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Levothyroxine Treatment and Occurrence of Fracture of the Hip
Michael C. Sheppard, MB, PhD;
Roger Holder, BSc;
Jayne A. Franklyn, MD, PhD
Arch Intern Med. 2002;162:338-343.
ABSTRACT
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Background Levothyroxine sodium is widely prescribed and has been implicated as
a cause of reduction in bone mineral density and, therefore, suggested to
be a major contributor to the risk of osteoporotic fractures.
Objective To investigate whether levothyroxine use increases the risk of developing
osteoporotic fractures.
Methods We conducted a population-based, case-control analysis of the risk of
a femur fracture in a large cohort of patients who had been prescribed levothyroxine.
We used the United Kingdom General Practice (primary care) Research Database
to identify 23 183 patients who had been prescribed long-term thyroid
hormone therapy and to identify for each patient taking levothyroxine 4 controls
matched for age, sex, primary care practice, and duration of registration
on the database. The number of patients who had sustained a fracture of the
proximal femur was ascertained for each group, together with drug therapies
and medical diagnoses likely to affect fracture risk.
Results Of the 23 183 patients prescribed thyroid hormone, a mean ±
SE of 1.61% ± 0.08% had sustained a fracture of the femur, compared
with 1.44% ± 0.04% of 92 732 controls (P
= .06). When analyzed according to sex, a significant difference in rate of
fracture between patients taking levothyroxine and controls was found in males
(P = .008). Compared with controls, patients taking
levothyroxine had higher reported rates of medical diagnoses and therapies,
potentially confounding the fracture risk. Independent predictors of the occurrence
of fracture after adjustment for other factors were age (adjusted odds ratio
[AOR], 1.11; 95% confidence interval [CI], 1.10-1.11; P<.001), medical diagnoses including rheumatoid arthritis (AOR in
females, 1.69; 95% CI, 1.27-2.26; P<.001), excessive
use of alcohol (AOR in females, 3.05; 95% CI, 1.94-4.76; P<.001), and prescription of drugs (eg, anticonvulsants; AOR in
females, 2.49; 95% CI, 2.00-3.09; P<.001). Prescription
of levothyroxine was an independent predictor of fracture occurrence in males
(AOR, 1.69; 95% CI, 1.12-2.56; P = .01) but not females
(AOR, 1.03; 95% CI, 0.92-1.16; P =.60).
Conclusions The lack of association between fracture and levothyroxine prescription
in the whole cohort is reassuring, although an independent association between
levothyroxine prescription and fracture occurrence in male patients suggests
that levothyroxine may contribute to fracture risk in this specific group.
INTRODUCTION
IT IS WELL ESTABLISHED that overt hyperthyroidism increases bone turnover
and bone resorption, leading to decreased bone mineral density (BMD)1-2 and an increased risk of osteoporotic
fractures. In a US population-based study of 9516 women 65 years or older,
a history of hyperthyroidism (present in 9.2% of the cohort) was shown to
represent an independent risk factor for hip fracture (relative risk, 1.8;
95% confidence interval [CI], 1.2-2.6), even after adjusting for femoral neck
BMD.3 In addition, in our United Kingdom population-based
study of mortality in a cohort of 7209 patients with a history of hyperthyroidism
who had been treated with radioiodine, there was a significant excess of mortality
due to fracture of the femur (standardized mortality ratio, 2.9; 95% CI, 2.0-3.9).4
Although the influence of overt hyperthyroidism on fracture risk appears
clear, debate currently surrounds the question of whether more minor degrees
of thyroid hormone excess, such as that often found in patients undergoing
levothyroxine sodium therapy, are also associated with osteoporosis risk.
Early studies5-6 reported significantly
reduced bone mass in patients undergoing prolonged treatment with levothyroxine.
