Full text of DOI:10.1359/jbmr.2001.16.3.581

JOURNAL OF BONE AND MINERAL RESEARCH
Volume 16, Number 3, 2001
© 2001 American Society for Bone and Mineral Research
Use of Inhaled Corticosteroids and Risk of Fractures
T.P. VAN STAA,1–3 H.G.M. LEUFKENS,1 and C. COOPER3
ABSTRACT
Treatment with systemic corticosteroids is known to increase the risk of fractures but little is known of the
fracture risks associated with inhaled corticosteroids. A retrospective cohort study was conducted using a
large UK primary care database (the General Practice Research Database [GPRD]). Inhaled corticosteroid
users aged 18 years or older were compared with matched control patients and to a group of noncorticosteroid
bronchodilator users. Patients with concomitant use of systemic corticosteroids were excluded. The study
comprised 170,818 inhaled corticosteroid users, 108,786 bronchodilator users, and 170,818 control patients.
The average age was 45.1 years in the inhaled corticosteroid, 49.3 years in the bronchodilator, and 45.2 years
in the control groups. In the inhaled corticosteroid cohort, 54.5% were female. The relative rates (RRs) of
nonvertebral, hip, and vertebral fractures during inhaled corticosteroid treatment compared with control
were 1.15 (95% CI, 1.10–1.20), 1.22 (95% CI, 1.04–1.43), and 1.51 (95% CI, 1.22–1.85), respectively. No
differences were found between the inhaled corticosteroid and bronchodilator groups (nonvertebral fracture
RR ؍ 1.00; 95% CI, 0.94–1.06). The rates of nonvertebral fractures among users of budesonide (RR ؍ 0.95;
95% CI, 0.85–1.07) and fluticasone propionate (RR ؍ 1.03; 95% CI, 0.71–1.49) were similar to the rate
determined for users of beclomethasone dipropionate. We conclude that users of inhaled corticosteroids have
an increased risk of fracture, particularly at the hip and spine. However, this excess risk may be related more
to the underlying respiratory disease than to inhaled corticosteroid. (J Bone Miner Res 2001;16:581–588)
Key words: osteoporosis, corticosteroid, epidemiology, fracture, inhaled
of oral corticosteroids led to substantial increases in fracture
risk. Among people using doses of 7.5 mg prednisolone
daily or more, the risk of hip fracture was doubled and that
of vertebral fracture was increased 4-fold.(5) Previous stud-
ies have suggested that inhaled corticosteroid treatment
induces short-term changes in biochemical markers of bone
turnover, although the clinical relevance of these findings is
unknown.(6,7) Studies addressing changes in bone density
have yielded conflicting results.(8–19) Generally, these have
been cross-sectional surveys; they report significant dose-
dependent decreases in bone density among patients using
inhaled corticosteroids.(10,11,16,19) However, there are few
INTRODUCTION
NHALED CORTICOSTEROIDS are known to be effective in
reducing inflammation of the bronchial mucosa and have
I
become an integral component in the treatment of inflam-
matory respiratory disorders such as asthma.(1) Current
guidelines for the management of asthma advocate early
intervention with inhaled corticosteroids as a first-line treat-
ment.(2) Although safer than systemic corticosteroids, in-
haled corticosteroids have been associated (particularly at
higher doses) with adrenal suppression and unwanted sys-
temic effects such as skin thinning, bruising, and cata-
ract.(3,4) Oral corticosteroid therapy is an established cause data on the effect of inhaled corticosteroids on fracture risk.
of osteoporosis. In a previous study, we showed that the use Because these fractures are associated with considerable
1Department of Pharmacoepidemiology and Pharmacotherapy, University of Utrecht, Utrecht, The Netherlands.
2Procter & Gamble Pharmaceuticals, Staines, United Kingdom.
