The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1989-1994
Copyright © 1997 by The Endocrine Society
Antiresorptive Therapy in Hyperthyroid Patients: Longitudinal Changes in Bone and Mineral Metabolism
Esteban Jódar1,
Manuel Muñoz-Torres,
Fernando Escobar-Jiménez,
Miguel Quesada,
Juan D. Luna and
Nicolás Olea
Services of Endocrinology (Catedra de Medicina Interna I) and
Nuclear Medicine (N.O.), University Hospital, and the Department of
Biostatistics, Faculty of Medicine (J.D.L.), Granada University,
Granada, Spain
Address all correspondence and requests for reprints to: Dr. Manuel Muñoz-Torres, Plz. Isabel La Católica, 2, 3°A, Granada E-18009, Spain.
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Abstract
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The effect of antiresorptive therapy with nasal calcitonin (CT) in
recently diagnosed hyperthyroid patients on conventional medical
therapy as well as the evolution of bone metabolism were assessed.
Forty-five patients with recent-onset hyperthyroidism (<12 weeks) were
sex and menopause stratified and randomly allocated to treatment with
carbimazole (Neotomizol), carbimazole plus low dose CT (Calsynar; 100
IU/day, 2 days/week), or carbimazole plus high dose CT (Calsynar; 100
IU/day, 14 days/month). Bone mineral density was measured by dual x-ray
absorptiometry in lumbar spine, femoral neck, and Ward’s triangle at
0, 9, and 18 months of treatment. We also determined free
T4, free T3, TSH, osteocalcin, total and bone
alkaline phosphatases, tartrate-resistant acid phosphatase, type I
collagen C telopeptide, and urinary hydroxyproline every 3 months of
follow-up. No significant difference was observed among treatments. A
euthyroid state was attained at 3 months. Bone mass increased
significantly at the 9 month evaluation (P <
0.05), with a 5–10% net gain during follow-up. Nevertheless, final
bone mass was 4–8% smaller than expected. Bone formation markers were
increased at 0 and 3 months, with reductions at 6–9 months; resorption
bone markers showed a significant reduction at the 3 month
evaluation.
These results indicate that the euthyroid state partially reduces
hyperthyroidism-associated osteopenia, with a bone mass recovery period
during the 6–9 early months of effective treatment. This recovery
phase is characterized by raised bone formation markers and reduced
bone resorption markers. The treatment with nasal CT at the doses
assayed has no additional effect over that of attainment of the
euthyroid state.
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Introduction
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PREVIOUS hyperthyroidism is a risk factor
for osteoporosis (1, 2), a major public health problem. In
histomorphometric studies, reconstruction of the remodeling sequence in
patients with hyperthyroidism discloses a marked shortening of both the
resorptive and formative phases of the remodeling cycle, with a
negative balance of 9–10 µm/remodeling cycle (3). Osteoclastic and
osteoblastic activities are enhanced, with a predominance of bone
resorption resulting in increased levels of bone turnover markers (4)
and in decreased bone mass, as determined by single photon
absorptiometry (5), dual photon absorptiometry (6), and dual x-ray
absorptiometry (7, 8), which is the most rapid, accurate, and
reproducible method to evaluate bone mineral density (BMD) (9, 10).
Serum bone alkaline phosphatase determined by immunoradiometric assay
(IRMA) and serum type I collagen C-terminal telopeptide (ICTP)
determined by RIA have been introduced recently as formation and
resorption bone turnover markers, respectively (11). These precise bone
markers could clarify, in a prospective study, the existence of a bone
mass recovery period after attainment of euthyroidism that has been
suggested in patients treated with radioiodine (12). Moreover, recent
reports have suggested the reversibility of thyrotoxic bone disease
after more than 4 (13), 5 (14), or even 1 yr of euthyroidism (15).
Nevertheless, prospective studies to determine the potential benefits
of bone antiresorptive therapy in patients with TSH-suppressive
L-T4 therapy have been proposed (16, 17, 18).
Calcitonin (CT) is a potent inhibitor of osteoclast activity. Normal or
low basal serum CT levels have been reported in hyperthyroid patients
(19); however, the effect of exogenous CT in hyperthyroid patients is
greater than that in normal controls (20).
This is the first prospective study designed to evaluate the evolution
of axial BMD, bone turnover markers, and the potential effects of bone
antiresorptive therapy with nasal salmon CT in hyperthyroid patients
receiving standard medical treatment.
