COPD Inhalers' Link to Fracture Risk Supported in Pooled Trials

Chronic obstructive pulmonary disease (COPD) treatments involving inhaled corticosteroids (ICSs) were associated with a greater risk for fractures, a meta-analysis of several dozen randomized trials found.

Use of inhaled ICSs was associated with a 19% increased fracture risk when compared to treatment without ICSs (RR 1.19, 95% CI 1.04-1.37), and that risk held steady when treatment lasted 12 months or more, reported Ruiying Wang, MD, of Shanxi Medical University in China, and coauthors in BMC Pulmonary Medicine.

No increased risk was observed for ICS monotherapy, and the overall link appeared greater when ICS was used in combinations, such as with a long-acting beta-agonist (LABA) or as triple therapy with a LABA plus long-acting muscarinic antagonist (LAMA):

• ICS alone: RR 1.07 (95% CI 0.86-1.33)
• ICS/LABA: RR 1.30 (95% CI 1.10-1.53)
• Triple therapy: RR 1.49 (95% CI 1.03-2.17)

"Currently, it is still controversial that inhaled corticosteroids increase the risk of fracture in patients with COPD. Whether inhaled glucocorticoids increase the risk of fracture in patients with COPD may depend on the timing, dose, and dosage form of the ICSs treatment," Wang and colleagues said.

Subgroup analysis showed that the predictors of fractures were budesonide in high doses via metered-dose inhaler devices, whereas fluticasone furoate and fluticasone propionate in different inhalation devices had no relationship with increased fractures.

The investigators noted that COPD patients tend to be elderly and have various complications, and long-term inhalation of glucocorticoids may increase their risk of fractures.

"The exact mechanisms by which ICSs increase the risk of fracture in COPD patients are unclear. However, due to malnutrition, inflammatory response, and previous exposure to corticosteroids, COPD patients are at risk of fracture porosity and fracture," study authors wrote.

"Long-term and intensive ICS therapy may lead to a small part being absorbed and have systemic effects, resulting in increased bone absorption and decreased bone formation. Moreover, osteoporosis is an important complication of COPD," they added.

Included in the meta-analysis were 44 randomized clinical trials totaling 87,594 patients.

Meeting inclusion criteria were studies that included patients with COPD, treatment interventions including any kind of inhaled glucocorticoids, utilizing non-ICS treatments as a control, and trials that reported fracture events in their results. Observational reports, studies with patients who had asthma or unknown diagnoses, and studies where ICSs were involved in both study cohorts were not included.

Studies were retrieved in October 2022 and were updated in November 2022. Of the 44 trials analyzed, 31 evaluated ICS/LABA therapy compared with control groups (including LAMA only, LABA only, LAMA/LABA, or placebo groups), while 13 evaluated triple therapy in comparison to control groups (including LAMA only, LABA only, LAMA/LABA, or placebo groups). Follow-up periods of the studies ranged from 3 to 36 months.

Factors associated with an increased risk of fracture were average participant age of 65 or above (RR 1.27, 95% CI 1.01-1.61) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III disease (RR 1.18, 95% CI 1.00-1.38).

Limitations to the meta-analysis include lack of fracture classification, possible publication bias as a result of manual retrieval, as well as the heterogeneity in how each randomized trial could report complications and medical histories.

Nevertheless, the pooled data have value as several large-scale randomized controlled trials have already individually failed to link ICSs and fractures directly, and trials tend to exclude people with severe fracture porosity and fractures, authors of the meta-analysis argued.

"Therefore, the impact of ICSs on fracture risk in patients with COPD may be significantly greater in the real-world," Wang and colleagues said.

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