3MRC Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
581

582
VAN STAA ET AL.
morbidity and mortality(21) and because the frequency of National Formulary [BNF] category 3.1) but never used
utilization of inhaled corticosteroids has risen steeply in inhaled or systemic corticosteroids; and (b) a control group
recent decades, it is important to address this issue.
who received nonsystemic corticosteroid prescriptions (top-
We therefore performed a retrospective cohort study us- ical, aural, ophthalmic, or nasal) but never used inhaled or
ing a population-based British registration system in which systemic corticosteroids, bronchodilators, or cromoglycate
around 1.8% of all adults were registered users of inhaled (BNF, 3.1–3.3).(32) We selected these two comparison
corticosteroids. Our objective was to contrast the fracture groups to evaluate the effects of underlying respiratory
risks of patients exposed to inhaled corticosteroids, those disease on fracture incidence.(33) The control patients were
with obstructive airway disease or asthma using nonsteroid matched by age (within 5 years and, if no patient was found,
inhaled bronchodilators only, and control subjects.
within 10 years), gender, and medical practice. Topical
corticosteroids were the most frequently used nonsystemic
corticosteroid in both comparison groups (75% of the bron-
chodilator and 76% of the control groups). The age- and
gender-specific fracture incidence in the control group was
similar to that of the general population in the GPRD.(34)
MATERIALS AND METHODS
The data used in this retrospective cohort study was
obtained from the General Practice Research Database
(GPRD), owned by the Medicines Control Agency in the
United Kingdom. This database comprises the entire
computerized medical records of a sample of general
practitioners (GPs) in the country. GPs play an essential
role in the UK health care system because they are
responsible for primary health care and specialist refer-
rals. All members of the population are registered with a
single practice, which centralizes the medical informa-
tion not only from the GPs themselves but also from
specialist referrals and hospital attendances. The current
study included all 683 practices currently incorporated in
the GPRD and thereby comprised a 6% sample of the UK
population. The data recorded in the GPRD included
demographic information, prescription details, clinical
events, preventive care provided, specialist referrals, hos-
pital admissions, and their major outcomes.(22–27) Clinical
data are stored and retrieved by means of the Oxford Med-
ical Information Systems (OXMIS) codes for diseases that
are cross-referenced to the International Classification of
Diseases (ICD-9).(23,26) Each entry into the GPRD is vali-
dated internally by cross-checking within the practice and
by comparisons with external statistics.(22–27) Only data
from practices that pass this quality control are compiled to
form the GPRD. Several independent validation studies
have confirmed a high level of completeness and validity of
the GPRD, specifically with regard to recording of hip and
other limb fractures.(28–31)
Follow-up
The baseline date for each inhaled corticosteroid user was
defined as the date of the first inhaled corticosteroid pre-
scription after their practice enrollment date in GPRD. Each
inhaled corticosteroid user was followed from baseline until
they sustained a fracture; until 91 days after the last inhaled
corticosteroid prescription; or until the patient’s change of
practice, death, or the end of the study (whichever date
came first). Bronchodilator users were followed from the
first bronchodilator prescription until they sustained a frac-
ture; until 91 days after the last bronchodilator prescription;
or until the patient’s change of practice, death, or the end of
the study (whichever date came first). The control patients
were followed from a randomly selected baseline.
In an analysis of the reversibility of fracture risk after
cessation of inhaled corticosteroids, each user who stopped
therapy before the end of study was followed from 91 days
after the last inhaled corticosteroid prescription until they
sustained a fracture or were censored. Patients were in-
cluded in this analysis whether or not they had sustained
previous fractures during follow-up.
