Risk of Fracture and Osteoporosis in Patients With COPD and Inhaled Corticosteroids Treatment

Abstract

BACKGROUND:

There are disputes whether inhaled corticosteroids (ICS) increase the incidence of fracture or osteoporosis among patients with COPD. The aim of this meta-analysis was to assess the effect of ICS treatment on the risk of fracture and osteoporosis in subjects with COPD.

METHODS:

This study included parallel-group randomized controlled trials (RCTs) comparing ICS and control (non-ICS) therapy for subjects with COPD that reported adverse events including fractures or osteoporosis. Studies were found using MEDLINE/PubMed, Embase, and Cochrane Library databases between 1998–September 2022. Pooled risk ratios (RRs) and 95% CIs were calculated for primary outcomes.

RESULTS:

A total of 61,380 participants from 26 RCTs were included in the meta-analysis. Exposure to ICS did not increase the risk of fracture (RR 1.10 [95% CI 0.98–1.23], P = .10) or osteoporosis risk (RR 0.93 [95% CI 0.49–1.79], P = .84) in subjects with COPD.

CONCLUSIONS:

ICS use did not increase the incidence of fracture or osteoporosis in subjects with COPD.

Introduction

COPD is a chronic inflammatory disease characterized by persistent respiratory symptoms and irreversible air-flow obstruction.¹ Combinations of inhaled corticosteroids (ICS) and long-acting bronchodilators are widely used to reduce respiratory symptoms and prevent exacerbations of the disease.² The efficacy of ICS-containing treatment for COPD is controversial. Whereas ICS constituents lead to clinical benefits in terms of exacerbation prevention in patients with blood eosinophil counts > 300/µL, they lack benefit with blood eosinophil < 100/µL.³ Furthermore, there are growing concerns about the safety of ICS use in COPD, including pneumonia, osteoporosis, diabetes, and tuberculosis infection.⁴ Despite these risks, ICS have been used in patients with COPD at low risk of exacerbation in various countries.^5,6

A previous systematic review by Loke et al⁷ demonstrated that long-term ICS use was associated with an increased risk of fracture in COPD. Nonetheless, current studies focusing on the relationship between ICS and bone effects have shown inconsistent results. Two trials surveyed the effects of ICS use on bone mineral density among subjects with COPD, which found no difference between ICS and non-ICS groups.^8,9 Similarly, according to the reported adverse events in several randomized controlled trials (RCTs), ICS use did not appear to increase the bone fracture rate compared to non-ICS therapy.^10,11 Therefore, the association between ICS treatment in COPD and the development of fracture or osteoporosis remains unknown.

This meta-analysis was designed to evaluate whether exposure to ICS increases the incidence of adverse events including fractures and osteoporosis in subjects with COPD.

Methods

This meta-analysis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.¹² We enrolled the analysis protocol in the PROSPERO database (registration number CRD42022369684).

Search Strategy

MEDLINE/PubMed, Embase, and Cochrane Library were searched for related studies from 1998–September 2022. Prior systematic reviews were searched for additional research, and only publications in English were considered. Included studies were not limited by geographic area of enrollment. The supplementary material presents the detailed search strategy (see related supplementary materials at http://www.rcjournal.com).

Inclusion and Exclusion Criteria

The eligible studies had to be RCTs that compared ICS and control (non-ICS) therapy for subjects with a definite diagnosis of COPD and reported adverse events including fractures or osteoporosis. We excluded observational studies, conference abstracts, case reports, and animal studies. Patients with exacerbations or comorbid with asthma were not enrolled.

Data Extraction, Risk of Bias, and Quality of Evidence Assessment

Two independent authors scanned the titles and abstracts of all retrieved results, assessed eligibility by reading the full text, and collected data from the selected studies. The quality of included studies was evaluated individually by 2 reviewers based on the Cochrane Handbook for Systematic Reviews of Interventions.¹³ Quality of the evidence for our pooled results was independently assessed by 2 reviewers using the GRADE system.¹⁴ The reviewers resolved discrepancies through discussion.

