Objectives We aimed to assess the association between long-term use of inhaled corticosteroids (ICS) and bone adverse effects in patients with asthma.
Design Systematic review and meta-analysis of fracture risk and changes in bone mineral density with long-term ICS use in asthma.
Methods We initially searched MEDLINE and EMBASE in July 2013, and performed an updated PubMed search in December 2014. We selected randomised controlled trials (RCTs) and controlled observational studies of any ICS (duration at least 12 months) compared to non-ICS use in patients with asthma. We conducted meta-analysis of ORs for fractures, and mean differences in bone mineral density. Heterogeneity was assessed using the I2 statistic.
Results We included 18 studies (7 RCTs and 11 observational studies) in the systematic review. Meta-analysis of observational studies did not demonstrate any significant association between ICS and fractures in children (pooled OR 1.02, 95% CI 0.94 to 1.10, two studies), or adults (pooled OR 1.09, 95% CI 0.45 to 2.62, four studies). Three RCTs and three observational studies in children reported on bone mineral density at the lumbar spine, and our meta-analysis did not show significant reductions with ICS use. Three RCTs and four observational studies in adults reported on ICS use and bone mineral density at the lumbar spine and femur, with no significant reductions found in the meta-analysis compared to control.
Conclusions ICS use for ≥12 months in adults or children with asthma was not significantly associated with harmful effects on fractures or bone mineral density.
- CLINICAL PHARMACOLOGY
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Strengths and limitations of this study
Comprehensive search of two databases with independent study selection and data extraction.
Included both observational and randomised studies in adults and/or children with asthma.
Heterogenous nature of studies and the outcome measures which were available for analysis.
Inability to properly assess differences between drugs, type of inhaler device or dose-responsiveness.
Asthma is a chronic inflammatory condition that affects both adults and children. There is a substantial body of evidence that suggest inhaled corticosteroids (ICS) are effective at controlling symptoms, improving lung function and reducing acute exacerbations.1 They are therefore considered the gold standard first-line preventative therapy and are widely recommended in national and international guidelines.2 ,3
However, long-term ICS use may be associated with adverse effects such as cataract, osteoporosis, fractures and reduction in growth velocity in children.4 Concerns surrounding these potential harms may have a negative effect on ICS adherence, thus exposing patients to poorer asthma control and a potentially higher risk of needing oral corticosteroids for acute exacerbations.4 Certain age groups, such as children or postmenopausal women may be particularly susceptible to adverse effects on bone metabolism and formation, and this therefore remains an area of concern for these patients.
The existing meta-analyses of ICS and bone adverse effects have usually included data from participants with chronic obstructive pulmonary disease (COPD)5–7 and to date, there has been less focus on the effects in asthma alone. Patients with asthma may not share the same susceptibilities to osteoporosis as the patient with COPD because of differences in risk factors such as cigarette consumption, multimorbidity and nutritional problems that are prevalent in patients with COPD.8 ,9 It therefore remains unclear whether patients with asthma have a greater or lesser risk of bone adverse effects than those with COPD and a further review is necessary to clarify these risks for patients with asthma alone.
Hence we aimed to analyse the effects of long-term (≥12 months) ICS use in patients with asthma alone, concentrating on fracture and bone mineral density (BMD) outcomes.
Study selection criteria
We aimed to focus on long-term, important but infrequent adverse effects on bone and as such, eligible studies had to have >20 users of each ICS formulation, with follow-up of at least 12 months in duration.
Our inclusion criteria for RCTs were (1) parallel-group RCT; (2) participants with asthma of any severity; (3) ICS as the intervention versus a control treatment, where the comparison groups consisted of ICS versus other asthma therapy (or placebo), or ICS in combination with long-acting β-agonist (LABA) versus a LABA alone; and (4) stated aim to evaluate fractures or BMD.
We also evaluated controlled observational studies (case control, prospective cohort or retrospective cohort) reporting on risk of fractures or change in BMD with any ICS exposure compared to those without ICS exposure.