As a result, much concern was generated about the potential risk of premature
development of osteoporosis in patients receiving levothyroxine therapy.7 However, several well-conducted studies have since
failed to demonstrate any detrimental effect on bone mass in levothyroxine-treated
patients, even in those with thyroid hormone excess indicated by suppression
of serum thyrotropin concentrations.8-9
Two recent meta-analyses10-11
of published literature have addressed this controversy and have concluded
that thyroid hormone treatment, both in specific groups with suppressed serum
thyrotropin and those with normal serum thyrotropin levels, is associated
with reduction in BMD. These studies of BMD did not, however, address the
question of whether levothyroxine therapy was a risk factor for fracture incidence
or mortality. A study12 of 1100 patients undergoing
levothyroxine replacement in Scotland found no significant differences in
fracture rates in patients taking levothyroxine when compared with the general
population, whereas another small study13 found
no significant differences in fracture rates in 160 postmenopausal women with
thyroid disease compared with 140 controls without.
In view of the prevalence of levothyroxine prescription in the general
population and hence the potential importance for public health of an increased
risk of osteoporotic fracture in levothyroxine users, we used the United Kingdom
General Practice Research Database (GPRD) to investigate whether a diagnosis
of fracture of the femur in a large cohort of patients receiving levothyroxine
was more common in those taking thyroid hormone therapy than a matched control
group.
PATIENTS AND METHODS
SELECTION OF PATIENTS AND CONTROLS
Patients undergoing long-term thyroid hormone replacement (termed levothyroxine
cases) and controls were identified from the GPRD. This database includes
standardized sets of information collected from approximately 3.5 million
patients in 500 primary care (general) practices in the United Kingdom (representative
of the United Kingdom as a whole) and has been described in detail elsewhere.14-15 The baseline cohort was composed
of all patients older than 15 years whose information was recorded on the
GPRD. Those currently taking levothyroxine or triiodothyronine and who had
been prescribed this therapy for at least 1 year were identified from computerized
prescribing records, and details of dose and duration of therapy were retrieved.
Four controls matched for age, sex, registration with the same primary care
practice, and duration of registration with the database were selected for
each patient who had been prescribed thyroid hormone. Potential cases and
controls with any record in the database of hyperthyroidism or prescription
of antithyroid medication were excluded, and no control had any history of
prescription of levothyroxine or triiodothyronine.
IDENTIFICATION OF THE FEMUR FRACTURE AND CONFOUNDING DIAGNOSES AND
DRUG THERAPIES
The end point investigated was fracture of the proximal femur. Data
on fracture occurrence and date of fracture were retrieved by searching computerized
records using Oxford Medical Information System codes for fracture of the
femur or hip. To investigate potential confounding factors, information was
also retrieved for the levothyroxine group and controls regarding prescription
of drugs known to affect bone metabolism and hence fracture risk (gonadal
steroids, thiazide diuretics, glucocorticoids, calcitonin, tamoxifen citrate,
calcium supplements, bisphosphonates, vitamin D or analogues, and anticonvulsants),
as well as major medical diagnoses likely to affect risk of fracture of the
femur. These medical diagnoses were chronic renal and liver disease, diabetes
mellitus, rheumatoid arthritis, inflammatory bowel disease, hyperparathyroidism,
osteomalacia, chronic pancreatitis, celiac disease, epilepsy, excessive alcohol
use, and major cancers associated with metastasis to bone (breast, prostate,
kidney, thyroid, multiple myeloma, lung, and colon).
STATISTICAL ANALYSIS
Quantitative variables were compared between groups using t tests and Mann-Whitney U tests. For categorical
variables, individual associations were studied using  2 tests
and calculation of odds ratios and relative risks. Logistic regression was
used to identify the combinations of factors that best predicted the probability
of fracture of the femur for the levothyroxine group and the controls.
RESULTS
A total of 23 183 patients older than 15 years who had been prescribed
thyroid hormone replacement for at least 1 year were identified, together
with 4 controls matched to each patient prescribed thyroid hormone therapy
(n = 92 732 controls). Of those prescribed thyroid hormone replacement,
98.5% were receiving levothyroxine and 1.5% were prescribed triiodothyronine
(those taking triiodothyronine were included with those taking levothyroxine
for subsequent analysis of results). The mean dose of levothyroxine prescribed
was 107 µg/d, with a mean recorded duration of 3.1 years (recorded duration
range, 1-22 years). Levothyroxine cases and control subjects were well matched
for age and sex (mean ± SE age, 65.0 ± 15.3 years vs 65.0 ±
15.3 years; 88.3% female in both groups). The age distribution of levothyroxine
cases and controls was as follows: age 16 to 19 years, 0.26%; 20 to 29 years,
1.56%; 30 to 39 years, 4.72%; 40 to 49 years, 10.30%; 50 to 59 years, 16.88%;
60 to 69 years, 22.94%; 70 to 79 years, 25.11%; 80 to 89 years, 15.37%; and
90 years or older, 2.86%.
