Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies
- 1School of Medicine, University of East Anglia, Norwich, UK
- 2Department of Medicine, Division of Pulmonary, Critical Care and Sleep Disorders Medicine, University of Louisville, Kentucky, USA
- 3Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Correspondence to Yoon K Loke, School of Medicine, University of East Anglia, Norwich NR4 7TJ, UK;
Contributors YKL and SS conceptualised the review and drew up the protocol. YKL, SS and RC were involved in study selection and data extraction. YKL and RC performed the data analysis. YKL, RC and SS drafted and revised the manuscript.
- Received 24 January 2011
- Accepted 28 April 2011
- Published Online First 20 May 2011
Background The effect of inhaled corticosteroids (ICS) on fracture risk in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to evaluate the association between ICS and fractures in COPD.
Methods MEDLINE, EMBASE, regulatory documents and company registries were searched up to August 2010. Randomised controlled trials (RCTs) of budesonide or fluticasone versus control treatment for COPD (≥24 weeks duration) and controlled observational studies reporting on fracture risk with ICS exposure vs no exposure in COPD were included. Peto OR meta-analysis was used for fracture risk from RCTs while ORs from observational studies were pooled using the fixed effect inverse variance method. Dose–response analysis was conducted using variance-weighted least squares regression in the observational studies. Heterogeneity was assessed using the I2 statistic.
Results Sixteen RCTs (14 fluticasone, 2 budesonide) with 17 513 participants, and seven observational studies (n=69 000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p=0.04; I2=0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p<0.001; I2=37%), with each 500 μg increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p<0.001).
Conclusion Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures.
- Inhaled corticosteroids
- chronic obstructive pulmonary disease
- COPD pharmacology
Funding SS is supported by the Johns Hopkins Clinical Research Scholars Program. This publication was made possible by Grant Number 1KL2RR025006-03 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. Information on the NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.