We excluded studies that recruited mixed groups of participants (asthma/COPD) if the outcomes were not separately reported according to specific disease condition. We excluded crossover trials and studies that considered only oral corticosteroid use without reporting the effects of inhaled corticosteroids.
We initially searched MEDLINE and EMBASE in June 2013 using a broad strategy for a wide range of adverse effects potentially associated with ICS use, and we subsequently updated this through a more focused PubMed search in December 2014 (see eAppendix 1 for search terms and restrictions). We also manually looked through the bibliographies of included studies as well as existing systematic reviews for any other articles that may be potentially suitable.
Two reviewers (MT and PB) independently, and in duplicate scanned all titles and abstracts and excluded articles that clearly were not RCTs or observational studies of ICS in patients with asthma. We proceeded to assess full-text versions of potentially relevant articles and conducted more detailed checks against our eligibility criteria, focusing on bone and fracture adverse effects. A third researcher (YKL or AMW) evaluated the decision on inclusion or exclusion in discussion with the two reviewers.
Study characteristics and data extraction
We used preformatted tables to record study design and participant characteristics, definition of asthma, pharmacological agent (dose, device and frequency), and duration of follow-up. Two reviewers independently extracted data (MT and PB) on relevant outcomes, where we prespecified fracture risk of primary interest, and BMD at the lumbar spine or the femur as secondary end points. Any discrepancies were resolved through the involvement of a third reviewer (DG or YKL or AMW) after rechecking the source papers.
Risk of bias assessment
Two reviewers independently assessed the reporting of blinding of participants and personnel, randomisation sequence, allocation concealment, withdrawals and the loss to follow-up in RCTs. In order to assess validity of the associations between adverse effects and ICS use, we extracted information on participant selection, ascertainment of exposure and outcomes, and methods of addressing confounding in observational studies.10
We aimed to use a funnel plot and asymmetry testing to assess publication bias provided that there were more than 10 studies in the meta-analysis, and the absence of significant heterogeneity.11
We pooled trial data using Review Manager (RevMan) V.5.3.2 (Nordic Cochrane Center, Copenhagen, Denmark). We used the inverse variance method to pool ORs for fracture events, and mean differences for BMD (g/cm2). In accordance with the recommendations of the Cochrane Handbook, we derived any SDs from 95% CIs or p values.12 We assessed statistical heterogeneity using the I2 statistic with I2>50% indicating a substantial level of heterogeneity.
If a trial had more than one group of non-ICS users as controls, we analysed data for ICS versus placebo (if available) in preference to data from active comparators such as ICS versus nedocromil, montelukast or disodium cromoglycate. If combination formulations were evaluated in the trial, we chose unconfounded comparisons based on ICS used together with the other drug versus other drug alone.
If a trial had several arms involving different ICS doses, we combined all the ICS arms together as recommended by the Cochrane Handbook.13
We did not have a pre-registered protocol.
We screened 1887 potentially relevant articles, and finally included 18 studies in our systematic review (comprising 7 RCTs,14–20and 11 observational studies).21–31 The process of study selection is shown in figure 1.
Four of the RCTs focused solely on children,14 ,15 ,19 ,20 while the remaining three were in adults.16–18 Treatment duration was up to 4 years in one study,15 while the remaining six trials had ICS therapy for between 52 and 104 weeks. Intervention arms of the trials included fluticasone (5 trials), budesonide (3 trials) and mometasone (one trial). Fluticasone and mometasone were the ICS used in the intervention arms of one trial, and in this trial, we evaluated the results of all ICS users combined against montelukast.18
Five of the observational studies focused solely on children,21–23 ,25 ,29 while the remainder looked at adults or a mixture of age groups. The observational studies looked at wider range of ICS than the RCTs, with the inclusion of beclometasone, flunisolide and triamcinolone users.
Randomised controlled trials (n=7)
Overall, four of the RCTs reported an appropriate method of sequence generation, while five provided details on how concealment of allocation was achieved. With regards to blinding, five trials reported the use of double-blinding. Ascertainment of BMD was consistently performed through dual-energy X-ray absorptiometry (DEXA) scans, but the trials did not state how and when fracture diagnoses were confirmed. One major limitation that affected all the trials stemmed from discontinuations and substantial losses to follow-up for measurement of BMD outcomes at final time-points.