Of the 23 183 patients prescribed levothyroxine, 373 (1.61% ±
0.08%) had sustained a fracture of the femur, compared with 1340 of 92 732
controls (1.44% ± 0.04%) (P = .06, 2 analysis). Findings in terms of comparison of fracture occurrence
were similar when the levothyroxine cases and controls 60 years or older (which
comprised 66.28% of the total) were considered alone (levothyroxine cases,
fracture in 2.30% ± 0.11%; controls, fracture in 2.08% ± 0.05%; P = .09). When patients in the study were divided into
groups according to sex, a significant difference in fracture occurrence between
levothyroxine cases and controls was evident only for the group of males prescribed
levothyroxine (females: levothyroxine cases, 1.67% ± 0.08%, vs controls,
1.55% ± 0.04%, P = .22; males: levothyroxine
cases, 1.17% ± 0.20%, vs controls, 0.68% ± 0.08%, P = .008). The mean dose of levothyroxine prescribed to female patients
was significantly lower than that prescribed to male patients (105.7 ±
0.4 µg/d vs 120.6 ± 1.2 µg/d, P<.001),
but for each sex, the levothyroxine dose prescribed to those who had sustained
a fracture was not significantly different (P = .32)
than that prescribed to those who had no history of fracture (females: 100.1
± 2.8 µg/d vs 105.7 ± 0.4 µg/d; males: 114.1 ±
9.0 vs 120.6 ± 1.2 µg/d).
MEDICAL DIAGNOSES AND DRUG THERAPIES AND FRACTURE OCCURRENCE
Both female and male patients who had been prescribed levothyroxine
had significantly higher reported rates of several medical diagnoses likely
to be associated with increased risk of fracture of the femur (Table 1). In addition, a higher rate of prescription of thiazide
diuretics, glucocorticoids, and anticonvulsants was evident in the levothyroxine
groups compared with controls, whereas gonadal steroids, calcium supplements,
and vitamin D were also prescribed more frequently (Table 1). The relevance of these major diagnoses and drug therapies
to fracture risk was confirmed when levothyroxine and control groups were
investigated separately. Significant associations between fracture occurrence
and inflammatory bowel disease and diabetes mellitus were evident among females
in both the levothyroxine and control groups (Table 2). Furthermore, prescriptions of glucocorticoids and anticonvulsants
were associated with increased fracture likelihood in both the levothyroxine
and control groups, as were prescriptions of calcium supplements and vitamin
D among females, whereas prescription of estrogen replacement therapy was
associated with reduced likelihood of fracture in females (Table 2).
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Table 1. Prevalence of Major Medical Diagnoses and Drug Therapies Among
Levothyroxine Groups and Controls*
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Table 2. Relative Risk (95% Confidence Interval) of Fracture of Femur
Among Levothyroxine Cases and Controls Associated With Medical Diagnoses and
Drug Therapies
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INDEPENDENT ASSOCIATIONS OF FACTORS WITH OCCURRENCE OF FRACTURE
After allowing for associations of other factors with fracture, age,
diagnoses of diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis,
and excessive alcohol use were independently associated with fracture risk
in females (Table 3). Anticonvulsant
prescription and prescription of calcium supplements were also associated
with fracture in females, but prescription of levothyroxine was not significantly
(P = .60) associated with fracture occurrence in
females (Table 3). In males, age,
excessive alcohol use, and prescription of anticonvulsants were similarly
independently associated with likelihood of fracture, as was levothyroxine
prescription (P = .01) (Table 3). There was, however, no significant relationship among
males prescribed levothyroxine between the dose of levothyroxine given and
the likelihood of fracture (P = .97).
