QJM Advance Access originally published online on July 3, 2007
QJM 2007 100(8):509-517; doi:10.1093/qjmed/hcm056
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Inhaled corticosteroids and the risk of fracture in chronic obstructive pulmonary disease
From the University of Nottingham, Division of Epidemiology and Public Health, Nottingham City Hospital, Nottingham, UK
Address correspondence to Dr R.B. Hubbard, Respiratory Medicine, Clinical Sciences Building, Nottingham City Hospital, Nottingham NG5 1PB. email: richard.hubbard{at}nottingham.ac.uk
Received 17 January 2007 and in revised form 17 April 2007
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Summary |
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Background: Inhaled corticosteroids are used increasingly to treat people with COPD, but the extent to which these drugs increase the risk of fracture is unclear.
Aim: To quantify the dose–response relationship between fracture risk and inhaled corticosteroids in people with COPD, independent of the effects of percent predicted FEV1 and oral corticosteroids.
Design: Nested case-control study.
Methods: Cases and controls were COPD patients aged 
40 years or more at diagnosis, with a FEV1 measurement recorded in The Health Improvement Network database, up to 5 July 2005. Cases (people with a fracture event after 1 January 1998, n = 1235) were assigned up to four controls (n = 4598), matched by gender and general practice.
Results: Mean FEV1 was 57.5% in cases, and 58.5% in controls. Inhaled corticosteroids had been prescribed in 69% of cases (median dose 269 mcg/day) and 66% (226 mcg/day) of controls. Oral corticosteroids had been prescribed in 60% of cases (median annual prescription rate 0.6) and 56% of controls (also 0.6 per year). Risk of fracture increased with increasing mean daily doses of inhaled corticosteroid (p for trend 0.007), and was most marked in those whose daily dose was 1600 mcg (OR 1.80, 95% CI 1.04–3.11). This effect was virtually unchanged by adjustment for mean percent predicted FEV1 and annual prescription rate for oral corticosteroids (OR for highest dose exposure 1.74, 95% CI 1.00–3.01).
Discussion: Our findings add to the evidence that the use of inhaled corticosteroids is associated with a small increase in fracture risk, particularly at higher doses.
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Introduction |
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The long-term use of oral corticosteroids is associated with an increased risk of fracture, and there is good evidence that this increase starts with daily doses as low as 2.5 mg.1 Although people with connective tissue diseases may use oral corticosteroids for long periods of time, most people with COPD do not. However, people with COPD are increasingly exposed to the long-term use of inhaled corticosteroids. In general, these drugs are far safer than their oral counterparts, but they are absorbed into the circulation, and do exert systemic effects.2 For example, inhaled corticosteroids given at clinically relevant doses suppress the hypothalamic-pituitary axis to the same degree as several milligrams of oral corticosteroid, raising the possibility that these drugs may increase the risk of fracture after some years of use.3,4 Further evidence of the systemic adverse effects of inhaled corticosteroids on connective tissues comes from clinical trial evidence that these drugs cause bruising and accelerated bone loss in older people with COPD, and bone growth retardation in children.5–8
A number of studies have investigated the association between the use of inhaled corticosteroids and fracture; while some studies have reported a positive association, others have not.9–15 The main reasons for this inconsistency appear to be the different approaches used to try to control for oral corticosteroid exposure and the severity of airflow obstruction. To confidently exclude confounding by exposure to oral corticosteroids, sufficient data duration before the fracture event is needed to estimate the extent of oral corticosteroid exposure accurately, and to date most studies have only had a few years of prescribing data available.9–11,13 Since the severity of airflow obstruction may be a risk factor for fracture in itself, some studies have tried to allow for this by using prescriptions for other bronchodilator drugs as a proxy marker of disease severity, and this has produced varying results.10,11,13,16 Spirometry provides a more direct measure of severity of airflow obstruction, and following the introduction of national guidelines and the new general practitioner contract in the UK, spirometry data are now routinely available in computerized general practice databases.