Observational studies (n=11)
We felt that only four studies took account of a good range of variables when tackling baseline confounding.26 ,27 ,29 ,30 Assessment of compliance or adherence to ICS use was reported in four studies.21 ,22 ,30 ,31 Fracture events were typically recorded through administrative codes while one study relied on patient self-report. Ascertainment of BMD was through DEXA scans. Overall, we felt that most of the studies were at moderate to high risk of bias due to the above limitations, with four studies possibly of slightly better methodological quality because of adequate outcome ascertainment and adjustment for confounders.26 ,27 ,29 ,30
Fractures with ICS
We identified one large long-term RCT in children that reported adjusted fracture rate of 5.7 per 100 patient years with budesonide as compared to 5.1 per 100 patient years with placebo (p=0.53).32 Similarly, there was no significant increase in likelihood of fracture in a meta-analysis of two observational studies in children, (OR 1.02, 95% CI 0.94 to 1.10, I2=0%)27 ,29 as shown in figure 2. The point estimates of fracture risk was not significantly elevated at higher dose levels, with one study demonstrating an OR of 1.15 (0.89 to 1.48) for children with ≥20 prescriptions,27 and the other study reporting an OR of 1.17 (0.93 to 1.45) for children using a daily dose of >400 μg beclomethasone dipropionate equivalents.29
No consistent association between ICS use and fracture risk in adults was seen in the pooled estimate from four observational studies (overall OR 1.09, 95% CI 0.45 to 2.62; figure 2).26 ,28 ,30 ,31 There was substantial heterogeneity in this meta-analysis (I2=76%), with Sosa's study reporting significantly increased fracture risk,28 while the others did not.
However, we judged a study by Sosa et al28 to be at high risk of bias because the control group consisted of relatives and neighbours of patients, the type of ICS was not reported and there were no statistical adjustments for confounders. In this data set, Johannes et al26 was the only study reporting fractures according to dose, but this did not demonstrate any consistent trend towards elevated risk at higher doses.
Lumbar spine BMD
Three RCTs and three observational studies reported on comparative change at the lumbar spine in children.15 ,19 ,20 ,22 ,23 ,25 (figure 3) ICS use was not associated with significant reductions in BMD as compared to controls in RCTs (mean difference −0.0018 g/cm2; 95% CI −0.0051 to 0.0015 g/cm2; I2=46%) or observational studies (mean difference −0.0075 g/cm2; 95% CI −0.044 to 0.028 g/cm2; I2=42%). There was no clear signal of dose responsiveness in one observational study that separated participants into different dose levels,25 whereas one RCT suggested that longer term users of budesonide with greater cumulative doses had lower BMD compared to those who received lower cumulative doses.20
Three RCTs and four observational studies reported on comparative change in BMD at the lumbar spine in adults (figure 4).16–18 ,24 ,28 ,30 ,31 ICS use was not associated with significant reductions in BMD as compared to controls in RCTs (mean difference −0.0019 g/cm2; 95% CI −0.0075 to 0.0038 g/cm2; I2=0%) or observational studies (mean difference −0.0055 g/cm2; 95% CI −0.047 to 0.058 g/cm2; I2=45%).
Femur/hip BMD for adults
There were three RCTs and four observational studies reporting comparative change in BMD at the femur or hip in adults (figure 4).16–18 ,24 ,28 ,30 ,31 ICS use was not associated with significant reductions in BMD as compared to controls in RCTs (mean difference 0.0020 g/cm2; 95% CI −0.0030 to 0.0070 g/cm2; I2=0%) or observational studies (mean difference 0.0070 g/cm2; 95% CI −0.045 to 0.059 g/cm2; I2=73%).
