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Original Research: COPD |

Use of Inhaled Corticosteroids and the Risk of Fracture* FREE TO VIEW

Richard Hubbard, DM; Anne Tattersfield, MD; Chris Smith, MA; Joe West, PhD; Liam Smeeth, PhD; Astrid Fletcher, PhD
Author and Funding Information

*From the Division of Epidemiology and Public Health (Drs. Hubbard, West, and Mr. Smith) and Division of Respiratory Medicine (Dr. Tattersfield), University of Nottingham, Nottingham; and Department of Epidemiology and Population Health (Drs. Smeeth and Fletcher), London School of Hygiene and Tropical Medicine, London, UK.

Correspondence to: Richard Hubbard, DM, Respiratory Medicine, Clinical Sciences Building, Nottingham City Hospital, NG5 1PB, Nottingham, UK; e-mail: Richard.Hubbard@nottingham.ac.uk



Chest. 2006;130(4):1082-1088. doi:10.1378/chest.130.4.1082
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Published online

Background: Previous studies have found an association between the use of inhaled corticosteroids and fracture, but the extent to which this association is due to inhaled corticosteroids or to related factors, such as the severity of airflow obstruction, is disputed. We report a new approach in which we combine data on people with airflow obstruction from a large Medical Research Council study of the assessment and management of older people in the community with longitudinal data from their computerized general practice records.

Methods: Our cohort includes 1,671 study participants with a diagnosis of asthma or COPD (mean age, 80.6 years). We determined the dose-response relationship between inhaled corticosteroid exposure and time to first fracture using Cox regression, allowing for a wide range of potential confounding factors.

Results: During a mean follow-up period of 9.4 years, 982 patients (59%) received a prescription for an inhaled corticosteroid and 187 patients had a fracture. After adjusting for the effects of age and gender, we found a dose-related increase in fracture risk with exposure to inhaled corticosteroids (rate ratio for mean daily dose > 601 μg, 2.53; 95% confidence interval [CI], 1.65 to 3.89; overall trend p < 0.0001). The results were similar after adjusting for oral corticosteroid exposure, airflow obstruction diagnosis, historical fracture, and bronchodilator use (rate ratio, 4.21; 95% CI, 2.19 to 8.13), and also in the subset of people with no exposure to oral corticosteroids (rate ratio, 4.54; 95% CI, 1.23 to 16.74).

Conclusions: Our findings provide further evidence that inhaled corticosteroid use is an independent risk factor for fracture.

Figures in this Article

Inhaled corticosteroids are used widely,1but they may have systemic adverse effects such as suppression of the hypothalamic-pituitary-adrenal axis and bruising.25 From the public health perspective, however, the greatest concern is the possible increased risk of fracture.6 The rate of decline in bone mineral density over 3 years was measured in subgroups from two large trials23 of inhaled corticosteroids in patients with COPD with conflicting results. The rate of decline was not increased in patients receiving budesonide, 800 μg/d, in the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease3; but was increased, at the lumbar spine and femoral neck, in patients receiving triamcinolone acetonide, 1,200 μg/d, in the larger Lung Health Study.2 Three large observational studies79 have reported an inverse relationship between dose of inhaled corticosteroid and bone mineral density.

Four studies1013 have investigated the relationship between inhaled corticosteroid exposure and fracture using health-care data sets; and although all have shown an association between the two, there is disagreement as to whether inhaled corticosteroids are contributing directly to this association, or whether it is all due to confounding factors. The studies have been limited by short duration of follow-up, in each case < 4 years, and by lack of information on a number of potentially important confounder variables such as physical activity, activities of daily living, and socioeconomic status. To overcome these problems, we have combined data collected during the Medical Research Council (MRC) study of assessment and management of older people in the community with computerized general practice data, with > 9 years of follow-up. This has enabled us to quantify the dose-response relationship between inhaled corticosteroid use and fracture.

