Inhaled Corticosteroids associated with increased risk of fracture in patients with COPD

Chronic obstructive pulmonary disease (COPD) is a third leading cause of death in world. It is a heterogeneous airway disease, characterized by persistent respiratory symptoms and gradual airflow limitation. Patients with COPD have an increased risk of osteoporosis and fractures, but screening and prophylactic measures to prevent both disorders are often neglected in this population.

Inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs) are three independent inhaled drugs, which can be used alone or in combination in the process of the disease progression to reduce the burden of COPD. The fracture risk of patients with COPD treated with ICSs is controversial and large-scale randomized controlled trials also couldn’t give a proper insight into the problem. The Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) suggests ICS use has been restricted only to selected COPD patients mainly based on the risk of exacerbations, high blood eosinophilia, or asthmatic.

The recent systematic review and meta-analysis including 44 RCTs was conducted to reveal the effect of inhaled corticosteroids on the fracture risk of COPD patients. The findings of the review are published in BMC Pulmonary Medicine. The review found that inhalation therapy with ICSs, especially ICS/LABA or triple therapy, was associated with increased the risk of fracture in patients with COPD compared with inhaled therapy without ICS. Moreover, different inhalation devices of the same drug also had differences in risk of fracture.

The two reviewers independently retrieved randomized controlled trials of inhaled corticosteroids or combinations of inhaled corticosteroids in the treatment of COPD from PubMed, Embase, Medline, Cochrane Library, and Web of Science. The primary outcome was a fracture event. This study was registered at PROSPERO (CRD42022366778).

The key findings of the study are

• Out of Forty-four RCTs were performed in 87,594 patients. Inhaled therapy containing ICSs (RR, 1.19; 95%CI, 1.04–1.37; P = 0.010), especially ICS/LABA (RR, 1.30; 95%CI, 1.10–1.53; P = 0.002) and triple therapy (RR, 1.49; 95%CI, 1.03–2.17; P = 0.04) were significantly associated with the increased risk of fracture in COPD patients when compared with inhaled therapy without ICSs.

• Subgroup analyses showed that treatment duration ≥ 12 months (RR, 1.19; 95%CI, 1.04–1.38; P = 0.01), budesonide therapy (RR, 1.64; 95%CI., 1.07–2.51; P = 0.02), fluticasone furoate therapy (RR, 1.37; 95%CI, 1.05–1.78; P = 0.02).

• The mean age of study participants ≥ 65, and GOLD stage III(RR, 1.18; 95%CI, 1.00–1.38; P = 0.04) were significantly associated with an increased risk of fracture.

• In addition, budesonide ≥ 320 ug bid via MDI (RR, 1.75; 95%CI, 1.07–2.87; P = 0.03) was significantly associated with the increased risk of fracture.

Researchers concluded that “Inhalation therapy with ICSs, especially ICS/LABA or triple therapy, increased the risk of fracture in patients with COPD compared with inhaled therapy without ICS. Treatment duration, mean age of participants, GOLD stage, drug dosage form, and drug dose participated in this association. Moreover, different inhalation devices of the same drug also had differences in risk of fracture.”

Reference: Peng, S., Tan, C., Du, L. et al. Effect of fracture risk in inhaled corticosteroids in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. BMC Pulm Med 23, 304 (2023). https://doi.org/10.1186/s12890-023-02602-5