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Subjects and Methods
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Patients
Forty-five Spanish patients with recent onset (<12 weeks) of
endogenous hyperthyroidism were enrolled from the out-patient clinic at
the University Hospital of Granada (Granada, Spain). All patients were
Caucasian. No patient was taking oral contraceptives, calcium
supplements, vitamin D preparations, or other medications that might
affect bone density. None had a history of hepatic or renal disorders,
alcoholism, early menopause, or any other major medical condition. All
subjects gave informed consent, and the study protocol was approved by
the hospital’s ethical committee.
Study design
The eligible patients were classified into three strata
according to sex and menopause (stratum 1, men; stratum 2,
premenopausal women; stratum 3, menopausal women). In each stratum, the
patients were randomly assigned to receive carbimazole (CMZ; Gruppo
Ferrer, Barcelona, Spain; Neotomizol; 45 mg/day initially with later
adjustment to normalize serum free T4 and TSH; group A),
CMZ plus low dose nasal salmon CT (Calsynar; Rhône-Poulenc-Rorer,
S.A., Madrid, Spain; 100 IU/day, 2 days/week; group B), or CMZ plus
high dose nasal salmon CT (Calsynar; 100 IU/day, 14 days/month; group
C). The follow-up period was 18 months, with visits at 3-month
intervals by the same investigator (E.J.).
Assessments
The study protocol included assessment of BMD by dual energy
x-ray absortiometry (Hologic QDR1000, Hologic, Waltham, MA) at 9-month
intervals in lumbar spine (LS; L2–L4), femoral neck (FN), and Ward’s
triangle (WT). The in vivo precision (coefficient of
variation) was better than 2% at lumbar and femoral sites of
measurement. Two thousand five hundred and fifty-two healthy normal
subjects (1331 females and 1221 males) served to establish the mean BMD
in the healthy Spanish population and to calculate the z-score for each
BMD measurement (number of SDs of the patient’s value from
the mean of the control population in a 5-yr age band). The
characteristics of this reference population have been described
previously (21). Vertebral fractures and calcifications were excluded
by x-ray study.
Morning samples of venous blood were taken from patients at 3-month
intervals. Serum was assayed for TSH [RIA-gnost hTSH, Gif-Sur-Yvette,
France; reference values (RV), 0.5–5 µU/mL], free
T4 (RIA-mat FT4,
Byk-Sangtec Diagnostica, Dietzenbach, Germany; RV, 0.9–2.0 ng/dL),
free T3 (RIA-coat FT3,
Byk-Sangtec Diagnostica, Dietzenbach, Germany; RV, 3.8–8.3 pg/mL).
Serum total alkaline phosphatase (TOTALALP; Hitachi 704
autoanalyzer, Boehringer Mannheim, Mannheim, Germany; RV, 100–280
IU/L), bone alkaline phosphatase (BONEALP; Tandem-T, Ostase
ImmunoRadioMetric Assay, Hybritech Europe, Liege, Belgium; RV:
males, 12.4 ± 4.36 µg/L; females, 11.6 ± 4.11 µg/mL),
osteocalcin (BGP; Osteocalcin 125I RIA, Incstar Corp.,
Stillwater, MN; RV, 1.8–6.6 ng/mL), tartrate-resistant acid
phosphatase (Hitachi 704 autoanalyzer, Boehringer Mannheim; RV, 
7
IU/L), ICTP (Telopeptide ICTP[125I] RIA, Orion
Diagnostica, Espoo, Finland; RV, 1.8–5.0 µg/L), and fasting urine
hydroxyproline/creatinine ratio (OHP/Cr; hydroxyproline, Organon
Teknika, Boxtel, Holland; RV, <0.03) were also determined every 3
months as bone turnover markers. The initial determinations were made
before CT and/or CMZ treatment were begun. Forty-three healthy
volunteers from the staff and the students of our hospital served as
homogeneous controls for the bone turnover makers in Fig. 5
. Calcium
intake was estimated by a food frequency questionnaire (22), and
physical activity was estimated by self reports.
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Figure 5. Model of bone and mineral metabolism
evolution in hyperthyroid patients receiving standard medical
treatment.
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Compliance and adverse events
Compliance and adverse events were assessed by systematic
questionnaire at every visit of follow-up. The lack of adherence for 14
days or more was considered exclusion criteria. There were no dropouts,
but two patients (one from group B and one from group C) were excluded
because of noncompliance.