The Data Set

The MRC trial1415 of the assessment and management of older people in the community is a large, community-based, cluster, randomized trial comparing different methods of multidimensional screening in people aged ≥ 75 years. Trial participants were recruited through general practices between January 1995 and February 1999. The overall response rate for the trial was 78%.14 Participants completed a questionnaire providing details of domestic circumstances, activities of daily living, medical symptoms, smoking habit, and alcohol consumption. The MRC trial, including review of primary care records, was approved by the local research ethics committee for each general practice, and written consent was obtained to review primary and secondary care medical records.

Collection of computerized general practice records was done in collaboration with general practice software (EMIS; Egton Medical Information Systems; Leeds, UK), and our methods were designed to preserve patient anonymity. The MRC trial includes 106 practices, but for this study we only contacted the 49 practices known to use EMIS. Thirty-nine practices agreed to take part in the study, and we were able to collect complete computerized general practice records from 31 practices. We extracted information on all prescriptions for inhaled, oral, and injected corticosteroids, all fracture events, and comorbid diagnoses from these computerized records.

Analysis

The date of MRC trial entry was used as our start date (Fig 1 ), and time to the first fracture was our outcome. The end date was the final date of computerized data collection (October 1, 2002) or date of death or first fracture. The incident person-time for each participant was calculated as the difference between the start and end date, and all fractures during this time are referred to as incident fractures. For this study, we limited the data set to people with a diagnosis of airflow obstruction (asthma, COPD, or both) to establish a data set in which everyone would potentially be eligible to receive an inhaled corticosteroid.

We identified all corticosteroid prescriptions during the incident person-time and calculated the total dose for each exposure, considering all inhaled corticosteroids to be equipotent. We hypothesized that the impact of inhaled corticosteroids on fracture risk would relate most closely to the cumulative lifetime dose of inhaled corticosteroids. We did not have lifetime prescription records, however, and so we modeled the impact of inhaled corticosteroid by using the mean daily dose as the best available proxy of cumulative exposure. We grouped the mean daily dose of inhaled corticosteroid as follows: ≤ 200 μg, 201 to 400 μg, 401 to 600 μg, and > 601 μg. We converted all prescriptions for oral corticosteroids into prednisolone equivalents, calculated the mean annual exposure for each person, and divided these data into quintiles. We repeated this process for injected corticosteroids, using the number of prescriptions as a proxy for dose. We subclassified the type of airflow obstruction according to the general practitioner-recorded diagnoses as asthma, COPD, or both. We identified all prescriptions for inhaled short-acting β-agonists, calculated the mean annual prescription rate for these drugs for each person, and divided these data into quintiles. We derived other markers of airflow obstruction severity including use of a nebulizer, and prescriptions for theophyllines and long-acting β-agonists. We also analyzed computerized general practice records predating the trial start date, which we defined as historical (Fig 1). Since most general practices were computerized in the late 1980s and early 1990s, we decided arbitrarily to ignore data before January 1, 1990, and defined the origin of our historical data as the first recorded event after this point. We then calculated the historical person-time as the difference between the historical origin and the trial start date, and used a similar process to that outlined above to extract exposure data.

We compared fracture incidence during the incident person-time between people with and without exposure to inhaled corticosteroids using Cox regression modeling (Stata version 7.0; StataCorp LP; College Station, TX). Initially, we controlled just for the effects of age (in 5-year age groups) and gender, and termed this the baseline model. We then fitted a model including all of our a priori confounders: mean annual incident and historical corticosteroid exposure, mean annual historical inhaled corticosteroid use, bronchodilator use, airflow obstruction diagnosis, and previous fracture. We explored the potential confounding effects of other exposure variables by adding each of these variables in turn to our baseline model, retaining any variables that changed the rate ratios for incident inhaled corticosteroid by > 10% in a multivariate model. Variables examined in this way included computer-record diagnoses of epilepsy, cerebrovascular disease, Parkinson disease, and rheumatoid arthritis; and a number of variables derived from the trial questionnaire including responses to whether the person reported living alone or not; problems with heating the house; falls; self-reported activity level; continence; activities of daily living; self-reported breathlessness; financial problems; lifetime smoking habit; alcohol consumption; a postal code-derived socioeconomic deprivation score (the Carstairs score, which is derived from four census indicators: low social class, lack of car ownership, overcrowding, and male unemployment); and population density score (calculated using 1991 census data at enumeration district level). We checked the proportional hazards assumption for our final model by plotting log-log plots and Schoenfeld residuals over time.

