0021-972X/00/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 3
Printed in U.S.A.
Changes in Parameters of Bone and Mineral Metabolism
during Therapy for Hyperthyroidism
HELEN PANTAZI
AND
PETER D. PAPAPETROU
Second Division of Endocrinology and Metabolism, Alexandra Hospital, Athens 115 28, Greece
ABSTRACT
Hyperthyroid patients have high bone turnover and negative calcium and phosphorus balance often associated with mild osteopenia.
Early during antithyroid treatment bone turnover decreases, the mineral balance is converted to positive, and sometimes hypocalcemia
occurs. The aim of this investigation was to study the mechanisms of
the changes in some parameters of bone and mineral metabolism after
treatment of thyrotoxicosis. Thirteen newly diagnosed patients with
Graves’ disease (seven postmenopausal women, four premenopausal
women, and two men) were studied longitudinally, every 6 weeks, for
1 yr after commencing antithyroid treatment with methimazole.
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
H
YPERTHYROIDISM is characterized by accelerated
bone turnover, which is caused from direct stimulation of bone cells by the high thyroid hormone concentrations
(1–3). Bone histomorphometry is consistent with preponderant osteoclastic resorption in cortical bone leading to increased porosity, whereas a reduction of the absolute bone
volume occurs less often in the cancellous bone (4, 5). The
biochemical markers of bone formation and bone resorption,
such as osteocalcin (OC) (6), alkaline phosphatase (ALP),
bone-specific ALP (B-ALP) (7), and urinary collagen pyridinoline (Upyr) or deoxypyridinoline (Udpd) cross-links
(8 –10) were elevated in hyperthyroid patients, indicating
increased bone turnover in favor of osteoclastic bone resorption. The hyperthyroid state, because of the increased mobilization of bone mineral, is associated with a tendency to
Received July 7, 1999. Revision received November 24, 1999. Accepted December 1, 1999.
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.
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. (J Clin
Endocrinol Metab 85: 1099 –1106, 2000)
hypercalcemia, which leads to suppression of circulating
PTH. Hyperphosphatemia, hypercalciuria, and hyperphospaturia often occur in hyperthyroid patients (5).
After treatment of hyperthyroidism, serum calcium falls
(5, 11), sometimes enough to cause tetany (11–13). 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
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PANTAZI AND PAPAPETROU
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.
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.
Subjects and Methods
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).
Patients
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 ⫻ plasma creatinine)/
(PCa ⫻ UCr)] ⫻ 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 enzymelinked 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
Statistical analysis
Results
The pretreatment level (week 0) of FT4 was 81.0 ⫾ 17.7
pmol/L (normal, 9 –23.2), decreased to 17.4 ⫾ 1.5 within 6
weeks after initiation of antithyroid therapy, and remained
within the normal range during the follow-up period of 1 yr
(Fig. 1A). 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 ⫻ e⫺K ⫻ 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 anti-
BONE METABOLISM DURING TREATMENT FOR THYROTOXICOSIS
FIG. 1. The asterisks denote significant differences from week 0, and
the shaded areas denote normal ranges.
thyroid 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
1101
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).
Subsequently, the patients were divided into two groups.
In the PREM group the four premenopausal women and the
two men were included, whereas the POSTM group comprised the seven postmenopausal women. The serum calcium level in the PREM group was higher than in the POSTM
group at week 0 (2.50 ⫾ 0.05 vs. 2.33 ⫾ 0.06 mmol/L) and
week 6 (2.47 ⫾ 0.02 vs 2.20 ⫾ 0.06; P ⫽ 0.003), whereas it was
not significantly different at later times. Plasma PTH was
significantly higher in the POSTM group on many occasions
throughout the follow-up period, and the seven patients in
whom PTH reached abnormally high levels (⬎6.84 pmol/L)
belonged to this group (Fig. 2D). 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
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FIG. 2. The asterisks denote significant differences from week 0 (A–E and G) or between groups (F and H).