Fracture assessment
We identified all patients who had a nonvertebral or
vertebral fracture recorded in their medical records during
follow-up. The classification of fractures was based on ICD
(ninth revision) categories. In an earlier study on oral cor-
Study sample
A nonconcurrent (retrospective) cohort study was con- ticosteroids, GPs were requested to confirm the diagnosis
ducted comparing patients using inhaled corticosteroids and to provide discharge summaries or diagnostic reports
with control patients. The inhaled corticosteroid users were for 150 hip and 150 vertebral fracture cases. The hip frac-
defined as permanently registered patients aged 18 years or ture was confirmed by the GP on the questionnaire in 91.0%
older who received one or more prescriptions for inhaled of cases and by discharge summary in 85.2% of cases. The
corticosteroids during the period of time from the enroll- vertebral fracture was confirmed on the GP questionnaire in
ment date of their practice in the GPRD up to the end of data 88.1% of cases and by radiographic report in 76.3% of
collection (December 1997). Inhaled corticosteroid users cases. According to the GPs, 96.4% of the vertebral frac-
who received a prescription for oral corticosteroids in the tures were diagnosed radiographically.(5) Factors associated
period of time from 6 months before to 91 days after the last with fracture and considered as potential confounding vari-
inhaled corticosteroid prescription were excluded from the ables included a history of previous fracture, rheumatoid
analysis. Two comparison groups were selected: (a) a bron- arthritis, hyperthyroidism, congestive heart failure, diabetes
chodilator group, which included adult patients who re- mellitus, seizures, anemia, dementia, depression, psychotic
ceived nonsystemic corticosteroid prescriptions (topical, au- disorder, cerebrovascular accident, back pain, or falls before
ral, ophthalmic, or nasal) and bronchodilators (British baseline. Prescriptions during follow-up for anticonvul-

INHALED CORTICOSTEROIDS AND RISK OF FRACTURES
583
TABLE 1. DEMOGRAPHIC AND MEDICAL CHARACTERISTICS OF INHALED CORTICOSTEROID AND COMPARISON GROUPS
Inhaled
corticosteroid group
Bronchodilator group
Control group
(n ϭ 170,818)
(n ϭ 108,786)
(n ϭ 170,818)
Follow-up
Total duration (person-years)
Mean duration of follow-up per subject (years)
Median duration of follow-up per subject (years)
Number of women
292,102
1.7
0.9
124,660
1.1
0.2
454,448
2.7
2.3
93,055 (54.5%)
65,824 (60.5%)
93,055 (54.5%)
Age (years)
Mean
Median
45.1
42
49.3
47
45.2
42
Medical Condition
Back pain year before
Diabetes mellitus
Emphysema
Rheumatoid arthritis
Falls year before
10,718 (6.3%)
4030 (2.4%)
2110 (1.2%)
1109 (0.6%)
1248 (0.7%)
9312 (8.6%)
3764 (3.5%)
557 (0.5%)
779 (0.7%)
1250 (1.1%)
10,601 (6.2%)
4435 (2.6%)
130 (0.1%)
1045 (0.6%)
1180 (0.7%)
Drug history in year prior to baseline
NSAIDs
Hormone replacement therapy
Fracture history in year prior to baseline
Nonvertebral fracture
Vertebral fracture
25,986 (15.2%)
6455 (3.8%)
23,467 (21.6%)
4773 (4.4%)
28,810 (16.9%)
6511 (3.8%)
1969 (1.2%)
87 (0.05%)
1358 (1.2%)
61 (0.06%)
1895 (1.1%)
71 (0.04%)
NSAIDs, nonsteroidal anti-inflammatory drugs.
sants, methotrexate, thiazide diuretics, anxiolytics, antipsy-
chotics, antidepressants, anti-Parkinson drugs, hormone re-
placement therapy, bisphosphonates, vitamin D, and
RESULTS
Inhaled corticosteroids were prescribed to 284,733 pa-
calcitonin also were considered as potential confounding tients, of whom 170,818 did not receive systemic cortico-
variables.(35,36)
steroids concomitantly. The inhaled corticosteroid cohort
(without concomitant use of systemic corticosteroids) was
followed for a mean period of 1.7 years per person, for a
Assessment of inhaled corticosteroid dose
total duration of 292,102 person-years, and received a mean
of 7.9 inhaled corticosteroid prescriptions per person. Be-
clomethasone dipropionate was the most frequently pre-
scribed inhaled corticosteroid (86.4% of all prescriptions).
