Abstract
There is accumulating evidence that the use of inhaled corticosteroids is associated with a dose-related reduction in bone mineral density. Whether this translates to an increase in fracture is unclear. We have used the General Practice Research Database to perform a case–control analysis, including 16,341 cases of hip fracture (mean age of 79 years, 79% female, median period prescribing data 2.7 years) and 29,889 control subjects, individually matched by age, sex, and general practice. Data for all prescriptions for corticosteroids and for potential confounders, including other drug use and comorbid illnesses, were extracted, and the impact of inhaled corticosteroid exposure was analyzed using conditional logistic regression. The risk of hip fracture was associated with exposure to inhaled corticosteroids with an odds ratio of 1.26 (95% confidence interval, 1.17 to 1.36). This odds ratio was reduced after adjusting the model for annual courses of oral corticosteroids, the only confounder of note (OR 1.19; 95% CI, 1.10 to 1.28). There was a dose–response relationship between inhaled corticosteroid use and hip fracture even after adjusting for the annual number of courses of oral corticosteroids (p trend = 0.007). In older subjects, the recent use of inhaled corticosteroids is associated with a dose-related increase in hip fracture.
Nearly 1 in 10 people in the United Kingdom over the age of 65 years has a diagnosis of asthma or chronic obstructive pulmonary disease (COPD), and most of these patients are prescribed an inhaled corticosteroid at some point (1). We have reported evidence that the cumulative dose of inhaled corticosteroids is inversely related to bone mineral density in young adults with mild asthma and little or no exposure to oral corticosteroids (2). A similar reduction in bone mineral density was seen in patients with COPD treated with inhaled triamcinolone in the Lung Health Study Research Group trial (3) and in two prospective cohorts of patients taking an inhaled corticosteroid for asthma (4, 5). These findings suggest that people taking an inhaled corticosteroid for long periods may have an increased risk of fracture.
Hip fracture is the most important fracture in terms of patient morbidity and mortality and for utilization of health service resources (6). Because hip fracture is common in the older population, a small increase in the risk of fracture associated with the use of inhaled corticosteroids could have a considerable public health effect. We have therefore investigated the association between the use of inhaled corticosteroids and hip fracture in a case–control study using data from the United Kingdom General Practice Research Database (GPRD) (7).
The GPRD is a longitudinal primary care database (7) that is derived from computerized recordings of routine care and that was first established in 1987. Contributing general practices are required to record a minimum of 95% of prescribing and morbidity events, and data quality is subjected to regular monitoring.
Our cases included all patients contributing to the GPRD with a recorded diagnosis of hip fracture. Where possible, two control subjects were matched individually to each case by age, sex, general practice, and start date for collection of prescribing data. Each case was assigned a date of diagnosis defined as the date of the first hip fracture, and matching control subjects were assigned an identical “pseudo date of diagnosis.”
We extracted information on all recorded prescriptions for inhaled corticosteroids during the exposure period and calculated the mean daily dose prescribed for each person by dividing the total dose prescribed (μg) by the exposure period; all inhaled corticosteroids were assumed to be equipotent. The mean daily dose was then recoded into categories to reflect common clinical use as follows: 100 μg or less, 101–200 μg, 201–400 μg, 401–800 μg, 801–1,600 μg, and more than 1,601 μg. We then extracted data on exposures to other forms of corticosteroids and a number of potential confounders, including smoking habit, body mass index, and recorded falls. We also performed a systematic data extraction for all other drug exposures (e.g., bisphosphonate exposure), grouped by subsection of the British National Formulary (8), and all diagnoses (e.g., ischemic heart disease), grouped by major disease headings based on the International Classification of Diseases.
The relationship between ever having a prescription for an inhaled corticosteroid and hip fracture was quantified by conditional logistic regression (STATA, version 7). The impact of potential confounders was assessed using a series of bivariate models, retaining variables that led to a change in the odds ratio (OR) for inhaled corticosteroids by 10% or more. For confounder variables, missing data were fitted as a separated category to ensure that nested models contained the same number of individuals. Exposure to other corticosteroid drugs was modeled as the mean number of prescriptions per year. In the multivariate model, we looked for evidence of interaction between inhaled corticosteroids and age, sex, and the other covariates by using multiplicative interaction terms. To define any relationship between inhaled corticosteroid dose and hip fracture, we estimated the ORs for each mean daily dose category by modeling dose category as a factored variable. We used a likelihood ratio test to test for trend, fitting dose category as a continuous variable and including an additional binary variable for “ever or never exposed to inhaled corticosteroids” in the model to allow the risk in the unexposed group to differ from the general relationship (9). We then repeated all analyses removing any subjects with one or more prescription for an oral corticosteroid.