Our aim was to quantify the dose–response relationship between mean daily dose of inhaled corticosteroids and fracture risk, allowing for the possible confounding effects of oral corticosteroid exposure and the severity of airflow obstruction as measured by spirometry. We used a large computerized general practice database to perform a nested case-control study, in which we restricted our study participants to people with a diagnosis of COPD and a reading for FEV1.
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Methods |
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The Health Improvement Network (THIN) contains data recorded by UK general practitioners as part of routine clinical care.17 This study used data recorded up to 5 July 2005.
Initially, we identified all people with COPD aged 40 years or more at diagnosis; our cases and controls were all drawn from this group. Our cases were people with a fracture, and the date of the first fracture was termed the index date. Since we specifically wanted to control for severity of airflow obstruction, we limited our study to fracture events after 1 January 1998, because recording of FEV1 in general practice was uncommon before this date. We selected up to four controls per case, matched by gender and general practice. All controls were contributing data to THIN at the time of their matched case's index date, and were assigned the same index date as their matched case.
For our main exposure, we extracted data on all prescriptions for inhaled corticosteroids, and calculated the dose of drug associated with each prescription, taking account of the preparation and quantity of drug prescribed. We then calculated the total dose of drug prescribed prior to the index date, and divided this by the duration of data available before index date to calculate a mean daily dose of inhaled corticosteroid for each person. We grouped these results by mean daily dose as follows: <100 mcg; 101–200 mcg, 201–400 mcg; 401–800 mcg; 801–1600 mcg; >1600 mcg. Because there were only limited data available on the dose equivalence of different inhaled corticosteroids and different delivery devices with regard to adverse effects, we adopted the conservative approach of assuming that all types of inhaled corticosteroid and all devices were equal. We then used a similar method to calculate the mean annual prescription rate for oral corticosteroids. To provide information on other potential drug confounders, we identified prescriptions for thiazide diuretics, anti-arrhythmics, anti-psychotics, anti-depressants, anxiolytics/hypnotics, hormone replacement therapy, drugs used to treat Parkinson's disease, non-steroidal anti-inflammatory drugs (NSAIDs), vitamin D, calcium supplements and bisphosphonates. In addition, we identified the following co-morbid conditions: previous fracture before 1 January 1998; ischaemic heart disease; cerebrovascular disease; epilepsy; hyperthyroidism; rheumatoid arthritis; dementia; cancer; and osteoporosis. We extracted data on smoking habit and number of cigarettes smoked per day. To estimate the severity of airflow obstruction, we calculated the percent predicted FEV1 using the prediction equations derived by Falaschetti et al.18 We used the recorded value of FEV1 closest in time to the index date, but also computed the average percent predicted value for FEV1 from all values recorded within 3 years of the index date. We explored the relationship between severity of air flow obstruction, and the use of both inhaled and oral corticosteroids in the control group by dividing the percent predicted FEV1 values into quintiles. In order to assess the validity of our FEV1 data, we quantified the relationship between FEV1 and both survival and hospital admission with COPD after the index date in the control population. For our survival analysis, we used COX regression; for our COPD admission analysis, we used logistic regression. In both analyses, we adjusted for sex and age.
We used conditional logistic regression to quantify the association between inhaled corticosteroid exposure and fracture risk, controlling for age in 10-year bands. Initially, we modelled inhaled corticosteroid exposure as a binary ever/never variable. We then added each potential confounder to this model in turn, retaining variables that changed the odds ratio for inhaled corticosteroid exposure by more than 10% in a multivariate model. Percent predicted FEV1 values and mean annual rate of oral corticosteroid prescriptions were modelled as continuous variables, but we also investigated the effects of modelling these variables as quintiles, and the effect of using a binary variable defined as ever/never exposed to oral corticosteroids. We then repeated the analyses using our variable for mean daily dose of inhaled corticosteroids.
We used Stata (v. 9.0) for all statistical analyses, and likelihood ratio tests for all hypothesis tests. The study protocol was approved by the Nottingham Ethics Committee.