Statistical analysis
The analysis of a nested design was carried out with three
factors included: group, time, and patient. Fixed effect factor were
groups and time (crossed), and random effect factor was patient, which
was nested in group. This study has a power of 75% to identify a 30%
difference in variances. When any factor or interaction between them
was significant, pairwise comparisons were carried out using the
Bonferroni method (because of unequal sample sizes). A covariance
analysis was used with this nested design to control different
variables by FT4. The mean ± SD
are shown for the different variables in tables, and the mean ±
SEM are shown in figures. P < 0.05 was
posed as the significance level. All analysis were carried out using
BMDP software (BMDP Statistical Software, Los Angeles, CA).
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Results
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The baseline characteristics of patients who were included in the
three groups were similar (Table 1). Hyperthyroid
patients showed a significant reduction in basal BMD, with values
approximately 10% lower than expected for age- and sex-matched
controls. The euthyroid state was attained [FEXP = 9.34
(6, 240) df; P < 0.001] at the 3 month evaluation
without differences among the three groups [FEXP = 1.60
(2, 40) df; P = 0.21; Fig. 1, A and B].
The lumbar and femoral BMD increased significantly [LS:
FEXP = 15.88 (2, 48) df; P < 0.001; FN:
FEXP = 13.84 (2, 48) df; P < 0.001; WT:
FEXP = 5.96 (2, 48) df; P < 0.01] at the
9 month evaluation without later gain (Fig. 2, A–C). No
significant difference was observed among the three groups [LS:
FEXP = 0.22 (2, 24) df; P > 0.70; FN:
FEXP = 0.45 (2, 24) df; P > 0.40; WT:
FEXP = 0.10 (2, 24) df; P > 0.50]. Three
of 43 patients failed to increase lumbar and femoral BMD, 1 of 15 in
group A and 1 of 14 in groups B and C, all of whom were premenopausal
females. Bone turnover markers were elevated at baseline when compared
with the final value, but there was no significant difference among
groups in the follow-up period. TOTALALP and BGP decreased
significantly into the normal range at the fourth visit (9 months; Fig. 3, A and B). BONEALP remained elevated at visit 2 (3
months) and decreased significantly at visit 3 (6 months; Fig. 3C). On
the other hand, bone resorption markers decreased significantly at
visit 2 (3 months; Fig. 4, A–C) to normal values,
except for ICTP which normalized at visit 3 (6 months).
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Figure 1. Evolution of thyroid function tests during
the follow-up. Data are shown as the mean ± sem. Group
A, Without CT; group B, low dose CT; group C, high dose CT. M, Month of
follow-up. *, P < 0.05 vs. basal.
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Figure 2. Evolution of the BMD during the follow-up.
Data are shown as the mean ± SEM. Group A, Without
CT; group B, low dose CT; group C, high dose CT. M, Month of follow-up.
*, P < 0.05 vs. basal.
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Figure 3. Evolution of bone formation markers during
the follow-up. Data are shown as the mean ± SEM.
Group A, Without CT; group B, low dose CT; group C, high dose CT. M,
Month of follow-up. *, P < 0.05 vs.
basal; +, P < 0.05 vs. 3 months;
•, P < 0.05 vs. 6 months.
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Figure 4. Evolution of bone resorption markers during
the follow-up. Data are shown as the mean ± SEM.
Group A, Without CT; group B, low dose CT; group C, high dose CT. M,
Month of follow-up. *, P < 0.05 vs.
basal; +, P < 0.05 vs. 3 months;
•, P < 0.05 vs. 6 months;  ,
P < 0.05 vs. 9 months.
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The adjustment by serum free T4 levels (by
analysis of covariance) was significant for BGP [FEXP =
7.83 (6, 239) df; P < 0.01], ICTP [FEXP
= 166.77 (6, 239) df; P < 0.001], and OHP/Cr
[FEXP = 59.79 (6, 239) df; P < 0.001]
and near significant for BONEALP [FEXP = 3.69 (6, 239) df;
P = 0.05]. No changes in significant differences were
observed; nevertheless, this analysis allowed us to generate an
evolutive model of the changes in the bone mineral metabolism for
hyperthyroid patients receiving standard medical treatment (Fig. 5
).
The extent and degree of adverse events are shown in Table 2. These events were mild, and medication did not have
to be discontinued.
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Discussion
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We demonstrate, as did other groups using similar methodology (6, 7, 15), a significant reduction in axial BMD in hyperthyroid patients.