Our dataset included 16,341 cases of hip fracture plus two matched control subjects for 13,548 cases and one matched control for 2,793 cases. The first hip fracture was dated August 1, 1987, and the last was dated November 22, 1999. The mean age of the cases was 79 years, and 12,854 (79%) were female (Table 1)
Cases (n = 16,341) | Control Subjects (n = 29,889) | |
|---|---|---|
| Mean age (SD) in years | 79.0 (12.1) | 78.9 (12.0) |
| Number females, % | 12,854 (79%) | 23,476 (79%) |
| Recorded falls | 4,681 (29%) | 2,671 (9%) |
| Smoking status | ||
| Current smoker | 1,304 (8%) | 1,587 (5%) |
| Ex-smoker | 469 (3%) | 834 (3%) |
| Non-smoker | 4,784 (29%) | 8,371 (28%) |
| Missing data | 9,784 (60%) | 19,097 (64%) |
| Body mass index, kgm−2 | ||
| 18.5 (Underweight) | 395 (2%) | 232 (1%) |
| 18.6 to 25 | 2,645 (16%) | 3,655 (12%) |
| 25.1 to 30 (Preobese) | 1,143 (7%) | 2,839 (10%) |
| ⩾ 30.1 (Obese) | 322 (2%) | 1,136 (4%) |
| Missing | 11,836 (72%) | 22,027 (72%) |
| Exposure to | ||
| Inhaled corticosteroids | 1,227 (8%) | 1,806 (6%) |
| Oral corticosteroids | 1,980 (12%) | 2,379 (8%) |
| Topical corticosteroids | 4,711 (29%) | 7,866 (26%) |
| Nasal corticosteroids | 677 (4%) | 1,259 (4%) |
| Injected corticosteroids | 580 (4%) | 967 (3%) |
| Other corticosteroids | 1,993 (12%) | 3,441 (12%) |
| Diagnosis of asthma | 553 (3%) | 958 (3%) |
| Diagnosis of COPD | 559 (3%) | 564 (2%) |
| Diagnosis of asthma and COPD | 325 (2%) | 377 (1%) |
The proportion of cases with a recorded diagnosis of asthma, COPD, or both asthma and COPD was 3, 3, and 2%, respectively, compared with 3, 2, and 1% for control subjects. There were a total of 46,765 prescriptions for inhaled corticosteroids, 39,374 (84%) for beclomethasone dipropionate, 6,521 (14%) for budesonide, and 870 (2%) for fluticasone propionate. The median daily dose of inhaled corticosteroid prescribed was 249 μg (interquartile range, 78 to 506 μg), and the proportion of hip fracture cases and control subjects that had been prescribed an inhaled corticosteroid was 8 and 6%, respectively. Patients for whom the recorded diagnoses included both asthma and COPD had a higher median daily dose of inhaled corticosteroid (360 μg) than patients with a recorded diagnosis of asthma alone (242 μg) or COPD alone (220 μg). Among the 3,033 subjects prescribed an inhaled corticosteroid, 90% were prescribed less than 800 μg a day, and only 1.6% were prescribed more than 1,600 μg a day. A total of 1,577 (52%) of the inhaled corticosteroid users had also received at least one prescription for an oral corticosteroid with a median annual exposure of 0.9 courses (interquartile range, 0.4 to 2.5). Further descriptive details of the participants are given in Table 1.