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TABLE 1. z-Score of U.NTx, OC, ALP, and uncoupling index
Week
U.NTx
OC
ALP
Uncoupling
index
0
6
12
18
24
30
36
42
48
54
9.3 ⫾ 1.3
5.7 ⫾ 1.2
3.7 ⫾ 0.6
4.3 ⫾ 0.7
4.2 ⫾ 0.9
3.1 ⫾ 0.7
2.2 ⫾ 0.7
2.5 ⫾ 1.1
1.7 ⫾ 0.4
0.9 ⫾ 0.4
2.2 ⫾ 0.2
4.0 ⫾ 0.6
3.2 ⫾ 0.5
2.9 ⫾ 0.3
3.3 ⫾ 0.4
2.8 ⫾ 0.4
1.8 ⫾ 0.4
1.3 ⫾ 0.6
1.2 ⫾ 0.3
0.7 ⫾ 0.5
2.2 ⫾ 0.6
6.0 ⫾ 1.0
5.9 ⫾ 0.9
5.2 ⫾ 1.1
3.8 ⫾ 1.0
2.8 ⫾ 0.8
2.3 ⫾ 0.9
2.5 ⫾ 1.0
2.1 ⫾ 0.6
1.0 ⫾ 1.1
7.1 ⫾ 1.2
1.6 ⫾ 1.0
0.5 ⫾ 0.5
1.4 ⫾ 0.6
0.8 ⫾ 0.8
0.2 ⫾ 0.6
0.3 ⫾ 0.5
1.1 ⫾ 0.6
0.5 ⫾ 0.3
0.2 ⫾ 0.6
Values are the mean ⫾ SEM. U.NTx, N-Telopeptides of collagen;
OC, osteocalcin; ALP, alkaline phosphatase. Uncoupling index ⫽
U.NTx ⫺ OC.
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.
Discussion
Biochemical markers of bone resorption, such as urinary
hydroxyproline (5), Upyr (9), serum pyridinoline, serum deoxypiridinoline cross-links, and Upyr as well as Udpd (10)
have been found to be elevated in the hyperthyroid state and
to fall significantly within a few weeks after the initiation of
antithyroid treatment. In our study the mean U.NTx was by
8-fold increased above the normal mean during the hyperthyroid phase and fell exponentially during the antithyroid
treatment, but failed to normalize completely as long as 1 yr
after the beginning of the treatment despite levels of serum
FT4 and FT3 constantly within the euthyroid range.
Mosekilde et al. (5) also noted a similar failure of urinary
hydroxyproline to normalize during prolonged antithyroid
treatment. In contrast, Garnero et al. (9) and Siddiqi et al. (10)
observed normalization of pyr and dpd cross-links within
several weeks of antithyroid treatment. These discrepancies
could be due to differences among the markers used in these
studies. U.NTx is considered to be the most bone-specific
1103
bone resorption marker among the markers mentioned
above (16). Increased soft tissue collagen degradation in hyperthyroidism may contribute to free collagen cross-links
(Upyr and Udpd) excreted in this disease (16), thus magnifying the difference in the cross-links excreted between the
hyper- and euthyroid states. However, another explanation
for the persistence of U.NTx levels above normal long after
euthyroidism was attained may be the marked and persistent
rise of plasma PTH that occurred in our patients, as indicated
by the positive linear correlation between PTH and U.NTx
found after week 12 of treatment, although only 28% of the
total variation of U.NTx is explained by PTH. In all 7 postmenopausal women in our study, PTH rose above the upper
normal limit of 6.84 pmol/L, whereas PTH in the 4 premenopausal women and the 2 men did not exceed this level.
All of the patients studied by Siddiqi et al. (10) were premenopausal. PTH was not determined in these studies (9,
10). A rise of PTH within normal range was also observed by
Mosekilde et al. (5) in treated hyperthyroid patients. It is
noteworthy that in the present study a positive linear correlation was found after week 12 between the by that time
normal serum T3 levels and U.NTx. Thus, after week 12 of
treatment, U.NTx was correlated to both PTH and T3 levels.
This finding also indicates that about 10% of the variation in
U.NTx was due to changes in the T3 level within the euthyroid range, and it could be hypothesized that a more vigorous antithyroid treatment in some cases could probably
cause a more pronounced fall in levels of bone resorption
markers. All of our patients had severe, newly diagnosed
thyrotoxicosis, presumably of several months duration. Possible differences in the severity and duration of thyrotoxicosis as well as in the intensity of the antithyroid treatment
could also account for the somehow different results between
the present and other investigations (9, 10).
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
(5–7, 9 –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 thy-
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FIG. 3. The asterisks denote significant differences from week 0 (A and C–H) or between groups (B).
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rotoxicosis 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
1105
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
1106
JCE & M • 2000
Vol 85 • No 3
PANTAZI AND PAPAPETROU
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 BALP 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.
Acknowledgments
We thank Miss Voula Thanou and Miss Vaso Ktena for their excellent
technical assistance and Dr. Evangelos Spanos for the measurements of
vitamin D metabolites.
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