depth) is unchanged, whereas the total work performed by osteoblasts (i.e. mean thickness of completed walls) is reduced. The normal cycle duration of approximately 200 days is halved in thyrotoxicosis. Thus, during the thyrotoxic status we found a 2-fold rise in the formation markers compared to the 9-fold increase in U.NTx. The high uncoupling index of 7.1 before treatment indicates an unbalanced bone turnover in favor of bone resorption and is probably due to some degree of direct inhibition of osteoblasts by high thyroid hormone levels. Such an effect may explain to some extent the additional rise in the formation markers associated with the declining levels of thyroid hormones (i.e. with the elimination of the osteoblastic inhibition) early in the course of antithyroid treatment; however, this rise in the formation markers could also be explained by the prolongation of the duration of the osteoblastic phase of the cycle that occurs during treatment. An alternative explanation for the relatively low pretreatment levels and the temporal pattern of change in the formation markers would be a shorter half-life of these markers due to increased degradation rate caused by thyrotoxicosis. However, Cooper et al. (7) have shown that most of the increment in ALP after treatment is due to B-ALP. This finding of increased amounts of B-ALP appearing in the serum as thyroid hormone levels were declining (7) is unlikely to be due to prolongation of its half-life unless a different degradation rate for the ALP isoenzymes is postulated. After the early temporal changes in the bone markers in our patients, the initially very high uncoupling index fell to nearly zero at about the week 30, indicating that a balanced bone turnover was reached by that time and was maintained thereafter.
The rise in plasma PTH from a suppressed low normal level during the
thyrotoxic status to high normal or above the upper limit of normal
within the first 12 weeks of antithyroid treatment is partly due to the
fall in serum calcium to slightly hypocalcemic levels during this
period, as indicated by the modest, but significant, negative linear
correlation noted between these two parameters in the present study.
However, the regulation of the temporal changes in PTH during the early
weeks of antithyroid treatment may be very complex and depend on other
factors as well. Hyperthyroid patients may have magnesium deficiency
and show decreased serum total and ionized magnesium concentrations
that increases during antithyroid treatment (19). To our knowledge
there is no published work correlating the rising serum magnesium level
to the PTH levels during treatment of thyrotoxicosis, and a possible
association among these two parameters is difficult to predict. One
possibility is that this rise of serum magnesium that occurs during a
state of magnesium deficiency may be able to stimulate a rise in PTH,
although the conventional effect of an increase in serum magnesium is
the suppression of PTH (19). On the other hand, the rising levels of
1,25-(OH)2D during treatment may attenuate the
rise in PTH by a direct inhibition of PTH secretion (20). The mean
fasting morning urinary excretion of calcium was initially 236 mg/g
creatinine and fell to 61 mg at week 12 of treatment, whereas FECa fell
from a mean pretreatment value of about 2% to a minimum of 0.6%. The
mean fasting urinary excretion of phosphorus was 282 mg/g creatinine
before treatment and increased to 452 mg at week 12, whereas a
concomitant rise in FEPi from 3.3% to 8.4% was noted. One partial
cause of these changes in fasting urinary calcium and phosphorus
excretion after antithyroid treatment should be the increasing PTH
levels, as indicated by the correlations found between PTH and Ca/Cr,
FECa, Pi/Cr, or FEPi and as is expected from the effects of PTH on the
renal handling of calcium and phosphorus (tubular reabsorption of
calcium is increased and that of phosphorus is decreased by PTH). A
decrease in the 24-h urinary excretion of calcium after antithyroid
treatment in hyperthyroid patients consuming an unrestricted diet was
also observed by Mosekilde et al. (11); however, these
researchers also found a decrease in the 24-h phosphaturia, in contrast
with our findings. Renal blood flow and glomerular filtration rate may
be high in patients with hyperthyroidism, and this along with the
increased mobilization of mineral from bone may account for the
increased phosphaturia in this disorder (21). Correction of these
abnormalities after treatment may cause a decrease in phosphate
excretion unless this is opposed by a significant rise in PTH, in which
the phosphaturic effect may predominate. The marked rise in PTH is a
likely explanation for the increased phosphate excretion in our
patients. The pretreatment level of 1,25-(OH)2D
was subnormal despite adequate vitamin D intake implied by the normal
level of 25OHD and rose to normal during the treatment. Reduced levels
of 1,25-(OH)2D in thyrotoxicosis have been
ascribed to reduced renal 1
-hydroxylase activity (22) and its
elevated MCR (23) and may account for the reduced intestinal calcium
absorption described in this disease (14).
