Studies of the risk of fracture associated with inhaled corticosteroids are inconclusive and are limited to short-term effects. We assessed whether long-term use increases this risk. We conducted a case control study nested within a population-based cohort of all Quebec elderly dispensed respiratory medications and followed for at least 4 years during 1988–2001. There were 9,624 new cases of fracture of the hip or upper extremities and 191,622 age-matched control subjects (mean age of 81 years). The rate of any such fracture for current inhaled corticosteroid use was not elevated (rate ratio [RR], 0.97; 95% confidence interval [CI], 0.92–1.03). For upper-extremity fracture, the rate increased by 12% (RR, 1.12; 95% CI, 1.04–1.19) with every 1,000-μg increase in the daily dose of inhaled corticosteroids, but not for hip fracture (RR, 0.97; 95% CI, 0.88–1.07). Among subjects followed for over 8 years, the rate of hip fracture was only elevated with daily doses of more than 2,000 μg of inhaled corticosteroids (RR, 1.61; 95% CI, 1.04–2.50). The rate was not elevated at any dose of nasal corticosteroids. In conclusion, the long-term use of inhaled and nasal corticosteroids at the usual recommended doses is not associated with a risk of fracture in older patients with respiratory disease.
Inhaled corticosteroids are effective drugs for the treatment of asthma, improving symptoms and reducing morbidity and mortality, even at low doses (1–6). They are now also being used to treat chronic obstructive pulmonary disease (7). Nasal corticosteroids are increasingly becoming first-line therapy for the regular control of allergic rhinitis (8). The consumption of these topical corticosteroids has consequently risen considerably since the 1980s (9–11) and is expected to rise further following the recommendations in several countries for their introduction earlier in the course of disease and at higher doses than ever in the past (12–14).
Safety concerns, including osteoporosis and fractures, have been expressed in relationship to the long-term use of topical corticosteroids (15). Clinical studies have shown that accelerated bone resorption occurs at all doses (16–18). Furthermore, several studies have reported dose-dependent decreases in bone density (19–21). However, whether these actually translate to fractures is unknown but is of great consequence as people age. Indeed, fracture incidence, morbidity, and mortality rise significantly after the age of 70 years (22–26).
To date, four observational studies have attempted to associate fractures with inhaled corticosteroids. The first, which found no association with hip fracture risk, had a study size too small to estimate the risk with precision (27). The second study, using a cohort of patients from the United Kingdom General Practice Research Database, found a small, albeit not significant, increase in risk for hip fracture (rate ratio [RR], 1.20; 95% confidence interval [CI], 0.99–1.45) for inhaled corticosteroid use relative to bronchodilator use, although the follow-up was short at 1.7 years (28). Another study using the General Practice Research Database found an increase in the risk of hip fracture (RR, 1.19; 95% CI, 1.10–1.28) for inhaled corticosteroid use relative to no inhaled corticosteroid use, mostly among subjects without asthma or chronic obstructive pulmonary disease, but with a longer follow-up at a median of 2.7 years (29). The last was a cohort study from Ontario, Canada, that found no increase in the risk of hip fracture (RR, 0.92; 95% CI, 0.75–1.12) for inhaled corticosteroid use relative to the use of proton pump inhibitors, although the follow-up was short at less than 1 year (30). Thus, to date, the epidemiologic studies assessing the risk of fracture associated with inhaled corticosteroids are inconclusive, and none has evaluated the effect of longer term use of these drugs.
In this study, we assessed whether and at what dose long-term inhaled and nasal corticosteroid use increases the risk of fracture among older patients dispensed respiratory medications.
We used the health databases of the Régie de l'assurance maladie du Québec. The databases contain information on demographics, all medical services rendered, along with the diagnostic code of the service (ICD-9 code) and, for people aged 65 years or older, all outpatient prescription medications dispensed.
A population-based cohort design with a nested case control analysis was used. The source population consisted of all subjects who between January 1, 1988, and December 31, 2001, were 65 years of age or older and were dispensed at least one respiratory medication during this period. The list of medications is provided in an online supplement. A cohort was formed from this source population by identifying all subjects with three or more prescriptions for these medications in any 1-year period and on at least two different dates. Cohort entry was taken as the date of the third prescription.