Our initial cohort included 10,552 patients, but the data set limited to patients with a diagnosis of airflow obstruction included 1,671 people, of whom 947 (57%) were female (Table 1 ). All subsequent results come from this data set. The mean age at start date was 80.6 years, and the mean number of incident and historical person-years was 4.7 (SD 1.9) and 4.7 (SD 1.9), respectively, giving a mean total duration of follow-up of 9.4 years.

A total of 982 patients (59%) had received one or more prescriptions for an inhaled corticosteroid during the incident person-time (Table 1), and the median daily dose prescribed was 219 μg (interquartile range, 80 to 443 μg). Among these people, 722 had received prescriptions for beclomethasone dipropionate only; 102 for budesonide only; 31 for fluticasone propionate only; 9 for all three inhaled corticosteroids; 63 for beclomethasone dipropionate and budesonide; 47 for beclomethasone dipropionate and fluticasone propionate; and 8 for budesonide and fluticasone propionate. A total of 773 patients had received a prescription for an inhaled corticosteroid during the historical person-time (median daily dose, 135 μg; interquartile range, 43 to 343 μg); of these, 701 patients had also received an incident prescription for an inhaled corticosteroid. Of the 689 people who had a prescription for an oral corticosteroid during the incident person-time, 529 patients also had an incident prescription for an inhaled corticosteroid. The number of people with prescriptions for oral corticosteroids during the historical person-time was 412, of whom 317 patients had an incident prescription for an inhaled corticosteroid. There was no association between Carstairs score and receiving a prescription for an inhaled corticosteroid.

One hundred eighty-seven people had an incident fracture, giving a crude rate for first recorded fracture of 23.7 per 1,000 person-years (Table 1). In our initial analyses, we found dose-related increases in fracture incidence in relation to incident and historical inhaled and oral corticosteroid exposure (Table 2 ). The rate ratio for people with a mean daily dose of > 600 μg was 2.53 (95% confidence interval [CI], 1.65 to 3.89), and the overall trend p value was < 0.0001. Among our a priori confounders, we found a marked increase in fracture incidence in people with previous fractures during the historical person-time (rate ratio, 2.24; 95% CI, 1.63 to 3.06) but no increased risk in association with the use of short-acting β-agonists, theophyllines, long-acting β-agonists, a nebulizer, and specific airflow obstruction diagnosis (Table 3 ). For our other potential confounders, although associations with fracture risk were found in the whole cohort (eg, rate ratio for each additional self-reported fall was 1.08; 95% CI, 1.04 to 1.12), in the data set of people with airflow obstruction used in this study we found no evidence of an increased risk of fracture in association with Carstairs score; local population density; smoking habit; alcohol consumption; prescriptions for injected corticosteroids; living alone; self-reported falls; shortness of breath; ankle swelling and incontinence; level of self-reported difficulty with walking; cutting toenails; dressing; cooking; housework; stair climbing; washing and shopping; and doctor-recorded diagnoses of epilepsy, Parkinson disease, and cerebrovascular disease.

The results from our model that included all of our a priori confounders were similar to that for the baseline mode (trend for p <0.001, Table 4 ). We found no evidence of statistical interaction between the effects of inhaled and oral corticosteroids (p = 0.75), and when we stratified the analyses on the basis of oral corticosteroid exposure the results were similar in the two strata (Table 4). In our final models, we found no evidence of effect modification by age or sex, or evidence that the proportional hazards assumptions were incorrect.