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Results |
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We identified a total of 61^102 people with a diagnosis of COPD in THIN. Of these, 1886 had a recorded fracture after 1 January 1998, including 243 (13%) hip fractures and 172 (9%) wrist fractures. We were able to match 7104 controls to our cases. We had sufficient data to calculate a percent predicted FEV1 value for 1235 (71%) cases and 4598 (71%) matched controls, and these are the people on which all subsequent analyses are based. Table 1 shows the distribution of cases and controls with and without information on predicted FEV1. Cases and controls with FEV1 data were similar with respect to age and sex, but cases and controls with no data on FEV1 were less likely to be recorded as current smokers, or to be receiving prescriptions for oral or inhaled corticosteroids.
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The mean age of our cases at fracture diagnosis was 69 years (SD 10), and 741 (60%) were females. The mean age of controls at index date was 68 years (SD 10), and 2683 (58%) were females. The median duration of prescribing data prior to index date was 10.9 years for cases and 10.6 years for controls. A total of 852 (69%) cases had been prescribed an inhaled corticosteroid, at a median daily dose of 269 µg/day (IQR 79–608). The equivalent figures for the controls were 3024 (66%) and 226 (IQR 69–539). Beclometasone dipropionate was the most commonly prescribed inhaled corticosteroid with 66% of the prescriptions followed by fluticasone propionate (18%) and then budesonide (16%). The limited number of people with exposure to fluticasone propionate and budesonide meant that we had insufficient statistical power to assess the effects of individual inhaled corticosteroids. A total of 736 (60%) cases had received a prescription for oral corticosteroids, with a median annual prescription rate of 0.62 (IQR 0.24–1.80). The equivalent figures for controls were 2569 (56%) and 0.62 (IQR 0.24–1.70). The mean percent predicted FEV1 values closest to the index date were 57.5% for cases, and 58.5% for controls. These values were similar when the mean within 3 years of the index date was considered (55.2% and 56.6%, respectively). During a mean follow-up period after index date of 2.2 years, a total of 321 controls died and 590 were admitted to hospital. Among the control population, the risk of both of these outcomes was strongly related to FEV1 (Table 2). More than 95% of cases and controls had a code suggesting current smoking within 3 years of the index date and of these, approximately 25% smoked >20 cigarettes per day.
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The distribution of other drug exposures and co-morbid illnesses by case status is given in Table 3. Cases were more likely than controls to have received a prescription for anti-depressants, anxiolytics/hypnotics, NSAIDs, vitamin D, calcium supplements and bisphosphonates, and also more likely to have a diagnoses of cerebrovascular disease and osteoporosis.
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In the control group, the frequency of use, and dose prescribed, of both inhaled corticosteroids and oral corticosteroids increased progressively with increasing severity of airflow obstruction (Table 4). In our full case–control set, when we modelled oral corticosteroid exposure as a binary ever/never variable, we found some evidence that exposure was associated with an increased risk of fracture (OR 1.21, 95%CI 1.05–1.39, p = 0.007). This effect was attenuated, however, after adjusting for mean daily dose of inhaled corticosteroid (OR 1.16, 95%CI 0.99–1.36, p = 0.07). When modelled in quintiles, again people prescribed more courses of oral corticosteroids had a higher risk of fracture (p for trend=0.03), but it was no longer significant after adjusting for exposure to inhaled corticosteroids (p for trend=0.2). The risk of fracture was highest in people with the lowest level of percent predicted FEV1, but overall there was no statistical evidence of a linear trend between fracture risk and FEV1, either before or after adjustment for exposure to inhaled corticosteroid (Table 5). The risk of fracture increased with age (OR per additional 10 years 1.19, 95%CI 1.11–1.27, p for trend = 0.008) and the following potential confounder variables were statistically associated with fracture: a diagnosis of cerebrovascular disease, osteoporosis or cancer; recorded prescriptions for anti-psychotics, antidepressants, anxiolytics/hypnotics, NSAIDS, vitamin D, calcium or bisphosphonates.