Budesonide (11.1%) and fluticasone propionate (2.4%)
were prescribed less frequently. The group of bronchodila-
tor users included 108,786 patients, followed for a mean
duration of 1.1 years per person, and the control group
170,818 subjects followed for a mean of 2.7 years per
For each inhaled corticosteroid user who received at least
two prescriptions during follow-up, the daily corticosteroid
dose over the total treatment period was estimated by di-
viding the total dose of prescribed beclomethasone dipropi-
onate or equivalent (in micrograms) by the treatment time.
Budesonide was considered dose-equivalent to beclometha-
sone. Fluticasone propionate was considered to be twice as
potent as either budesonide or beclomethasone.(32) The person.
Table 1 summarizes baseline characteristics of the in-
treatment time was taken as the time from the first inhaled
corticosteroid prescription until the last recorded supply
date after the last prescription. Three dose categories were
assigned: low dose (less than 300 ␮g/day), medium dose
(300–700 ␮g/day), and high dose (700 ␮g/day or more).
haled corticosteroid and comparison groups. As expected,
the age and gender distributions of inhaled corticosteroid
and control groups were similar: the mean age was 45 years
and 54.5% were female. The bronchodilator group was
slightly older (average of 49 years) and included more
women (60.5%). There were no major differences between
the three groups in baseline fracture history. Around 1% in
each cohort reported a history of nonvertebral fractures in
the year before baseline.
During follow-up, the incidence of nonvertebral fractures
was 1.4 fractures per 100 person-years in the inhaled cor-
ticosteroid group, 1.4 in the bronchodilator group, and 1.1 in
the control group (Table 2). After adjustment for potential
Statistical methods
Incidence rates for fractures were calculated by dividing
the number of cases by the total number of person-years of
follow-up.(37) Adjusted relative rates (RRs) were estimated
using Cox proportional hazards models that included age,
gender, and selected confounding variables.

584
VAN STAA ET AL.
TABLE 2. INCIDENCE OF FRACTURES AMONG INHALED CORTICOSTEROID USERS, CONTRASTED BY COMPARISON GROUP WITH
USERS OF NONSTEROID BRONCHODILATORS AND CONTROLS
Inhaled
corticosteroid
group
Bronchodilator control group
Control group
(n ϭ 170,818)
(n ϭ 108,786)
(n ϭ 170,818)
No. of
cases
No. of
cases
Adjusted RR
(95% CI)
No. of
cases
Adjusted RR
(95% CI)
Rate
Rate
Rate
Nonvertebral
Forearm
Hip
3936
1.4
1752
1.4
1.00
(0.94–1.06)
1.02
(0.90–1.15)
1.20
4811
1061
331
1.1
1.15
(1.10–1.20)
1.13
(1.03–1.25)
1.22
846
299
195
0.3
0.1
0.1
382
178
119
0.3
0.1
0.1
0.2
0.1
(0.99–1.45)
0.90
(1.04–1.43)
1.51
Vertebral
192
0.04
(0.71–1.14)
(1.22–1.85)
Figures in bold are relative rates for fracture after adjusting for age, sex, coexisting disease, concomitant drug treatment, and a baseline
history of fracture and back pain.
confounding variables (coexisting disease, concomitant
drug treatment, and a baseline history of fracture or back
pain), the rate of nonvertebral fractures was significantly
elevated among inhaled corticosteroid users when compared
with control patients (RR ϭ 1.15; 95% CI, 1.10–1.20). No
difference was apparent in nonvertebral fracture risk be-
tween the inhaled corticosteroid and bronchodilator groups
(RR ϭ 1.00; 95% CI, 0.94–1.06). The crude RR in the
inhaled corticosteroid group compared with the bronchodi-
lator group was 0.95 (95% CI, 0.90–1.01) and the RR
adjusted for age and gender was 0.99 (95% CI, 0.94–1.05).
Inhaled corticosteroid users also had a significantly higher
rate of hip fracture than controls (RR ϭ 1.22; 95% CI,
FIG. 1. Age- and gender-specific incidence rates of nonvertebral
fracture among users of inhaled corticosteroids, nonsteroid bronchodi-
lators, and controls.