This reduction was similar in magnitude to that observed previously and
was partially restored after attainment of the euthyroid state. Even
so, after the 18-month period of follow-up, this recovery was
incomplete, with a 5% deficit compared to values in sex- and
age-matched controls. Some studies with smaller number of patients (15)
and using different methodologies (14) have suggested a potential
reversibility of hyperthyroid bone disease. Our data show a significant
increase limited to the first 9 months of treatment, so it seems
uncommon to expect a total recovery of bone mass. In this sense, an
initial increase in bone mass can be due to the filling of bone spaces
that are undergoing exaggerated remodeling. This mechanism, because of
the increase in active remodeling units that characterizes hyperthyroid
osteopenia, make the interpretation of short term studies difficult.
Moreover, even a small deficit may leave these patients at jeopardy for
fracture in their lifetimes.
Although CT given intranasally has been shown to be an effective
treatment for postmenopausal osteoporosis (23), we have failed to prove
any significant effect on bone metabolism in hyperthyroid bone disease,
which is also characterized by increased bone turnover (3). Even with a
stratified design to control the influence of sex and menopause, no
significant difference was observed in the evolution of bone mass or in
the bone metabolism markers assayed. Moreover, there was no significant
difference in osteoporosis risk factors or in biochemical
characteristics among the three groups at baseline. On the other hand,
several male and postmenopausal female patients have been included in
this study; although they did not influence the results, our
conclusions do not apply specifically to male or menopausal female
subjects. The lack of effect of CT may be due to the low number of
patients included or to the low dose, high catabolism (24), or lack of
effectiveness of CT in the hyperthyroid state as has been shown in
animal studies (25). Our data suggest that the effect of restoration of
the euthyroid state is greater than the potential benefits of CT at the
doses employed. This agrees with the lack of influence of the menopause
in the BMD from patients with active hyperthyroidism (8). So,
hyperthyroidism exerts a profound alteration in bone dynamics and
surpasses the effects of sex, menopause, and antiresorptive treatment
with CT at the doses used in this study. In our opinion, the efforts
might be directed to the early restoration of euthyroidism and to the
correction of risk factors for osteoporosis. Nevertheless, the doses of
CT used were relatively low (800 and 1400 IU/month) compared with the
FDA-approved dose for the treatment of osteoporosis (3000
IU/month).
As expected, the baseline levels of formation (TOTALALP, BONEALP, and
BGP) and resorption (tartrate-resistant acid phosphatase, ICTP, and
OHP/Cr) bone turnover markers were elevated. A direct correlation
between several bone turnover markers and thyroid hormone levels has
been shown in different studies (4, 12). This is esspecially true for
ICTP, which has been suggested to be a good indirect marker of thyroid
status (26). It was necessary, therefore, to control BMD values and
bone turnover markers by thyroid hormone levels to search for subtle
differences. The reconstruction of the changes in bone metabolism of
hyperthyroid patients once adjusted by serum FT4
showed the presence of a recovery period, apparently limited to the
first 9 months of treatment. This period is characterized by increased
levels of bone formation markers during 3–6 months that return to
normal values thereafter. Osteocalcin showed delayed evolution, as
expected from its direct relation with the mineralization process (11).
On the other hand, bone resorption markers tend to normalize earlier in
the follow-up. Again, CT treatment did not change the evolution of bone
turnover markers, a process totally dependent on thyroid function
status. Moreover, BMD increased significantly at the 9 month
evaluation. Overall, this picture suggests that the main changes in
bone mineral metabolism in hyperthyroid patients occur in the first
9–12 months of medical treatment according to observations after
radioiodine treatment (12), but these changes are insufficient to
normalize BMD. The final bone loss, although mild, could account for
the higher risk of developing osteoporotic fractures observed in
epidemiological studies (27).
In summary, this study shows that restoration of the euthyroid state
partially reduces hyperthyroidism-associated osteopenia, with a bone
mass recovery period focused on the first 6–9 months of effective
treatment. This recovery phase is characterized by elevated levels of
bone formation markers and reduced bone resorption markers. The
treatment with nasal CT at the doses assayed has no additional effect
over attainment of the euthyroid state.
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Footnotes
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1 Present address: Service of Endocrinology. University Hospital 12 de
Octubre, Madrid, Spain. 
Received December 30, 1996.
Revised March 3, 1997.
Accepted March 11, 1997.
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Top
Abstract
Introduction