An increased risk of hip fracture was associated with a number of the potential confounders studied, including prescriptions for oral corticosteroids (OR per course per year 1.07; 95% confidence interval [CI], 1.05 to 1.08) and topical corticosteroids (OR 1.02; 95% CI, 1.00 to 1.03), a history of one or more falls (OR 4.67; 95% CI, 4.39 to 4.95), being a current smoker (OR 1.49; 95% CI, 1.37 to 1.62), being underweight (body mass index less than 18.5; OR 2.40; 95% CI, 2.02 to 2.86), cerebrovascular disease (OR 1.89; 95% CI, 1.76 to 2.03), nonpsychotic psychiatric illness (OR 1.94; 95% CI, 1.85 to 2.04), nonmalignant blood disorders (OR 1.85; 95% CI, 1.73 to 1.97) and prescriptions for laxatives (OR 1.97; 95% CI, 1.89 to 2.07), hypnotics (OR 1.68; 95% CI, 1.60 to 1.77), antipsychotics (OR 2.79; 95% CI, 2.60 to 2.99), tricyclic antidepressants (OR 1.78; 95% CI, 1.69 to 1.89), and opioid analgesics (OR 1.94; 95% CI, 1.81 to 2.07). In contrast, hip fracture was reduced in subjects who were mildly overweight (body mass index, 25 to 30; OR 0.55; 95% CI, 0.51 to 0.60), and it was not associated with the use of nasal or injected corticosteroids.
A prescription for an inhaled corticosteroid was associated with a small increase in the risk of hip fracture in the univariate analysis (OR 1.26; 95% CI, 1.17 to 1.36). Among the potential confounders, the only exposure that changed this association was oral corticosteroid use, which reduced the OR slightly to 1.19 (95% CI, 1.10 to 1.28). When the analysis was restricted to cases and control subjects with no exposure to oral corticosteroids, the OR was reduced further to 1.08 (95% CI, 0.96 to 1.21). Limiting the dataset to include only subjects with complete data for both smoking habit and body mass index and with no exposure to oral corticosteroids gave similar results (OR 1.26; 95% CI, 0.93 to 1.70). None of the multiplicative interaction terms was statistically significant, and in particular, the impact of inhaled corticosteroids was not modified by specific airflow obstruction diagnosis (p = 0.67). The relationship between inhaled corticosteroid use and hip fracture was dose-related (Table 2)
Univariate Analysis | Multivariate Analysis† | Restricted Dataset‡ | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Inhaled Corticosteroids* | Cases
(n = 16,341) | Control Subjects
(n = 29,889) | Odds Ratio | 95% CI | Odds Ratio | 95% CI | Odds Ratio | 95% CI | |||
| 0 | 15,114 (92.5%) | 28,083 (94.0%) | 1 | 1 | 1 | ||||||
| ⩽ 100 μg | 335 (2.1%) | 555 (1.9%) | 1.09 | 0.95 to 1.26 | 1.06 | 0.93 to 1.22 | 0.96 | 0.79 to 1.16 | |||
| 101 to 200 μg | 164 (1.0%) | 267 (0.9%) | 1.14 | 0.94 to 1.39 | 1.09 | 0.89 to 1.32 | 0.92 | 0.69 to 1.23 | |||
| 201 to 400 μg | 289 (1.8%) | 411 (1.4%) | 1.32 | 1.13 to 1.54 | 1.23 | 1.06 to 1.44 | 1.09 | 0.85 to 1.39 | |||
| 401 to 800 μg | 286 (1.8%) | 394 (1.3%) | 1.37 | 1.17 to 1.60 | 1.27 | 1.08 to 1.48 | 1.35 | 1.05 to 1.73 | |||
| 801 to 1,600 μg | 128 (0.8%) | 156 (0.5%) | 1.54 | 1.22 to 1.96 | 1.39 | 1.09 to 1.76 | 1.22 | 0.82 to 1.83 | |||
| ⩾ 1,601 μg | 25 (0.2%) | 23 (0.1%) | 2.18 | 1.23 to 3.84
ptrend = 0.0006 | 1.87 | 1.06 to 3.33
ptrend = 0.007 | 2.20 | 0.85 to 5.72
ptrend=0.013 | |||
Figure 1. Dose–response relationship between mean daily dose of inhaled corticosteroids and hip fracture (adjusted for exposure to oral corticosteroids).
[More] [Minimize]The results of this study of over 16,000 hip fractures suggest that among older patients the recent use of an inhaled corticosteroid is associated with a small dose-dependent increase in the risk of hip fracture.