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Table 3. Significance of Association of Variables With Fracture Occurrence
After Adjusting for Other Associations
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COMMENT
The data presented in this analysis of a very large United Kingdom population
indicate that fracture occurrence is not more common in those prescribed levothyroxine
than in a carefully matched cohort. The data nonetheless reveal that fracture
of the femur is significantly associated with levothyroxine therapy in males,
after correction for other confounding risk factors. Our observations have
considerable implications for current practice given the prevalence of levothyroxine
therapy among the general population and concern about levothyroxine use and
fracture risk. A prevalence study performed in the West Midlands region of
the United Kingdom revealed that 0.8% of a population of all ages received
levothyroxine; this figure rose to 4.8% in the group older than 60 years.16 Other prevalence studies in the United Kingdom,17 Sweden,18 and the
United States19 have provided similar findings,
such that in the United States, 6.9% of a sample population older than 58
years were prescribed levothyroxine.19 In the
United Kingdom, levothyroxine is prescribed almost exclusively for well-established
indications of primary or secondary thyroid failure, although in other countries
thyroid hormone is sometimes prescribed for other indications, such as obesity
or hyperlipidemia.19
The bone density data described5-6,8-11
suggest that patients undergoing long-term levothyroxine therapy may be at
increased risk of osteoporotic fractures, especially postmenopausal women
and those with subclinical hyperthyroidism (defined biochemically by suppression
of serum thyrotropin concentrations). There is, however, a paucity of information
about fracture risk in such subjects. The studies of fracture risk in subjects
taking levothyroxine published so far3, 12-13
have produced conflicting results. One of the most extensive studies addressing
the risk of fracture was that of Cummings et al.3
Potential risk factors for hip fracture were assessed in 9516 white women
65 years or older who had had no previous hip fracture. Of the cohort of women,
1170 (12.3%) were taking thyroid hormones at the time of review and 36% of
these reported a history of hyperthyroidism. Current thyroid hormone therapy
was significantly associated with hip fractures (relative risk, 1.6; 95% CI,
1.1-2.3) in an age-adjusted model, but not in a multivariate model after adjustment
for a history of hyperthyroidism. These negative findings in women with respect
to levothyroxine agree with the results of the present study for women and
with those of a small case-control study of 116 postmenopausal women with
fractured femur in whom the odds ratio for levothyroxine prescription was
0.67 (95% CI, 0.32-1.41).20
The present study used the GPRD to identify and investigate fracture
in the largest cohort of patients (both male and female) prescribed levothyroxine
studied so far. Patients and controls with a history of previous hyperthyroidism
were excluded to remove the influence of this confounding factor observed
in the study by Cummings et al and to allow investigation of any specific
effect of levothyroxine therapy. The GPRD has been described in detail14 and used extensively for research and audit.15 A limitation of the present study was that information
was not verified with patient primary care or hospital records because of
the size of the cohorts retrieved. It is notable, however, that good agreement
between GPRD prescribing data and national data from the Prescription Pricing
Authority has been described, and, in addition, the sensitivity and positive
predictive value of computerized information regarding major medical diagnoses
have also been shown to exceed 90%,14-15
confirming earlier work by Jick and colleagues.21-22
It is likely, therefore, that patients prescribed levothyroxine and those
sustaining fracture of the femur were correctly identified, but the duration
of levothyroxine therapy is likely to be underreported since previous records
may have been incompletely transferred to the database at the time of its
introduction. This factor was taken into account by matching of patients and
controls for duration of registration on the GPRD. For this reason, we have
not examined the relationship between fracture occurrence and date of commencement
of levothyroxine therapy. In addition, data regarding serum thyrotropin concentrations
were not available, so the current or previous prevalence of subclinical hyperthyroidism
secondary to levothyroxine therapy in the present cohort can only be estimated
from other cohorts investigated biochemically. Such studies have revealed
that the prevalence of subclinical hyperthyroidism in those prescribed levothyroxine
may be as high as 21%,16 although this figure
is now likely to be lower because of concerns over BMD data during the past
10 years and a perceived trend toward prescription of lower doses.