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The risk of fracture was higher in relation to ever/never exposure to inhaled corticosteroids, but not significantly so (OR 1.13; 95%CI 0.98–1.30; p = 0.09). This odds ratio was not altered by adjusting our model for any of the potential confounders identified above (cerebrovascular disease, osteoporosis or cancer; recorded prescriptions for anti-psychotics, antidepressants, anxiolytics/hypnotics, NSAIDS, vitamin D, calcium or bisphosphonates). In addition, our results were not altered by adjusting the model for exposure to oral corticosteroids and percent predicted FEV1. In our dose–response analysis, the risk of fracture increased with increasing mean daily dose of inhaled corticosteroids (pt 0.007, Table 6), particularly for daily doses >1600 mcg, and this pattern was also unchanged after allowing for the impact of all of our potential confounder variables. Finally, there was no evidence of effect modification according to use of oral corticosteroids (p = 0.34) or to the level of predicted FEV1 (p = 0.16).
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Discussion |
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In this large case–control study of people with COPD with more than 10 years of prescribing data, use of inhaled corticosteroids was associated with a small dose-related increase in fracture risk, independent of the severity of airflow obstruction and exposure to oral corticosteroids. These data add to the growing body of evidence that inhaled corticosteroids can have an adverse effect on bone.5,7,8
Strengths and weaknesses
The main strengths of our study are the large sample size, the restriction of the study population to individuals with a diagnosis of COPD, the long duration of prescribing data, and the availability of spirometry data. Its main potential weaknesses are the lack of lifelong prescribing data, and concerns about the accuracy of spirometry measurements. Although we did not have lifelong prescribing information, we did have an average of >10 years of data, and so unless the rates of oral corticosteroids prescription were radically different before this time, we should be able to control adequately for long-term oral corticosteroid exposure. In fact, exposure to oral corticosteroids was low in our study, with just under half of people having no exposure at all and a prescription rate amongst the exposed of only one course of oral corticosteroids every other year. Despite the very low level of exposure to oral corticosteroids, there was still an increase in fracture risk with exposure to these drugs that bordered on statistical significance (p = 0.07). However, when we adjusted our models for oral corticosteroid exposure, this did not change the association between mean daily dose of inhaled corticosteroid and fracture risk. It thus seems unlikely that confounding by oral corticosteroid use explains the observed effect of mean daily dose of inhaled corticosteroid on fracture risk. We also looked at a wide variety of additional potential confounders and, as expected, were able to demonstrate an increased risk of fracture in association with the use of antidepressants and hypnotics, and with a diagnosis of osteoporosis. However, none of these exposures confounded the relationship between exposure to inhaled corticosteroid and fracture risk, and so none of these variables were included in our final models.
Primary-care doctors in the UK have been encouraged to record FEV1 measurements for patients with COPD since the introduction of the British Thoracic Society guidelines, and are now paid specifically to record these data.19 To date there have been few studies of the accuracy of such measurements, but in one study of 61 general practices, values reported from community tests were marginally higher than those reported from the hospital setting, although both had good reproducibility.20 In one smaller study, recordings in general practice were on average 0.07 l lower that the equivalent hospital readings.21 In our study, 70% of those with a diagnosis of COPD had a recorded FEV1 value, and the lower an individual's FEV1, the more likely they were to be receiving treatment for COPD. The mean percent predicted value for FEV1 was about 60%, and <20% of study patients had severe COPD on FEV1 criteria. These figures are very similar to those from general practice data from Holland.22 Further evidence to support the validity of our FEV1 measurements comes from the observation that this variable strongly predicted both mortality and hospital admission in controls, particularly those in the lowest quintile of percent predicted FEV1. The relationship between FEV1 and fracture followed a similar, though less marked, pattern in our dataset, with the risk of fracture being highest in people with the lowest level of FEV1, but overall no statistically significant trend was observed across all values of percent predicted FEV1. FEV1 did not confound the association between inhaled corticosteroids and fracture, partly because there was no dose–response relationship between FEV1 and fracture, but also because the dose–response relationship between FEV1 and daily dose of inhaled corticosteroids, although statistically significant at the 5% level, was not marked. Furthermore, our results remained unchanged when the average value of FEV1 from all measurements performed within 3 years of the index date was used, rather than the closest recorded value of FEV1 to the index date.