The accuracy of hip fracture diagnoses within the GPRD is known to be high (10), and by individually matching our control subjects to cases, we were able to minimize confounding by age and sex and local clinical and community factors. Our finding of an increased risk of hip fracture with the use of antidepressant and antipsychotic drugs has been reported before (11, 12), as has the association with current smoking, previous falls, strokes, and being underweight (6). None of these factors confounded the association between inhaled corticosteroids and hip fracture, however. As the GPRD does not contain information on lung function or physical activity, we could not adjust our analyses directly for these variables, and thus, we cannot exclude the possibility that these factors may have influenced our results. We did adjust our analyses for the mean number of annual prescriptions for oral corticosteroids, however, and this should be a reasonable marker of disease severity.
We defined mean daily dose of inhaled corticosteroids from prescriptions, which are obtained intermittently, and thus, some misclassification of dose may occur when the period of prescribing data is short. Any such misclassification is unlikely to be systematically associated with subsequent hip fracture, however; thus, it will tend to bias our results toward unity. Some random misclassification of oral corticosteroid dose may also be present for the same reason, and this would limit our ability to adjust fully for this important confounder. To try to address this problem, we performed a post hoc analysis on the data from cases and control subjects with at least 1, 2, and 3 years of exposure data. In each case, the results were similar to our initial analyses.
The limited duration of prescribing data also meant that we could not exclude the possibility that the increase in fracture among patients recently prescribed an inhaled corticosteroid was due to a greater annual exposure to oral corticosteroids before data collection started, that is, that recent use of inhaled corticosteroid is a proxy marker of more marked earlier exposure to oral corticosteroids. Such a bias would be expected to affect patients with asthma more than those with COPD, as asthma is usually diagnosed much earlier in life, but we did not find this. Furthermore, it seems unlikely that many of these patients would have been exposed to higher doses of oral corticosteroids in the past, as our dataset is derived from the general population, in which the majority of patients have mild disease and are prescribed low doses of inhaled corticosteroids and infrequent courses of oral corticosteroids. We believe therefore that the small dose-related increase in fracture risk associated with the use of inhaled corticosteroids is likely to be due in part to a direct effect of inhaled corticosteroids on bone metabolism.
Few previous studies have had sufficient statistical power to determine the association between inhaled corticosteroids and fracture, and there have been no large case–control studies of inhaled corticosteroids and hip fracture. In an earlier study of the GPRD, van Staa and colleagues used a cohort approach and found evidence of an increase in nonvertebral fractures as a whole associated with the use of high doses of inhaled corticosteroids (13). In this study, however, the median duration of prescribing data for patients using inhaled corticosteroids was less than 1 year, and there were only 67 patients with hip fracture. Some of the early studies looking at bone mineral density showed a reduction in patients taking an inhaled corticosteroid, (14–16), but others did not (17–20). Most were too small to address this question. More recently, three larger observational studies in patients with asthma have found a dose-related decrease in bone mineral density in patients taking an inhaled corticosteroid (2, 4, 5). Two large clinical trials over 3 years in patients with COPD have given conflicting results, however, possibly because of differences in the type or dose of the inhaled corticosteroid given. The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP) trial (21) found no evidence that 800 μg a day of budesonide led to an accelerated decline in bone mineral density, whereas the larger Lung Health Study (3) found that treatment with 1,200 μg a day of triamcinolone acetonide caused a reduction in bone mineral density at the lower lumbar spine and femur. The magnitude of the effects seen in the three observational studies in asthma and in the Lung Health Study would be expected to lead to a small increase in fracture risk if the magnitude of the short-term effects on bone mineral density hold true when treatment is continued over longer periods. Our findings are in keeping with such an effect.
Thus, our data suggest that in older patients there is a small dose-related association between the recent use of an inhaled corticosteroid and the risk of hip fracture and that this association is only partly explained by exposure to oral corticosteroids. This figure may be higher for future generations who will have been exposed to inhaled corticosteroids from an earlier age, although some of the increase in risk may be offset if courses of oral corticosteroid are avoided. The risk of adverse effects, as always, has to be weighed against the substantial benefits of inhaled corticosteroids (22). The clinical implication is that patients with asthma and COPD should not take higher doses of inhaled corticosteroids than they need to control their airflow obstruction.
The authors thank Alan Dean, Hassy Devalia, Sam Rowlands, and Alison Bourke from the Epidemiology and Pharmacology Information Core for their expert advice in using the GPRD. The authors also thank Sarah Lewis (University of Nottingham) for statistical advice and John Britton for reviewing the manuscript.
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