In summary, we have shown that in selected patients with severe hyperthyroidism the biochemical markers of bone resorption and formation continue to be slightly elevated for almost a year after the initiation of antithyroid treatment and the attained euthyroid state, and this is indicative of on-going high rate of bone remodeling. The mechanism underlying these events seems to be the following. The fall in thyroid hormones to normal levels is associated with marked reduction of osteoclastic bone resorption early in the time course (expressed by a fall in U.NTx), leading to reduced mobilization of bone mineral and an early fall in serum calcium. Increased osteoblastic activity follows, as indicated by the farther rise in bone formation markers during the first several weeks of treatment; this may be due to the combined effects of an anabolic action of PTH and other factors [such as insulin-like growth factor I (IGF-I)], the cessation of an inhibitory effect of high levels of thyroid hormones on osteoblasts, and the prolongation to normal of the previously shortened duration of the osteoblastic phase of the bone cycle. The rise in OC could be due partly to a direct stimulation of the synthesis of this protein by the increasing 1,25-(OH)2D (20). This anabolic phase is associated with increased deposition of mineral to bone, which leads to prolongation of low serum calcium up to the nadir, slightly hypocalcemic, level at week 12. The fall in serum calcium should be a cause of the marked rise in plasma PTH during the first 12 weeks of treatment. The low serum calcium level limits the filtered load of calcium, and this combined with the elevated PTH decreases renal calcium excretion. The reason for the sustained levels of PTH at a relatively high plateau beyond week 12 and why this phenomenon is more pronounced in postmenopausal women are not clear. The rise in PTH, possibly with a synergic effect of the rising 1,25-(OH)2D (20), is responsible for the maintenance of slightly increased bone turnover for several months after the beginning of antithyroid treatment.
In favor of a possible anabolic role of the elevated PTH are the recent findings by Dempster et al. (24) that mild primary hyperparathyroidism accounts for the preservation of the cancellous bone in postmenopausal women. The restoration of BMD 8 yr after combined medical and surgical treatment of hyperthyroidism proved to be inferior in the younger individuals in one study (25). The younger women in the present study had lower PTH and ALP levels, and this may explain the findings of the above study (25). The elevated PTH also 1) enhances the synthesis of 1,25-(OH)2D, thus promoting the intestinal absorption of calcium; and 2) reduces urinary calcium excretion. Despite these calcium conservation mechanisms, serum calcium remains relatively low for a long time after the beginning of treatment because of the increased bone formation and calcium accretion to bone, which leads to a reduction of the porosity of the compact bone (5). Measurements of BMD have also shown that thyrotoxic osteoporosis may be a potentially reversible disorder (26), although some controversy on this matter exists. Recently, Siddiqi et al. (10) observed an inverse correlation between B-ALP and BMD 1 yr after the beginning of antithyroid therapy and considered an elevated B-ALP to predict poor restoration of BMD in treated thyrotoxic patients. It would be interesting to know the PTH levels in the patients of this investigation, because the possibility that a high B-ALP may signify low intake or malabsorption of calcium was not excluded (10).
In conclusion, our data indicate that in some patients with severe thyrotoxicosis, apart from the major effects of the falling thyroid hormone levels, the rise in PTH that occurs early and may last for several months after the initiation of antithyroid treatment seems to play a role in inducing some of the temporal changes in the biochemical bone markers and in mineral metabolism. A probable role for the rise in PTH in the restoration of bone density after treatment should be considered. However, another mechanism could also be responsible for the reversal of the catabolic bone status of hyperthyroidism to anabolic during antithyroid treatment. Miell et al. (27) found that in hyperthyroidism, despite normal or high IGF-I levels, IGF bioactivity is reduced, probably because of high levels of IGF-binding protein-1, a known inhibitor of IGF activity. Treatment of thyrotoxicosis reverses this abnormality. The rise in IGF bioactivity may therefore be a contributing factor to the reversal of the bone metabolism status from catabolic to anabolic.
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Acknowledgments |
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Received July 7, 1999.
Revised November 24, 1999.
Accepted December 1, 1999.
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References |
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,25-hydroxyvitamin D in
hyperthyroidism. Acta Endocrinol (Copenh). 110:70–74.This article has been cited by other articles:
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  A. Zanglis, D. Andreopoulos, and N. Baziotis Influence of L-Thyroxine Therapy on Parathyroid Hormone Concentrations Clin. Chem., June 1, 2008; 54(6): 1092 - 1093. [Full Text] [PDF]
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 S. Naessen, K. Carlstrom, R. Glant, H. Jacobsson, and A. L. Hirschberg Bone mineral density in bulimic women - influence of endocrine factors and previous anorexia. Eur. J. Endocrinol., August 1, 2006; 155(2): 245 - 251. [Abstract] [Full Text] [PDF]
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F Azizi, L Ataie, M Hedayati, Y Mehrabi, and F Sheikholeslami Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine Eur. J. Endocrinol., May 1, 2005; 152(5): 695 - 701. [Abstract] [Full Text] [PDF]
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 M. I. Surks, E. Ortiz, G. H. Daniels, C. T. Sawin, N. F. Col, R. H. Cobin, J. A. Franklyn, J. M. Hershman, K. D. Burman, M. A. Denke, et al. Subclinical Thyroid Disease: Scientific Review and Guidelines for Diagnosis and Management JAMA, January 14, 2004; 291(2): 228 - 238. [Abstract] [Full Text] [PDF]
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N. F. Col, M. I. Surks, and G. H. Daniels Subclinical Thyroid Disease: Clinical Applications JAMA, January 14, 2004; 291(2): 239 - 243. [Abstract] [Full Text] [PDF]
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