Consistency with other studies
There are good data from clinical trials that inhaled corticosteroids act systemically and suppress endogenous steroid production to the same extent as low doses of oral corticosteroids.3,4 Evidence from clinical trials also shows that inhaled corticosteroids may act on bone and slow growth in children.7 The Lung Health Study reported that bone mineral density was decreased in COPD patients treated with inhaled triamcinolone, although these findings were not supported by Euroscop, a similar trial of Budesonide.5,6 Several cohort studies have reported that the use of inhaled corticosteroids by patients with asthma is associated with lower bone mineral density, and a recently published cohort study of 2000 men aged >65 years in Hong Kong identified the diagnosis of COPD and the use of inhaled corticosteroids as independent risk factors for reduced bone mineral density.23–25
Most epidemiological studies of inhaled corticosteroids and fracture risk to date have used computerized medical datasets. For example, in a recent large case–control study using the UK General Practice Research Database, De Vries et al. found an association between the use of inhaled corticosteroids and fracture, and a similar association between fracture risk and the use of bronchodilators.13 When both exposure variables were modelled simultaneously, both effects were reduced, and the authors concluded that much of the association between fracture risk and inhaled corticosteroids was explained by the severity of the underlying airflow obstruction. However, given that 76% of cases and 72% of controls were exposed to both types of drugs, and that the effect of bronchodilators was also markedly reduced in their analyses, exposure to bronchodilators may have acted as a proxy for exposure to inhaled corticosteroids, rather than specifically for severity of airflow obstruction. An alternative interpretation of these data is that bronchodilators rather than inhaled corticosteroids increase the risk of fracture, but given the evidence from clinical trials that inhaled corticosteroids cause bruising and suppression of the hypothalamic-pituitary axis, this explanation seems less likely to us. In a similar smaller case-control study, Suissa et al. also found an association between the use of inhaled corticosteroids and fracture risk that was again attenuated by adjusting the models for bronchodilator use—the independent effects of bronchodilators are not reported in this paper.11 Other similar studies did not adjust for bronchodilator use, and most (but not all) of these concluded that there was an association between use of inhaled corticosteroids and fracture risk.9,12,14,15,26 Our study directly examines, and excludes, the influence of severity of airflow obstruction using FEV1 readings, and thus (we believe) provides a more accurate assessment of the effect of inhaled corticosteroids on fracture risk in people with COPD.
Previous studies of inhaled corticosteroids and fracture risk have classified dose in a number of different ways, making comparisons difficult to interpret. In studies reporting an association between inhaled corticosteroid use and fracture risk, most of the excess risk comes from the highest dose category.9–13,26 Equally, in this study, most of the excess risk came from people using 1600 mcg/day. As has been done for oral corticosteroids, further work is required to determine whether a safe threshold exists for these drugs.
Clinical relevance
Inhaled corticosteroids are of proven benefit for the treatment of asthma and are commonly used in people of all ages with this condition. In contrast, the beneficial effects of inhaled corticosteroid in patients with COPD are less clear, but they may reduce the frequency of acute COPD exacerbations.27 Our study provides further evidence of a small increase in fracture risk associated with the use of inhaled corticosteroids in people with COPD, particularly at doses exceeding 1600 mcg/day. This effect was not explained by the severity of airflow obstruction or the use of oral corticosteroids. Further research is required in patients with COPD to establish the lowest effective dose of inhaled corticosteroids to maximize the benefits of these drugs while minimizing their adverse effects.
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Acknowledgments |
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We would like to thank Hassy Dattani from EPIC for her support in using THIN data. RH had the original idea for the study, CS did the initial data extraction and manipulation, MP-R did all of the statistical analysis, and was responsible for drafting the paper. All authors had full access to all of the data in the study, and collectively take responsibility for the integrity of the data and the accuracy of the data analysis. All authors were involved in editing the paper prior to submission, and have seen and approved the final version of the paper. There are no conflicts of interest for any of the authors.
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6. Pauwels R, Lofdahl C-G, Laitinen LA, Schouten JP, Postma DS, Pride N, Ohlsson SVl. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue to smoke. N Engl J Med (1999) 340:1948–53.
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