1.04–1.43); again the rate was similar to that of the bron-
chodilator group (RR ϭ 1.20; 95% CI, 0.99–1.45). The rate
of nonvertebral fractures among users of budesonide (RR ϭ
0.95; 95% CI, 0.85–1.07) and fluticasone propionate (RR ϭ
1.03; 95% CI, 0.71–1.49) was similar to that of beclometha-
sone dipropionate. The average age of subjects who only the control group. These differences in incidence were most
used beclomethasone dipropionate (n ϭ 143,436) was 45 pronounced in younger subjects and were not apparent
years and 53.8% were female. Among those who used above age 75 years.
fluticasone propionate only (n ϭ 2322), the mean age was
Table 3 compares the incidence of fractures in the three
44 years and 56.6% were female. Finally, those only using inhaled corticosteroid dose categories (for patients who
budesonide (n ϭ 17,284) were aged 47 years on average and received at least two prescriptions). Comparing the inhaled
58.3% were female.
corticosteroid users with the control group, a dose response
Figure 1 shows the age-specific incidence rates of non- was found for hip and vertebral fractures. With a standard-
vertebral fracture among men and women in the cohort ized daily dose of Ͻ300 ␮g beclomethasone per day, hip
according to their oral corticosteroid use. Fracture rates in fracture risk was 0.95 (95% CI, 0.67–1.34), rising to 1.06
women rose exponentially with advancing age among the (95% CI, 0.80–1.40) at doses of 300–700 ␮g, and 1.77
control patients such that for women aged 85 years or more, (95% CI, 1.31–2.40) at doses of 700 ␮g/day or more.
the incidence was 4.5 per 100 person-years. The incidence Vertebral fracture showed a similar dose-related risk gradi-
among female users of inhaled corticosteroids was higher at ent with the highest risk in the high-dose inhaled cortico-
most ages relative to women in the control group, but it was steroid group compared with the control patients (RR of
comparable with female users of bronchodilators. Among 2.50). There was no consistent trend in the rate of fractures
men, nonvertebral fracture incidence fell to a nadir in among inhaled corticosteroids users compared with the
midlife but rose more steeply after 65 years of age. Again, bronchodilator users.
incidence rates tended to be greater among those using
Figure 2 shows the incidence of fractures before, during,
inhaled corticosteroids and bronchodilators compared with and after inhaled corticosteroid and bronchodilator treat-

INHALED CORTICOSTEROIDS AND RISK OF FRACTURES
585
FIG. 2. Incidence of nonvertebral fracture before, during, and after
inhaled corticosteroid or nonsteroid bronchodilator treatment stratified
by dose.
ment. The incidence of nonvertebral fractures was similar
among the three dose groups of inhaled corticosteroids and
the bronchodilator group before commencement of treat-
ment. The largest increase in fracture incidence during
treatment was observed in the high-dose inhaled corticoste-
roid group (rate of 1.7 cases per 100 person-years in the first
year of treatment compared with 1.3 in the year before).
Similar patterns were found for hip, vertebral, and forearm
fractures. The rates in the bronchodilator group also in-
creased after commencement of treatment (from 1.3 in the
year before to 1.6 during the first year of treatment). After
cessation of treatment with either bronchodilators or inhaled
corticosteroids, the rates declined toward baseline levels in
all groups. The rate of fractures did not vary over time in the
control group (rate of 1.1 in the first year of follow-up and
1.0 in the fifth year).
DISCUSSION
In this cohort study we have examined fracture incidence
among patients who used inhaled corticosteroids, patients
with respiratory disease using noncorticosteroid inhaled
bronchodilators, and a control population sample not using
inhaled treatment. The results point to an increased risk of
fracture (particularly at the hip and vertebral body) among
patients who used inhaled corticosteroids, as well as those
who used inhaled noncorticosteroid bronchodilators, when
compared with patients not using these drugs. Fracture risks
tended to decline after cessation of inhaled corticosteroid or
bronchodilator treatment. The findings suggest that low-
dose inhaled corticosteroid therapy, at the doses included in
this study, is not associated with an increased risk of frac-
ture; however, patients with chronic respiratory disease who
use any inhaled therapy appear to be at increased risk when
compared with a population control group.
