Fracture Risk in COPD Increases With Extended Duration of Corticosteroid Use

The use of inhaled corticosteroids (ICS) for the treatment of chronic obstructive pulmonary disease (COPD) does not increase the risk for fractures, according to a new case-controlled study published in Chest.¹

However, longer-term use with high doses of ICS, was associated with moderate but significant increases in fracture risk.

The researchers assembled a cohort of 240,110 participants newly-treated for COPD, aged 55 years and older (mean age, 75 years), from the Quebec, Canada healthcare database for a mean follow-up of 5.3 years. All participants had filled prescriptions for at least 3 respiratory medications (including beta agonists, anticholinergics, theophylline, or ICS) on at least 2 occasions during any 1-year period from 1990 to 2005.

A total of 19,396 fractures were recorded (mean rate, 15.2 per 1000/year), including 9868 hip fractures and 4821 fractures of the radius and ulna. When compared with 384,478 age and sex-matched controls (up to 20 per fracture patient; 72% female), no increase was associated with ICS use at any dose (relative risk [RR], 1.00, 95% CI, 0.97-1.03), relative to non-use as long as 4 years after the event.

At 4 years, moderate differences in risk between ICS users and controls began to emerge. Overall fracture risk with ICS doses of 1000 mcg (fluticasone equivalents) or higher increased by 10% (RR, 1.10; 95% CI, 1.02-1.18), with specific risks of 12% (RR, 1.12; 95% CI, 1.01-1.24) for ≥1000 mcg of fluticasone and (RR 1.11; 95% CI 1.01-1.21) ≥1600 mcg of budesonide.

At 5 years of ICS exposure, doses of >750 mcg were associated with 5% increases in hip or upper extremity fracture risk, which increased up to 10% with more than 5 years of use.

“We did not specifically examine differences in risk by type of fracture (hip vs upper extremity) — the numbers were too small to allow precise estimates of risk with prolonged use of high doses,” Anne Valerie Gonzalez, MD, MSc, of the Division of Respiratory Medicine at McGill University Health Center, Montreal, Quebec, Canada, explained in an interview with Pulmonology Advisor.

Overprescription of ICS in COPD “is a reality,” the researchers wrote, “with a large cross-sectional survey highlighting the frequent use of ICS in patients at low risk of exacerbations.²” Results of the current study confirmed similar rates of fracture risk in elderly people with chronic respiratory diseases (reported by the same group of investigators), which showed a relative 6% rate of increase (RR, 1.06; 95% CI, 1.01-1.12) for every increase of 1000 mcg daily dose of ICS (beclamethasone equivalents).³

The investigators were particularly concerned with the potential for higher fractures in postmenopausal women in the study, as osteoporosis is a commonly comorbidity in COPD. Although reported fracture rates were significantly higher in women than in men (20.4 per 1000/year vs 9.2 per 1000/year, respectively), they did not find that dose-dependent fracture risks to ICS increased with duration of use at higher rates in women vs men.

“These results do not allow us to recommend specific ICS doses for specific durations,” Dr Gonzalez said. “However, these results should be taken in consideration when weighing the risks and benefits of prescribing ICS to patients with COPD, particularly for a prolonged period of time. The prescribed dose should be kept as low as possible.”

Disclosures: This research was funded in part by Novartis Pharmaceuticals Canada, Inc.

References

1. Gonzalez AV, Coulombe J, Ernst P, Suissa S, Long-term use of inhaled corticosteroids in COPD and the risk of fracture [published online July 14, 2017], Chest. doi:10.1016/j.chest.2017.07.002
2. Vestbo J, Vogelmeier C, Small M, Higgins V. Understanding the GOLD 2011 strategy as applied to a real-world COPD population. Respir Med. 2014;108(5):729-736.
3. Suissa S, Baltzan M, Kremer R, Ernst P. Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med 2004;169(1):83-88.