A case was defined as the first fracture of the hip or upper extremities occurring after 4 years of follow-up to ensure sufficient time to assess exposure information. Subjects with such a fracture during the first 4 years of follow-up, as well as subjects with a vertebral fracture before cohort entry, were excluded. The date of the case defining fracture was called the index date.
For each case, up to 20 age-matched control subjects were selected at random from all subjects who entered the cohort on the same year as the case and who were born within 6 months of the birth date of the case. Control subjects also had to be at risk on the date (index date) of their corresponding case event.
All prescriptions of corticosteroid medications dispensed during the entire period before the index date were obtained. To combine the different corticosteroids, dose equivalencies were established. For oral corticosteroids, the dose equivalencies were taken directly from Haynes (31). Equivalencies for inhaled and nasal corticosteroids were chosen on the basis of relative topical potency and what guidelines consider to be comparable doses (12). The equivalencies used are provided in an online data supplement.
Covariates included age, sex, and the severity of respiratory disease, as well as other conditions associated with the risk of fracture (32). We quantified the severity of respiratory disease, independently of inhaled corticosteroid use, by counting the number of dispensed prescriptions of β-agonists, ipratropium bromide, and theophylline and measuring the concurrent use of oral corticosteroids. We also adjusted for other drugs that might increase the risk of fractures (additional details are provided in an online supplement) (33–38). For adjustment purposes, exposure to these drugs was considered at any time during the 4-year period before the index date, except for the central nervous system–acting drugs, for which a 90-day period was used.
The primary analysis was based on the corticosteroid exposure during the 4-year period before the index date. Crude and adjusted RRs of fracture for inhaled and nasal corticosteroid use were estimated by conditional logistic regression, with nonuse during the 4-year period as the reference. Subjects were considered as current users if the last prescription was dispensed within 90 days of the index date. The cumulative dose during the 4-year span was computed by summing the dose equivalents of all prescriptions of the inhaled and nasal formulations. The mean daily dose was taken as the cumulative dose divided by the time from the date of the first prescription to the index date. To assess longer term effects, all analyses were repeated for the subset of subjects who had 8 years or more of cohort follow-up. Age and calendar time were inherently accounted for by the matching. Further adjustment factors included sex and the severity of respiratory disease, as well as all other covariates measuring conditions associated with the risk of fracture. Additional details are provided in an online supplement. All analyses were performed using SAS statistical software (SAS Institute Inc., Cary, NC).
The source population contained 352,697 people, of whom 202,007 belonged to the respiratory cohort defined by three or more prescriptions for respiratory drugs in any 1-year period. After excluding 61,208 subjects with less than 4 years of follow-up and 7,773 with a previous fracture of the hip, upper extremities, or vertebrae, the cohort included 133,026 subjects. We identified 9,624 new cases of fracture of the hip or upper extremities that occurred during follow-up and selected 191,622 age-matched control person-moments from the risk sets. Of these, 3,326 are fractures of the hip, and 6,298 are fractures of the upper extremities.