We describe a prospective cohort analysis of 1,671 people with a diagnosis of airflow obstruction, a mean age of 81 years, and 9.4 years of prescribing and diagnostic data on average. We found a dose-response relationship between inhaled corticosteroid use and the risk of fracture that was independent of incident and historical exposure to oral corticosteroids, specific type of airflow obstruction diagnosis, use of bronchodilators, self-reported activities of daily living, and physical activity and socio-economic status. Our findings provide further evidence that inhaled corticosteroids have adverse effects on bone.

Our study was designed to combine the advantages of the detailed prescribing and diagnostic data available in computerized general practice records in the United Kingdom, with the more extensive information on potential confounders, such as physical activity, contained within the MRC trial of assessment and management of older people in the community. The potential limitations of our study that need consideration are statistical power, the older age of the study participants, residual confounding by historical exposure to oral corticosteroids, and bias arising from severity of airflow obstruction severity. Although our cohort is large, with more than double the length of follow-up compared to the previous longest study,12 we had insufficient statistical power to undertake a systematic analysis of individual fracture sites. All of our study participants were > 75 years old at the start of the study; and since fracture increases markedly with age, this will increase the statistical power available for our study. However, the older age of our cohort may mean that patients who acquire severe COPD at a younger age are excluded from our study. Since patients with milder disease should have lower levels of exposure to inhaled corticosteroids, it is possible that we have underestimated the true impact of inhaled corticosteroids on fracture risk in our study. In our analyses, we made the conservative assumption that the three different inhaled corticosteroids are equipotent with regard to fracture risk, mainly because at present there are insufficient data available to assign accurate dose equivalents for the systemic adverse effects of the different inhaled corticosteroids. In addition, as with previous studies, we did not have data on prescriptions for oral corticosteroids before entry to the study. Our study includes detailed prescribing data on oral corticosteroid exposure for 9.4 years on average, however, allowing us to adjust for oral corticosteroid exposure more fully than previous studies. In general, the level of exposure to oral corticosteroids in our study was low, with a median annual dose of only 144 mg of prednisolone in exposed people, equivalent to only one short course of prednisolone a year. In our analyses, we adjusted carefully for incident and historical oral corticosteroid exposure, and this did not change our results. Furthermore the dose-response relationship between inhaled corticosteroids and fracture risk was similar in people with and without any exposure to oral corticosteroids. Previous studies16have reported a direct correlation between the severity of airflow obstruction measured by FEV1 and bone mineral density. Without FEV1 measurements, we were not able to control directly for severity of airflow obstruction; but use of additional drugs, which have been shown previously to correlate with severity of airflow obstruction in general practice databases, did not appear to predict fracture risk.17 It is unlikely therefore that confounding by the severity of airflow obstruction is an important factor in our study.

The results of our previous observational study8 of inhaled corticosteroids and bone mineral density suggest that it is the lifetime cumulative dose of inhaled corticosteroids that determines bone damage. Since we did not have lifetime prescribing data, we used mean daily dose of inhaled corticosteroid in our model as the best available proxy. Our results need to be interpreted with this in mind, however, and although they suggest that the risk of fracture is doubled in people who have used an average of ≥ 400 μg/d of inhaled corticosteroid for an average of 4.7 incident person-years, in reality many of these people will have used inhaled corticosteroids for longer periods than this. The results should therefore not be directly extrapolated to an individual just starting to take an inhaled corticosteroid in whom the risk is likely to be lower, or to future cohorts of people who may use inhaled corticosteroids for their whole life beginning in childhood in whom the risk may be higher. As the follow-up time available from computerized general practice databases increases further, we will be able to move from using markers of annual inhaled and oral corticosteroid exposure to better estimates of cumulative corticosteroid exposure. Ultimately though, to provide the best estimates of the impact of corticosteroid exposure on fracture risk, we will need to have lifelong exposure data and these will not be available for another 30 to 50 years.