Statistical Analysis

Review Manager 5.3 (Cochrane, London, United Kingdom) was applied to perform statistical analysis. The outcomes of fracture and osteoporosis were measured as risk ratios (RRs) and their 95% CIs. The I² statistic was used to evaluate the heterogeneity among the studies. Sources of heterogeneity were explored through subgroups analysis based on the ICS type, daily dose, and treatment duration. We combined data through a fixed-effects model with the Mantel-Haenszel method if heterogeneity was unimportant. We utilized visual inspection of funnel plot to evaluate the risk of publication bias.

Results

Characteristics of the Eligible Studies

A total of 4,737 studies were identified, including 4,730 from the 3 databases and 7 from a previous meta-analysis.⁷ After the full-text assessment, 26 RCTs were included for this meta-analysis^{8,10,11,15-37} (Fig. 1). The characteristics of the included studies are summarized in Table 1. These studies included 61,380 participants, 59.3% of whom received ICS therapy. All were multi-center studies performed in various countries and published between 1998–2020. The intervention duration ranged from 12–156 weeks. Five ICS (budesonide, mometasone furoate, fluticasone propionate, fluticasone furoate, and triamcinolone) were included as single or combined therapies.

Fig. 1.

Flow chart.

Table 1.

Characteristics of Included Studies

Risk of Bias

The risk of bias is presented in Figure 2. The detection bias, attrition bias, reporting bias, and other bias were all low. Nineteen studies showed a low-risk bias. Five studies had an unclear risk for random sequence generation and allocation concealment. Three had an unclear performance risk, and one had a high risk for not blinding the participants and investigators.

Fig. 2.

Risk of bias summary.

The Effect of ICS on Fracture Risk

Twenty-four studies reported an association between ICS use and fractures.^{8,10,11,15-24,26-35,37} The fracture rate was 2.1% in ICS group and 2.0% in control (non-ICS) group, and there was no statistical difference in the risk of fracture (RR 1.10 [95% CI 0.98–1.23], P = .10) (Fig. 3) between the 2 groups. The combined effect estimate had no heterogeneity (I² = 0%), and the funnel plot appeared symmetrical (Figure S1; see related supplementary materials at http://www.rcjournal.com).

Fig. 3.

Forest plot for the effect of inhaled corticosteroids on fracture risk. ICS = inhaled corticosteroids; M-H = Mantel-Haenszel.

In order to investigate heterogeneity for the effect of ICS on fracture risk, subgroup analysis was performed by 3 study characteristics including ICS type, daily dose, and treatment duration (Table 2). The pooled estimates aligned with all ICS-type subgroups, and low heterogeneity was noted. Based on the Global Initiative for Asthma (https://ginasthma.org. Accessed October 17, 2022), the daily ICS dose subgroups consisted of low, medium, and high dose (Table S1; see related supplementary materials at http://www.rcjournal.com). The pooled results were consistent across the daily ICS dose subgroups (high dose RR 1.15 [95% CI 0.93–1.42], medium dose RR 1.10 [95% CI 0.96–1.26], low dose RR 0.83 [95% CI 0.55–1.28]). The 3 treatment duration subgroups were < 52, 52–155, and ≥ 156 weeks. The pooled results were consistent across the treatment duration subgroups.

Table 2.

Subgroup Analysis for the Effect of Inhaled Corticosteroids on Fracture Risk

The Effect of ICS on Osteoporosis Risk

Four studies reported on the occurrence of osteoporosis.^21,25,31,36 The rate of osteoporosis was 1.3% in the ICS group and 1.5% in the control group. ICS use was not associated with the risk of osteoporosis (RR 0.93 [95% CI 0.49–1.79], P = .84) (Fig. 4) in COPD, and there was no heterogeneity among studies (I² = 0%). Publication bias was not assessed because of the limited number of studies.

Fig. 4.

Forest plot for the effect of inhaled corticosteroids on osteoporosis risk. ICS = inhaled corticosteroids; M-H = Mantel-Haenszel.

