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OSTEOPOROSIS IN PATIENTS WITH HYPERTHYROIDISM
R. Kovatcheva1, T. Hadjieva2, G. Kirilov1
1
Clinical Center of Endocrinology, 2 Clinical Center of Nuclear Medicine and
Radiotherapy, Medical University, Sofia, Bulgaria
Abstract
Thyrotoxicosis is generally associated with increased excretion of Ca and P in
urine and stool. Bone remodeling is enhanced by thyroid hormones. Although both
osteoclastic and osteoblastic activities increase, bone resorption prevails with
manifest hypercalcemia in 1/3 of patients. Bone mass loss associated with
radiologically demonstrable demineralization of bone and occasionally with
pathological fractures is found especially in elderly women and recurrent disease.
The study enrolled two groups of patients: 1) 29 women with Graves disease, 15 in
menopause from 6,7 years, mean age 53,3 + 6,9 and 14 no menopausal, mean age
41 + 8,9; 53,3 % of menopausal women were active (TSH<0,3 mIU/L), mean
duration of the disease 3,6 + 3 years against 85,7 % of no menopausal women
with mean duration 1,6 + 1,2 years; 2) 44 women on suppressive therapy with
levothyroxine (L-T4); 16 in menopause from 7,9 + 5,2 years, mean age 56,6 + 5,6
and 28 no menopausal, mean age 36,5 + 9,4. The mean BMD in no menopausal
women was normal or osteopenic. In menopausal women was found different
degree of osteopenia and osteoporosis.
There was ……
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Key words: secondary osteoporosis, hyperthyroidism, L-T4 suppressive therapy
Introduction
The physiological effect of thyroid hormones is increased bone remodelling,
including both osteoclastic and osteoblastic activities. The typical feature of
thyroid hormone excess is the prevalence of bone resorption with consequential
bone mass loss (1).
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Thyrotoxicosis is associated with elevated serum concentrations of osteocalcin
and alkaline phosphatase and increased excretion of Ca and P in urine and stool.
Enhanced bone resorption is accompanied by elevated urine concentrations of
hydroxyproline and type I collagen cross linkages (2). Elevated concentrations
of these biochemical markers of bone turnover seem to correlate with serum
concentrations thyroid hormones. Decreased bone mass density (BMD) in
patients with thyrotoxicosis is reversible with efficient treatment (3). Bone mass
loss associated with radiologically demonstrable demineralization of bone and
occasionally with pathological fractures is found especially in elderly women
and recurrent disease (14).
The administration of high doses thyroid hormones to suppress the secretion of
thyroid-stimulating hormone (TSH) in patients with thyroidectomy for
differentiated thyroid cancer is considered the appropriate therapy. In patients
prone to osteoporosis, however, this therapy may increase the risk of fractures.
Suppressive doses of thyroid hormones have been reported to reduce or to have
no effect on BMD in women (12).
There is increasing interest in the studies of the effects of thyroid hormone
therapy on the development of osteoporosis. Suppressive therapy may accelerate
the development of osteoporosis. In contrast, substitution therapy with thyroid
hormone shows no harmful effect on BMD (10, 11).
Objective
The aim of this prospective study was to determine the changes in BMD of
patients with active thyrotoxicosis and patients on suppressive therapy with
thyroid hormones in order to compare the effect of endogenous overt
hyperthyroidism with those of exogenous subclinical thyrotoxicosis on BMD.
Patients and methods
Patients
The study included two groups of patients. The first one enrolled 29 women with
active Graves’ disease, mean age 47, 3 + 10 years, with mean duration of the
disease 2, 6 + 2, 5 years. Fifteen of them were in menopause from 6,7 years,
mean age 53,3 + 6,9 years, with mean BMI 25,4 + 4,9 kg/m2 and 14 no
menopausal women, mean age 41 + 8,9, with mean BMI 23,2 + 2,7 kg/m2. Eight
of menopausal women were with active disease (TSH<0,3 mIU/L), mean
duration of 3,6 + 3 years and 12 of no menopausal women, with mean duration
of 1,6 + 1,2 years (Table 1).
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Table 1. Age, BMI, TSH and duration of hyperthyroidism
Duration of
TSH (mIU/L)
hyperthyroidism
(years)
Groups
Mean age
(years)
BMI
(kg/m2)
Young
(14)
41 + 9
23,2 + 2,7
1,6 + 1,2
(0,5 – 5)
0,27 + 0,42
Menopausal
(15)
53 + 7
(1 – 17)
25,4 + 4,9
3,6 + 1,9
(0,5 – 9)
0,64 + 0,71
The second group consisted of 44 women on suppressive therapy with
levothyroxine (L-T4) after total thyroidectomy, mean age 43,8 + 9,5 years, with
mean duration of treatment 4,8 + 3,6 years. Sixteen of them were in menopause
from 7,9 + 5,2 years, mean age 56,6 + 5,6 years, with mean BMI 27,2 + 4,6
kg/m2 and 28 no menopausal, mean age 36,5 + 9,4, with mean BMI 24,5 + 3,9
kg/m2. The doses of L-T4, the duration of treatment and the intensity of TSH
suppression are shown on Table 2. None of the 44 patients on suppressive
therapy had metastases to bones or other distal organs………
Table 2. Age, BMI and duration of menopause
Groups
Mean age
(years)
BMI
(kg/m2)
Duration of
menopause
(years)
Young
(28)
36,5 + 9,5
24,5 + 3,9
-
Menopausal
(16)
56,6 + 5,6
27,2 + 4,6
7,9 + 5,2
(1 – 19)
Methods
In patients with Graves’ disease the thyroid function was assessed by
measurements of FT3 (normal range 3, 5 – 8, 0 nmol/l), FT4 (normal range 8, 0
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– 19, 0 nmol/l) and TSH (normal range 0, 27 – 4, 2 mU/l) and the active disease
state was defined when FT3 and FT4 were increased and TSH – suppressed. In
patients with L-T4 suppressive therapy only TSH and Tg were taken into
consideration.