Four previous studies1013 have used computerized health-care data sets to estimate the relation between inhaled corticosteroid use and fracture risk. All found evidence of a dose-related increase in fracture risk with the use of inhaled corticosteroids in their initial analyses, but a major limitation of all of the studies was the short duration of follow-up, which in each case was < 4 years. Three studies10,1213 were able to adjust for recent oral corticosteroid use, and this appeared to explained some of the association between inhaled corticosteroid use and fracture risk. Two studies1112 adjusted for the severity of underlying airflow obstruction, and again this appeared to explain some of the initial association between inhaled corticosteroid use and fracture risk. None of the previous studies have been able to allow simultaneously for oral corticosteroid exposure over a long period of time, severity of airflow obstruction as judged by the use of bronchodilators and self-reported breathlessness and exercise tolerance, and socioeconomic status; and for this reason we believe that our estimates of the impact of inhaled corticosteroids on fracture risk are likely to be the most accurate reported to date.

In summary, our findings demonstrate that people who use inhaled corticosteroids have an increased risk of fracture and that this increase is not explained by concurrent exposure to oral corticosteroids or level of physical activity. This conclusion is consistent with the evidence from clinical trials and observational studies25,79 that suggest that inhaled corticosteroids have systemic adverse effects on bone. Given the frequent use of these drugs in the general population, this has important public health implications. Inhaled corticosteroids are highly effective drugs for the treatment of asthma, but patients should be advised to use the lowest effective dose drugs to treat their airflow obstruction.

Abbreviations: CI = confidence interval; MRC = Medical Research Council

This work attributed to the University of Nottingham, Division of Epidemiology and Public Health, Clinical Sciences Building, Nottingham City Hospital.

The original idea for the study came from Drs. Hubbard and Tattersfield. The study was designed by Drs. Hubbard, Tattersfield, Smeeth, Fletcher, and Mr. Smith. Data collection and coordination were conducted by Dr. Hubbard and Mr. Smith, and the analysis was performed by Drs. Hubbard, West, and Mr. Smith. All authors contributed to the writing and the editing of the final manuscript.

Funding was provided by The Wellcome Trust.

None of the authors have any conflicts of interests.

Figure Jump LinkFigure 1. Schematic representation of the study design. GP = general practice.Grahic Jump Location
Table Graphic Jump Location
Table 1. Populations Demographics, Fracture Incidence, and Corticosteroid Exposure
Table Graphic Jump Location
Table 2. Dose Relationship Between Fracture Incidence and Inhaled and Oral Corticosteroid Exposure
* 

Adjusted for gender and age in 5-year bands.

 

p Value for trend < 0.0001.

 

p Value for trend of 0.09.

§ 

p Value for trend of 0.01.

Table Graphic Jump Location
Table 3. Relation Between Fracture Incidence and a Priori Confounder Variables
* 

Adjusted for gender and age in 5-year bands.

 

p Value for trend of 0.2.

 

p Value for trend of 0.6.

§ 

p Value for trend of 0.1.

 

p Value for trend of 0.12.

 

p Value for trend of 0.15.

# 

p Value for trend ≤ 0.0001.

Table Graphic Jump Location
Table 4. Relation Between Inhaled Corticosteroids and Fracture Incidence in Model Adjusted for All a Priori Confounders
* 

Adjusted for age in 5-year bands, gender, historical exposure to inhaled corticosteroids, historical and incident exposure to oral corticosteroids, quintile of short-acting β-agonist use, use of a nebulizer, use of theophyllines, and a diagnosis of asthma and/or COPD.

 

p Value for trend < 0.0001.

 

p Value for trend of 0.037.

We thank Dr. David Stables (Medical Director of EMIS) for his help study. We would also like to thank the Wellcome Trust for funding this project and the MRC for funding the original trial.