Previous studies examining the effects of inhaled corti-
costeroid therapy on bone density give conflicting results
with limited information on the risk of fractures.(8–20) This

586
VAN STAA ET AL.
study shows that users of inhaled corticosteroids have a scribed daily dose was not recorded systematically by the
fracture risk which is comparable with that of users of GPs and patients’ use may have been intermittent. The time
nonsteroid bronchodilators. Furthermore, users of different period of follow-up may have included periods without
types of inhaled corticosteroids have similar fracture risks in inhaled corticosteroid use. This may have resulted in an
this study, despite differences in systemic bioavailabil- underestimate of any excess fracture risk, as well as an
ity.(3,4,6) Other studies have found that fluticasone and underestimate of the inhaled corticosteroid dose. It has been
budesonide show less effect on bone metabolism than postulated that adverse skeletal effects only occur at doses
beclomethasone.(38–41) Two prospective studies observed over 1500 ␮g beclomethasone equivalent per day when
that fluticasone was associated with higher bone density used for long periods.(4) In this study, there were 3311
levels compared with beclomethasone.(42,43) The nature of (1.9%) patients who were using these higher doses for over
the inhaler device also has been reported to affect the 6 months. Given this relatively small number of patients, the
deposition of the inhaled corticosteroids and their systemic possibility of a more pronounced increase in fracture risk at
bioavailability.(3,6) However, this study found no consistent these higher doses of inhaled corticosteroids cannot be
difference in fracture risk between users of dry-powder excluded. However, any impact in actual clinical practice is
delivery system and metered-dose inhalers. likely to be small because of the low prevalence of utiliza-
We found no differences in fracture risk between the tion of these doses.
various types of bronchodilator drugs (72% of the broncho-
The control group in our study consisted of users of
dilator prescriptions were for ␤2-adrenoceptor stimulants, nonsystemic corticosteroids. The age- and gender-specific
7% were for ephedrine or orciprenaline, 13% were for overall fracture incidence in the control group was very
theophylline, and 6% were for antimuscarinic bronchodila- close to that of the general population in GPRD.(34) We
tors). Users of ephedrine or orciprenaline had a nonvertebral wished to select a control group similar in age, gender, and
fracture RR of 1.04 compared with users of selective ␤2- practice to the treatment group. However, documented pre-
adrenoceptor stimulants (95% CI, 0.86–1.26). For theoph- scription was a means of ensuring active registration at the
ylline users, the RR was 1.08 (95% CI, 0.85–1.36) and for practice. Therefore, we selected users of nonsystemic cor-
users of antimuscarinic bronchodilators, the RR was 1.01 ticosteroids as controls, because this would conservatively
(95% CI, 0.77–1.34). With respect to the possible role of (downwards) bias any estimate of risk associated with oral
these drugs in causing fracture, theophylline has been asso- corticosteroids. The exclusion of control patients with fre-
ciated with increases in serum calcium concentration and quent prescribing of nonsystemic corticosteroids, which
urinary calcium excretion(44,45) and osteoporotic changes in may be absorbed with frequent use, did not modify the
tail vertebrae have been reported in rats subjected to long- results.