Calcium metabolism and bone metabolic activity were determined by measuring
serum Ca (normal range 2, 2 – 2, 52 mmol/l), P (normal range 0, 87 – 1, 45
mmol/l) and ALP (normal range 70 – 170 U/l).
High-resolution ultrasonography of the neck was performed to check the thyroid
gland for nodules and to exclude parathyroid adenomas.
BMD of the forearm was assessed with osteometer type DXA, Norland, and
calculated in relation to the pique bone mass for cortical bone (proximal) and for
trabecular bone (distal). The results were interpreted in accordance with the
WHO criteria for normal and reduced BMD and osteoporosis (T-score) (4-6).
Statistical analysis
The data from the study were processed using percentage frequency analysis of
quantitive
variables, mean +SD, correlation analysis, T-test for dependent and independent
samples, one way Anova. The processing was done with the statistical software
SPSS for Windows, version 8.00 (7, 8).
Results
The group of hyperthyroid patients was divided in two age subgroups – young
and menopausal, which showed a significant difference in age and duration of
disease.
The data of bone metabolism and BMD of cortical (proximal site) and trabecular
(distal site) bone are shown at Table 3. All patients were with normal values of
serum Ca and P. The mean ALP was increased in the whole group, as well as in
the separate age groups – young and menopausal. In the young women group
and the entire group of hyperthyroid patients the mean BMD at the two sites
(proximal and distal) was osteopenic, while by menopausal women osteoporotic. There was a significant difference (p<0, 01) between serum ALP
and BMD at both sites in the two age groups. The group of young women
showed significant difference (p<0, 01) between proximal and distal BMD,
whereas in the menopausal group there was no statistical distinction. There was
a strong negative correlation in the whole group of hyperthyroid patients
between BMD at the two sites and age, as well as between BMD and ALP. The
same was found in the group of young women. In the group of menopausal
women there was a moderate negative correlation (p<0, 02) between TSH and
ALP.
Table 3. ALP and BMD in hyperthyroid patients
Groups
ALP (IU/L)
T prox (%)
T dist (%)
Young
(14)
193,5 + 124,3
83,4 + 13,5
89,2 + 17,5
Menopausal
(15)
246,6 + 88,5
70 + 10
71,3 + 15,9
Total
(29)
221 + 108,7
76,5 + 13,4
80 + 18,7
The group of patients on suppressive therapy with L-T4 was also divided in two
age subgroups – young and menopausal. There was no significant difference
between the mean daily dose of L-T4, the mean duration of treatment and the
intensity of TSH suppression (Table 4).
The mean BMD (proximal and distal) was normal in the young women group
and osteopenic in both the menopausal and the whole group. There was a
significant difference between proximal and distal BMD both in the young
women and the whole group, while no statistical significance was found in the
menopausal group. The comparison of proximal and distal BMD between the
two age groups showed no significant difference.
Table 4. Daily dose of L-T4, duration of treatment and TSH suppression
Groups
Duration of
L-Т4
suppression
(years)
Mean daily dose of
L-Т4
(g)
TSH
(mIU/L)
Young
(28)
4,6 + 3,6
(1 - 15)
178,6 + 30,2
(125 – 225)
0,16 + 0,2
Menopausal
(16)
5,3 + 6,8
(0,75 – 28)
170,3 + 33,5
(125 – 225)
0,24 + 0,3
Strong negative correlation was found in the whole group on suppressive therapy
with L-T4 between age and BMD (proximal and distal) (p<0, 01), ALP and
BMD (proximal) (p<0, 05); a positive correlation between age and ALP (p<0,
01).
a
b
Fig. 1: examples among some common hip scanning problems: (a) The scan did not go
far enough laterally and part of the femoral head is missing. (b)
The parallel among the two study groups – with hyperthyroidism and on
suppressive therapy with L-T4 showed significantly lower proximal BMD for
hyperthyroid patients of all ages. The distal BMD was also lower for all
hyperthyroid patients and for the young women group with hyperthyroidism…..
Discussion
Overt hyperthyroidism is an important risk factor for osteoporosis and fractures
(3, 9). Thyroid hormones accelerate the rate of bone remodeling, leading to a
negative calcium balance and a net bone loss that accelerates the development of
osteoporosis. Thyroid hormone seems to be more detrimental to cortical bone
(found in the hip and forearm) than to trabecular bone (found in the spine) (19).
This bone type depends predominantly to the estrogen level. In our study we
found a convincing difference in proximal and distal BMD in both age groups
with hyperthyroidism. These data support the thesis for target action of thyroid
hormone on cortical bone (18). There are some recent data about the mechanism
of bone loss by thyroid hormone. Abe E. et al. provide evidence for direct effects
of TSH on both components of skeletal remodeling – osteoblastic bone
formation and osteoclastic bone resorption, mediated via TSH receptor found on
osteoblast and osteoclast precursors (16). The group of menopausal hyperthyroid
women showed a strong negative correlation between TSH and ALP as a marker
of osteoblast function. Another suggestion proposes Kanatani M. et al. who
demonstrate the direct stimulatory effect of T3 on osteoclast formation and
differentiation (17). Other mechanism of osteoporosis secondary to
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hyperthyroidism is the association of Graves’ disease with vitamin D receptor
polymorphism (VDR-ApaI), described by Ban Y. et al. (15).
Whether subclinical hyperthyroidism significantly affects bone metabolism and
increases the risk of fractures remains a controversial issue (18, 19).
Serum concentrations of several markers of bone synthesis and reabsorption are
…….
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