In the present study, we found that the reported rate of fracture of
the femur was not significantly greater among the cohort of 23 183 patients
prescribed long-term levothyroxine therapy compared with a group of 92 732
control subjects. The same was true when comparison of the levothyroxine cases
and controls was confined to those in the cohort 60 years or older in whom
fracture is more likely to reflect osteoporosis and less likely to reflect
major trauma. When findings in females and males were analyzed separately,
however, it was evident that a significant difference in fracture occurrence
between levothyroxine users and controls was evident in the male group. This
sex difference may be explained by the higher levothyroxine dose prescribed
to males than females (which may in turn reflect a higher mean weight of males),
although the dose prescribed to those who had sustained a fracture was not
different than those who had not sustained a fracture, arguing against a cause-and-effect
relationship. The present findings in male patients are of interest, especially
because few studies of levothyroxine therapy and BMD have included male patients.
In fact, up to the time of a meta-analysis in 1996,11
BMD results in only 95 males in total had been published. The present data
highlight the need for further investigation of the effects of levothyroxine
therapy in males, since they may be at particular risk.
In addition to the lack of differences in likelihood of fracture between
those prescribed levothyroxine and their controls, it was clear that although
levothyroxine cases and controls were effectively matched for age, sex, primary
care practice, and length of registration on the database, they were not matched
in terms of potential confounding factors that affect fracture risk. Overrepresentation
of diseases such as diabetes mellitus, rheumatoid arthritis, and chronic liver
disease among those prescribed levothyroxine is likely to reflect association
of autoimmune thyroid disease (the major cause of hypothyroidism in iodine-replete
populations such as the United Kingdom) with other autoimmune disorders. In
addition, chronic diseases such as liver and renal disorders often result
in reduced circulating concentrations of levothyroxine and triiodothyronine
and may, therefore, lead to prescription of levothyroxine.23
Anticonvulsants have a similar influence on tests of thyroid function,24 which may explain the significant difference in rate
of prescription of this class of drug among levothyroxine users compared with
controls. Increased rates of prescription of gonadal steroids, calcium supplements,
and vitamin D may reflect concerns regarding osteoporosis risk among those
taking levothyroxine or prescription of these agents in those who have already
sustained a fracture. Increased frequencies of a second disease may also reflect
the tendency for a second disease to be diagnosed more frequently in an individual
already being followed up for another condition.25
Examination of fracture occurrence associated with chronic disorders
and drug therapies among either the levothyroxine group and controls confirmed
the established influence26-29
of such factors as rheumatoid arthritis, diabetes mellitus, and chronic renal
disease on risk of fracture in females; similar relationships were seen in
males but were generally not significant because of group sizes. Similarly,
a significant adverse influence of glucocorticoid and anticonvulsant therapy
was seen in levothyroxine cases and controls of both sexes, an especially
high prevalence of glucocorticoid therapy being observed in the male levothyroxine
group. A protective effect of estrogen replacement therapy was also observed
in females. An association between prescription of calcium supplements and
vitamin D and increased fracture occurrence is likely to reflect prescription
of these medications in those known to have osteoporosis or those who have
already sustained a fracture. Multivariate analysis confirmed a marked independent
influence of chronic diseases, such as rheumatoid arthritis, diabetes, and
inflammatory bowel disease, on fracture risk and an adverse effect of various
drugs (or the diseases for which they are prescribed, eg, epilepsy).
The finding of an independent influence of levothyroxine treatment on
fracture risk in males comprising part of a large cohort of patients is of
concern to those taking and prescribing levothyroxine, although the absence
of independent effect in the large female majority of the cohort is reassuring.
The present data in turn have important implications for public health in
view of the prevalence of thyroid hormone therapy.
AUTHOR INFORMATION
Accepted for publication June 6, 2001.
This work was supported by the Medical Research Council and the BUPA
Foundation, London, England, and the Research Committee of the West Midlands
R&D Directorate, Birmingham, England.
We are grateful to the UK Office for National Statistics, London, for
data retrieval and to M. J. S. Langman, MD, for his constructive comments.
Corresponding author and reprints: Michael C. Sheppard, MB, PhD,
Department of Medicine, The University of Birmingham, Queen Elizabeth Hospital,
Edgbaston, Birmingham B15 2TH, United Kingdom (e-mail: m.c.sheppard{at}bham.ac.uk).
From the Departments of Medicine (Drs Sheppard and Franklyn) and Statistics
(Mr Holder), The University of Birmingham, Birmingham, United Kingdom.
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