Cases and control subjects were 81 years of age at the index date. Table 1
Cases (n = 9,624)
Control Subjects (n = 191,622)
|Age, mean ± SD||80.7 ± 6.25||80.6 ± 6.22|
|Hospitalized during follow-up, %||79.5||69.5|
|Other fracture* in the 4 years before the index date||37.5||5.8|
|Drug treated conditions during the 4 years before the index date|
|Cardiovascular disease, %||77.1||77.0|
|Thyroid disorders, %||16.4||14.7|
|Rheumatic disease, %||1.8||1.2|
|Use of medications possibly associated with hip fracture risk during the 4 years before the index date|
|Other central nervous system drugs, %||37.6||26.4|
|Uses of central nervous system medication within 90 days of the index date|
|Other central nervous system drugs, %||20.9||12.8|
|Use of oral corticosteroids in the 4 years before the index date|
|Any use, %||37.7||33.1|
|Cumulative dose† in all subjects in mg, mean ± SD||907 ± 2,590||649 ± 2,102|
|Cumulative dose† in users in mg, mean ± SD||2,402 ± 3,766||1,959 ± 3,281|
|Cases||Control Subjects||Crude RR||RR||95% CI|
|Number of subjects||9,624||191,622|
|Use during 4 years before the index date|
|Any use, %||59.0||57.7||1.06||0.96||0.91–1.01|
|Current use,† %||31.9||30.7||1.08||0.97||0.92–1.03|
|Any use, %||19.1||19.4||0.98||0.96||0.90–1.01|
|Current use,† %||4.4||4.7||0.95||0.92||0.83–1.03|
|Cases||Control Subjects||Crude RR||RR||95% CI|
|Number of subjects||9,624||191,622|
|Mean daily dose† used during 4 years before the index date, μg|
|> 0 to 500 μg||3,255||66,699||1.01||0.94||0.89–0.99|
|> 500 to 1,000 μg||1,443||26,978||1.11||0.99||0.92–1.06|
|> 1,000 to 1,500 μg||643||11,450||1.16||1.05||0.95–1.16|
|> 1,500 to 2,000 μg||256||4,181||1.27||1.08||0.93–1.25|
|> 2,000 μg||76||1,198||1.32||1.11||0.86–1.43|
|Mean ± SD||323.0 ± 475.6||295.3 ± 449.4||1.15‡||1.06‡||1.01–1.12|
|Mean daily dose† used during 4 years before the index date, μg|
|> 0 to 100 μg||1,393||28,811||0.96||0.93||0.87–0.99|
|> 100 to 200 μg||268||5,035||1.06||1.03||0.90–1.18|
|> 200 μg||178||3,326||1.06||1.01||0.86–1.20|
|Mean ± SD||14.3 ± 50.5||14.2 ± 50.9||1.01‡||0.99‡||0.95–1.04|
|Cases||Control Subjects||Crude RR||RR||95% CI|
|Hip fracture Number of subjects||3,326||66,237|
|Mean daily dose,† μg|
|> 0 to 500 μg||1,115||23,398||0.95||0.88||0.81–0.96|
|> 500 to 1,000 μg||469||8,850||1.07||0.89||0.79–1.01|
|> 1,000 to 1,500 μg||208||3,752||1.12||0.92||0.77–1.09|
|> 1,500 to 2,000 μg||83||1,380||1.21||0.88||0.68–1.13|
|> 2,000 μg||26||383||1.37||1.03||0.66–1.59|
|Mean ± SD||306 ± 466||283 ± 440||1.13‡||0.97‡||0.88–1.07|
|Upper extremity fracture Number of subjects||6,298||125,385|
|Mean daily dose,† μg|
|> 0 to 500 μg||2,140||43,301||1.04||0.96||0.90–1.03|
|> 500 to 1,000 μg||974||18,128||1.13||1.05||0.96–1.15|
|> 1,000 to 1,500 μg||435||7,698||1.19||1.13||1.00–1.28|
|> 1,500 to 2,000 μg||173||2,801||1.30||1.18||0.98–1.42|
|> 2,000 μg||50||815||1.30||1.15||0.83–1.57|
|Mean ± SD||332 ± 480||302 ± 454||1.16‡||1.12‡||1.04–1.19|
Further analyses were performed in the subgroup of 3,701 cases and 73,858 control subjects, with at least 8 years of follow-up in the cohort. Most RRs were no different than unity. Only the use of more than 2,000 μg of inhaled corticosteroids per day for an average of 6 years was associated with an elevated risk of fracture (RR, 1.61; 95% CI, 1.04–2.50). This means that 58 subjects (95% CI, 24–1,767 subjects) would need to be treated with more than 2,000 μg of inhaled corticosteroids per day for 6 years to result in one extra fracture. The log-linear continuous dose–response analysis showed no definite increase (RR, 1.08; 95% CI, 0.98–1.20).
We have shown with this population-based nested case control study that the use of inhaled and nasal corticosteroids is generally not associated with an increased risk of fracture of the hip or upper extremities in older patients dispensed respiratory medications when used at the usual recommended doses over a 4-year period. There was, however, a small increase in overall fracture risk of 6% per 1,000 μg increase in mean daily dose, which was of borderline statistical significance. This increase was due entirely to an increase in the risk of an upper extremity fracture, which increased by 12% per each additional 1,000 μg of inhaled corticosteroid per day in beclomethasone-equivalent units. The increased risk was only apparent at daily doses of more than 1,000 μg, doses now required less frequently with the advent of effective combination therapy with long-acting inhaled β-agonists added to inhaled corticosteroids (39).