There was sparse data comparing different ICS molecules head to head. Ferguson et al14 measured lumbar spine BMD and reported a non-significant finding between children randomised to fluticasone propionate 100 μg twice daily as compared to budesonide, mean difference 0.0075 g/cm2 (95% CI −0.033 to 0.048 g/cm2). Maspero conducted a five arm trial that included mometasone and fluticasone propionate in adults. There were no significant differences in lumbar spine and femur BMD between the two compounds at the end of the trial.18
We did not proceed to constructing a funnel plot for detection of publication bias because we had less than 10 studies in the meta-analysis of each outcome, and there was substantial heterogeneity.
We focused our systematic review of RCTs and observational studies on skeletal adverse effects of ICS in patients with asthma. We did not find convincing evidence of increased fracture risk with ICS use in adults or children. Equally, there was no consistent evidence of any significant detrimental relationship between ICS use and BMD at the lumbar spine (in adults and children) or femur (in adults). There was insufficient data for us to detect any dose–response relationship, or to judge any potential differences between the available ICS molecules.
Our findings should be contrasted with those of other recent published reviews. There have been at least four systematic reviews evaluating fractures or BMD in ICS users, with two earlier reviews demonstrating a significant reduction in BMD but no definite impact on fractures.5 ,33 The most recent meta-analyses have identified a small but statistically significant dose-related increase in risk of fracture associated with ICS use in patients with COPD.6 ,7 Our findings differ from these other reviews as we have specifically focused on ICS use in patients with asthma. Here, we used very rigid selection criteria in an attempt to exclude patients with COPD from our meta-analysis.
The deleterious effects of ICS on BMD seen in previous meta-analyses could be explained in part by the higher prevalence of smoking in patients with COPD as previous studies have shown that smoking has a harmful effect on BMD, and increasing fracture risk.8 In addition, as a group, patients with asthma are likely to be younger and to have fewer comorbidities than those with COPD which may impact on BMD and fracture risk. Recent research indicates that multimorbidity (including cachexia and low-grade systemic inflammation) is often seen in patients with COPD,9 and it is conceivable that these factors may have a further negative impact on bone formation that accentuate the risks of ICS in COPD.
ICS therapy may have a positive impact on bone density through reduction of chronic inflammation and avoidance of need for acute short courses of oral corticosteroids during exacerbations. In addition, ICS may allow better control of asthma in patients such that they become more active, thereby slowing or preventing steroid-induced osteoporosis through the beneficial effects of physical activity on BMD. Bone mass can also be influenced by a wide range of other factors (such as nutrition, genetic make-up, endocrine status and amount of physical exercise),1 and ICS may therefore not be the most important influence on bone density in patients with asthma.
There are a number of limitations to our systematic review. Our search was limited to English language articles. Although, studies have attempted to assess skeletal adverse effects in many different ways, we have limited our review to clinically meaningful outcomes such as BMD in g/cm2 at lumbar spine and femur, and fractures. We did not have sufficient data from the primary studies for us to conduct meaningful analyses on different combinations of drug compounds, inhaler devices and dosage regimens. Some of the included studies were published more than a decade ago, and advances in asthma care may have made their findings less applicable to current-day patients. We recognise that there is potential for risk of bias (stemming from substantial loss to follow-up for BMD measurements) within this data set. Hence, we are unable to interpret the effects of ICS in very long-term use of ICS over a decade or more.
Our systematic review demonstrates that there is no consistent evidence of serious skeletal harm from use of ICS. Although there are intrinsic limitations to the evidence, we believe that our systematic review provides some reassurance to patients and prescribers of ICS. Our findings enables ICS users to judge the benefits and harms of their medication in a more accurate manner and helps to address concerns and uncertainty surrounding the exact risk of skeletal adverse effects.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Data supplement 1 - Online appendix
Contributors YKL and AMW conceptualised the review and obtained funding. YKL, DG, MT, PB and AMW selected studies and abstracted the data. YKL carried out the synthesis of the data and wrote the manuscript with critical input from all authors. YKL acts as guarantor for the paper.
Funding This manuscript presents a systematic review commissioned by Asthma UK (AUK-PG-2012-181), and we are grateful to the Asthma UK Research team for their guidance. The views expressed in this paper are those of the authors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.