Roberts, SJ, Bateman, DN (1994) Which patients are prescribed inhaled anti asthma drugs?Thorax49,1090-1095. [CrossRef] [PubMed]
 
The Lung Health Study Research Group.. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease.N Engl J Med2000;343,1902-1909. [CrossRef] [PubMed]
 
Pauwels, R, Lofdahl, C-G, Laitinen, LA, et al Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue to smoke.N Engl J Med1999;340,1948-1953. [CrossRef] [PubMed]
 
Donnelly, R, Williams, KM, Baker, AB, et al Effects of budesonide and fluticasone on 24-hour plasma cortisol.Am J Respir Crit Care Med1997;156,1746-1751. [PubMed]
 
Harrison, TW, Wisniewski, A, Honour, J, et al Comparison of the systemic effects of fluticasone propionate and budesonide given by dry powder inhaler in healthy and asthmatic subjects.Thorax2001;56,186-191. [CrossRef] [PubMed]
 
Tattersfield, AE, Harrison, TW, Hubbard, RB, et al Safety of inhaled corticosteroids.Proc Am Thorac Soc2004;1,171-175. [CrossRef] [PubMed]
 
Israel, E, Banerjee, TR, Fitzmaurice, GM, et al Effects of inhaled glucocorticoids on bone density in premenopausal women.N Engl J Med2001;345,941-947. [CrossRef] [PubMed]
 
Wong, C, Walsh, L, Smith, C, et al Inhaled corticosteroid use and bone mineral density in patients with asthma.Lancet2000;355,1399-1403. [CrossRef] [PubMed]
 
Tattersfield, A, Town, GI, Johnell, O, et al Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years.Thorax2001;56,272-278. [CrossRef] [PubMed]
 
Hubbard, RB, Smith, CJ, Smeeth, L, et al Inhaled corticosteroids and hip fracture: a population-based case-control study.Am J Respir Crit Care Med2002;166,1563-1566. [CrossRef] [PubMed]
 
van Staa, TP, Leufkens, HGM, Cooper, C Use of inhaled corticosteroids and risk of fractures.J Bone Miner Res2001;16,581-588. [CrossRef] [PubMed]
 
Suissa, S, Baltzan, M, Kremer, R, et al Inhaled and nasal corticosteroid use and the risk of fracture.Am J Respir Crit Care Med2004;169,83-88. [PubMed]
 
Lee, TA, Weiss, KB Fracture risk associated with inhaled corticosteroid use in chronic obstructive pulmonary disease.Am J Respir Crit Care Med2004;169,855-859. [CrossRef] [PubMed]
 
Smeeth, L, Fletcher, AE, Siu-Woon Ng, E, et al Reduced hearing, ownership, and use of hearing aids in elderly people in the UK: the MRC trial of the assessment and management of older people in the community; a cross-sectional survey.Lancet2002;359,1466-1470. [CrossRef] [PubMed]
 
Fletcher, AE, Jones, DJ, Bulpitt, CJ, et al The MRC trial of assessment and management of older people in the community: objectives, design and interventions. BMC Health Services Res. 2002;;2 ,.:21. [CrossRef]
 
Tattersfield, A, Town, GI, Johnell, O, et al Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years.Thorax2001;56,272-278. [CrossRef] [PubMed]
 
Soriano, JB, Maier, WC, Visick, G, et al Validation of general practitioner-diagnosed COPD in the UK General Practice Research Database.Eur J Epidemiol2001;17,1075-1080. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Schematic representation of the study design. GP = general practice.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Populations Demographics, Fracture Incidence, and Corticosteroid Exposure
Table Graphic Jump Location
Table 2. Dose Relationship Between Fracture Incidence and Inhaled and Oral Corticosteroid Exposure
* 

Adjusted for gender and age in 5-year bands.

 

p Value for trend < 0.0001.

 

p Value for trend of 0.09.

§ 

p Value for trend of 0.01.

Table Graphic Jump Location
Table 3. Relation Between Fracture Incidence and a Priori Confounder Variables
* 

Adjusted for gender and age in 5-year bands.

 

p Value for trend of 0.2.

 

p Value for trend of 0.6.

§ 

p Value for trend of 0.1.

 

p Value for trend of 0.12.

 

p Value for trend of 0.15.

# 

p Value for trend ≤ 0.0001.