The higher dose users of inhaled corticosteroids, who were dispensed the beclomethasone equivalent of over 1,500 μg per day, represented only 5% of all users of inhaled corticosteroids. A slight increase in risk of hip and upper extremity fracture combined appeared in the two strata that formed this high-dose group, with RR estimates of 1.08 and 1.11, both with confidence intervals that largely include 1. With the actual number of cases and control subjects obtained, the study had 90% power to detect a RR of 1.3 or higher for doses of inhaled corticosteroid above 1,500 μg per day and a RR of 1.5 or higher for doses above 2,000 μg per day.
The major strength of this study is its size, with over 9,500 cases and 191,000 control subjects selected from all subjects over 65 years of age in the population who were dispensed drug treatment for chronic respiratory disease between 1988 and 2001. Our study assessed the effect of inhaled corticosteroid use over at least a 4-year period. A crucial facet of our study is the completeness of drug information collected in the Régie de l'assurance maladie du Québec database that allowed us to separate the effects of oral corticosteroids from that of the inhaled variety and to estimate daily doses over a long period of time. This information was essential in permitting an accurate estimation of the safety thresholds of inhaled corticosteroid use and in eliminating confounding by use of oral corticosteroids.
Observational studies such as ours have limitations. Fractures occurring outside the province are not always included in the Régie de l'assurance maladie du Québec database, possibly inducing selection bias. However, the gravity of a hip fracture makes it unlikely that such an event is not recorded as the Régie de l'assurance maladie du Québec reimburses, in part, health-related expenses incurred outside the province. We also selected, as the outcome, fracture of the hip and upper extremities, and not vertebral fractures, to avoid underestimating the risk estimate because the latter do not always result in a medical intervention and would thus not be systematically recorded in the databases. Fractures of the hip and upper extremities have been validated previously in this database with 99.2% and 92.7% sensitivity (40). The measure of exposure, based on dispensed inhaled corticosteroids, is a common limitation of databases studies as it may not represent actual intake or even actual use. This limitation linked to low compliance and poor inhaler technique may have underestimated the risk. However, it is unlikely that subjects dispensed over 1,500 μg per day of inhaled corticosteroids over 4 years are not using these drugs. Another limitation arises from our restriction of the exposure period to the 4-year span before the index date. This was necessary, as prescription drug data were only available starting at 65 years of age. As a result, the use of oral corticosteroids before age 65 that may have affected bone mass could not be adjusted for. Nevertheless, the effects were similar among subjects who used oral steroids during the year before the index date and those who did not. Moreover, besides the cumulative use of oral corticosteroids, we also adjusted for the degree of severity of respiratory disease. Although we adjusted the RRs for several known risk factors, we did not have access to some potential confounding factors such as smoking, physical activity, or obesity. Patients with respiratory disease are more likely to be smokers and tend to have lower body mass index, both of which are risk factors for fracture. Physical activity, usually limited in patients with respiratory problems for whom inhaled corticosteroids are indicated, is associated with osteoporosis and the risk of fractures (32). We do not believe this to be a problem, however, as these associations are weak and thus are unlikely to affect our results in any substantial way. The one cohort study that specifically measured physical activity found no difference in physical activity between users and nonusers of inhaled corticosteroids (27).
The implications of our results for the treatment of respiratory disease are important. The fact that long-term use of inhaled corticosteroids does not appear to be associated with an increased risk of hip or upper extremity fracture, except at very high doses, suggests that the doses corresponding to the current treatment guidelines are safe.
S.S. has no declared conflict of interest; M.B. has no declared conflict of interest; R.K. has no declared conflict of interest; P.E. has been on the advisory boards, and has received speaker fees over the last three years, from GlaxoSmithKline (Canada), AstraZeneza (Canada), and Merck Frosst (Canada), compensation totaled approximately $10,000 Cdn from Merck Frosst (Canada).
The authors thank M. Jacques Barry of the Régie de l'assurance maladie du Québec for his assistance in obtaining the data and Ms. Sophie Dell'Aniello for assistance in data analysis.
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