Quality of the Evidence for Outcomes

The quality of the outcome for fracture risk was rated as having low-quality evidence, and the evidence for osteoporosis risk was rated as very low quality (Table S2; see related supplementary materials at http://www.rcjournal.com).

Discussion

Our analysis demonstrated that ICS exposure did not affect the risk of fracture in subjects with COPD. The outcome was supported by 2 previous meta-analyses. The first investigated the effect of ICS on the risk of fracture, mostly based on observational studies that included participants with COPD or other diseases.³⁸ That meta-analysis showed the fracture risk was not linked with ICS therapy in older individuals and seemed to increase mildly when a high ICS dose was used. The second study by Drummond et al³⁹also suggested no relationship between ICS use and fracture risk in subjects with COPD, but this finding was based on the reported adverse events of only 3 RCTs. Because ICS are delivered to the bronchi and lungs, the systemic bioavailability and side effects are thought to be minimal.⁴⁰ This might explain the similarity in the fracture risk between the ICS and non-ICS groups in our study. However, some studies indicated that long-term ICS therapy could increase the fracture rate among subjects with COPD. The systematic review by Weatherall et al⁴¹ focused on the effect of ICS treatment on the likelihood of bone fracture, which enrolled subjects with asthma and investigated non-spinal fractures only. They demonstrated that the fracture risk increased by approximately 12% when the daily dose was increased by 1,000 μg of beclomethasone equivalent, though the pooled result was statistically insignificant with 95% CI (1.00–1.26). In addition, this study was restricted by including only 5 case-control studies, of which 2 were based on the same database, and a high heterogeneity was observed. On the basis of 16 RCTs and 7 observational studies, Loke et al⁷assessed all types of fractures and concluded that the participants with COPD who treated with ICS had an increased risk of fracture. But the pooled results of included RCTs seemed somewhat indeterminant because the P value and 95% CI were near the threshold (P = .040 [95% CI 1.01–1.58]). That study also suggested a dose-dependent effect; the risk of bone fracture increased by 9% with each additional 500 μg beclomethasone or its equivalent. To our knowledge, our study is the largest meta-analysis for assessing the effect of ICS on the risk of fracture in COPD, indicating no association between ICS use and fracture risk.

Our study also found that ICS use was not associated with osteoporosis risk in COPD. This conclusion was consistent with some RCTs. The TORCH study by Ferguson et al⁴² indicated no difference in bone mineral density decline among subjects with COPD between those treated with ICS for 3 years and those who received a placebo, despite the high prevalence of osteoporosis in baseline. Similarly, a recent study that excluded patients with osteoporosis observed the treatments of ICS-containing were non-inferior to non-ICS therapies for the changes of bone mineral density in COPD.⁹ Nevertheless, a nested case-control study by Chiu et al⁴³ considered that ICS exposure in COPD was linked with a mildly increase in the risk of osteoporosis (odds ratio 1.053 [95% CI 1.020–1.087]). That study was limited by not using clinical diagnosis to define subjects and osteoporosis, lack of inspection results and laboratory data, and lack of adjustment for some important factors. Our study is the first meta-analysis to find evidence that ICS use did not increase the risk of osteoporosis in subjects with COPD.

Limitations

Our study had some limitations. This meta-analysis included only RCTs, leaving out observational studies of long-term ICS therapy among subjects with COPD. Most of these RCTs surveyed respiratory and mortality outcomes, which did not use specific methods to define fractures or osteoporosis, increasing the likelihood of misclassification or underdiagnosis. The mean therapy duration of the included trials was approximately 70 weeks, which might be inadequate for observing ICS-related side effects such as fractures and osteoporosis. Moreover, we did not assess the fracture risk by various classifications (eg, limb vs spinal or traumatic vs non-traumatic) and whether the risk changed by sex or lung function. Furthermore, we did not separate the placebo from the long-acting β agonist therapy in our non-ICS group.

Conclusions

ICS therapy did not affect the risk of fracture or osteoporosis risk among subjects with COPD.