term parenteral theophylline.(46) The clinical relevance of
A possible weakness of this study is the comparability of
these findings to fracture risk in routine clinical practice is the inhaled corticosteroid and bronchodilator groups. Con-
unknown. However, the consistency of the fracture risks trol for confounding was restricted to age, gender, and a
over different types of respiratory disease treatment sug- variety of medical diagnoses and treatments. A number of
gests that the underlying disease itself (reversible airway potential confounders, such as physical activity and baseline
obstruction) rather than a heterogeneous group of drugs is bone density, were not available. However, adjustments for
the true reason for the small increase in the risk of fracture. known confounders had little effect on the comparison of
Whether patients with reversible airways obstruction de- nonvertebral fracture rates between inhaled corticosteroid
velop fractures independently of the drugs used to treat and bronchodilator users. In addition, there was evidence to
them is not yet clear. In patients with chronic lung disease suggest that inhaled corticosteroid users had, on average,
not using corticosteroids, Praet reported decreases in bone more severe respiratory disease than the users of broncho-
density that were not confirmed by the findings of Reid and dilator drugs. The recorded duration of respiratory disease,
Riancho.(14,47,48) All three studies were small and the sever- number of visits to the GP for respiratory complaints, and
ity of lung disease may have varied considerably. It is also the prevalence of emphysema were all higher among the
possible that reversible airways obstruction influences the inhaled corticosteroid users. Despite this potential selection
risk of fracture through nonskeletal mechanisms.(49) For bias, the incidence of nonvertebral fractures was compara-
example, physical inactivity with concomitant muscle ble in the two groups. Another possible limitation of the
weakening and reduced coordination may increase the risk study is that lifetime data on corticosteroid use were not
of falling.(50) Although not the principal objective of this available, because information was restricted to the period
study, we examined the incidence rate of falls in our cohort. of GPRD data collection. Some patients may have received
Rates increased rapidly after commencement of inhaled oral corticosteroids before data collection. However, a pre-
corticosteroid treatment (1.2 per 100 person-years in the vious study using the GPRD suggested that a substantial
year before baseline in the high-dose group compared with proportion of the excess fracture risk caused by oral corti-
1.6 in the first 6 months of treatment). These findings costeroids might wane within 6 months of stopping treat-
necessitate further research, given the high prevalence of ment.(5) Also, analyses on patients with more than 2 years of
chronic respiratory disease and our observation of a signif- data before commencement of inhaled corticosteroid ther-
icant contribution to fracture risk.
apy showed similar results to those in the cohort as a whole.
The classification of inhaled corticosteroid dose was The RR of nonvertebral fracture in the inhaled corticoste-
based on an averaging over the time period between the first roid group compared with the bronchodilator group was
and last inhaled corticosteroid prescription because the pre- 0.96 (95% CI, 0.85–1.08) in this analysis; for the low-dose

INHALED CORTICOSTEROIDS AND RISK OF FRACTURES
587
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did not have information on the precise time-course of
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prescription for inhaled corticosteroids. For patients using
these drugs intermittently, follow-up would have included
periods without treatment as evidenced by the average 7.9
inhaler prescriptions annually. This may have resulted in an
underestimate of the excess fracture risk.
Several analyses were conducted to review the sensitivity
of these results to the method of analysis and control selec-
tion. Results did not materially change when adjustments
were made for calendar year of follow-up or alcohol use,
smoking, and body mass index (BMI). Limiting the length
of follow-up of control patients to the length of follow-up of
the inhaled corticosteroid users also did not modify the
results. Finally, the observation that fracture risk declined
after cessation of inhaled therapy (whether corticosteroid or
not) suggests possible ascertainment bias for fractures dur-
ing treatment. However, we have previously shown that
nonspine fracture identification has 90% accuracy in this
cohort.(5)
In conclusion, the results of this study suggest that users
of inhaled corticosteroids and other bronchodilators have an
increased risk of fractures, particularly at the hip and spine;
this excess risk is more likely to be related to the underlying
respiratory disease than to the inhaled corticosteroid use.
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ACKNOWLEDGMENTS
We thank EPIC, the GPRD license holder, for their sup-
port. The manuscript was prepared by G. Strange. Financial
support for this study was provided through a grant from
Procter & Gamble Pharmaceuticals, Ltd.
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Address reprint requests to:
Prof. C. Cooper, M.A., D.M., F.R.C.P.
MRC Environmental Epidemiology Unit
Southampton General Hospital
Southampton SO16 6YD, UK
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