Table Graphic Jump Location
Table 4. Relation Between Inhaled Corticosteroids and Fracture Incidence in Model Adjusted for All a Priori Confounders
* 

Adjusted for age in 5-year bands, gender, historical exposure to inhaled corticosteroids, historical and incident exposure to oral corticosteroids, quintile of short-acting β-agonist use, use of a nebulizer, use of theophyllines, and a diagnosis of asthma and/or COPD.

 

p Value for trend < 0.0001.

 

p Value for trend of 0.037.

References

Roberts, SJ, Bateman, DN (1994) Which patients are prescribed inhaled anti asthma drugs?Thorax49,1090-1095. [CrossRef] [PubMed]
 
The Lung Health Study Research Group.. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease.N Engl J Med2000;343,1902-1909. [CrossRef] [PubMed]
 
Pauwels, R, Lofdahl, C-G, Laitinen, LA, et al Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue to smoke.N Engl J Med1999;340,1948-1953. [CrossRef] [PubMed]
 
Donnelly, R, Williams, KM, Baker, AB, et al Effects of budesonide and fluticasone on 24-hour plasma cortisol.Am J Respir Crit Care Med1997;156,1746-1751. [PubMed]
 
Harrison, TW, Wisniewski, A, Honour, J, et al Comparison of the systemic effects of fluticasone propionate and budesonide given by dry powder inhaler in healthy and asthmatic subjects.Thorax2001;56,186-191. [CrossRef] [PubMed]
 
Tattersfield, AE, Harrison, TW, Hubbard, RB, et al Safety of inhaled corticosteroids.Proc Am Thorac Soc2004;1,171-175. [CrossRef] [PubMed]
 
Israel, E, Banerjee, TR, Fitzmaurice, GM, et al Effects of inhaled glucocorticoids on bone density in premenopausal women.N Engl J Med2001;345,941-947. [CrossRef] [PubMed]
 
Wong, C, Walsh, L, Smith, C, et al Inhaled corticosteroid use and bone mineral density in patients with asthma.Lancet2000;355,1399-1403. [CrossRef] [PubMed]
 
Tattersfield, A, Town, GI, Johnell, O, et al Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years.Thorax2001;56,272-278. [CrossRef] [PubMed]
 
Hubbard, RB, Smith, CJ, Smeeth, L, et al Inhaled corticosteroids and hip fracture: a population-based case-control study.Am J Respir Crit Care Med2002;166,1563-1566. [CrossRef] [PubMed]
 
van Staa, TP, Leufkens, HGM, Cooper, C Use of inhaled corticosteroids and risk of fractures.J Bone Miner Res2001;16,581-588. [CrossRef] [PubMed]
 
Suissa, S, Baltzan, M, Kremer, R, et al Inhaled and nasal corticosteroid use and the risk of fracture.Am J Respir Crit Care Med2004;169,83-88. [PubMed]
 
Lee, TA, Weiss, KB Fracture risk associated with inhaled corticosteroid use in chronic obstructive pulmonary disease.Am J Respir Crit Care Med2004;169,855-859. [CrossRef] [PubMed]
 
Smeeth, L, Fletcher, AE, Siu-Woon Ng, E, et al Reduced hearing, ownership, and use of hearing aids in elderly people in the UK: the MRC trial of the assessment and management of older people in the community; a cross-sectional survey.Lancet2002;359,1466-1470. [CrossRef] [PubMed]
 
Fletcher, AE, Jones, DJ, Bulpitt, CJ, et al The MRC trial of assessment and management of older people in the community: objectives, design and interventions. BMC Health Services Res. 2002;;2 ,.:21. [CrossRef]
 
Tattersfield, A, Town, GI, Johnell, O, et al Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years.Thorax2001;56,272-278. [CrossRef] [PubMed]
 
Soriano, JB, Maier, WC, Visick, G, et al Validation of general practitioner-diagnosed COPD in the UK General Practice Research Database.Eur J Epidemiol2001;17,1075-1080. [CrossRef] [PubMed]
 
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