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Side Effects With Inhaled Corticosteroids: Risk of Systemic Side Effects

Published in Asthma

While safety data have been reported for many clinical trials, there are few studies that have been adequately powered, or have long enough follow-up periods, to assess long-term systemic side effects with ICS. A systematic review conducted in collaboration between the American College of Chest Physicians, the American Academy of Allergy, Asthma, and Immunology, and the American College of Allergy, Asthma, and Immunology examined the evidence for potential systemic complications of ICS therapy for asthma. Evidence published up to the end of the year 2000 was considered. The results are summarized in Table 2. In brief, there was relatively good evidence for the effect of ICS on skin thinning and bruising, with a dose-response relationship identified. In older adults, ICS appeared to reduce bone mineral density after long-term, high-dose therapy and increased the risk of cataracts and glaucoma, although the evidence was not conclusive. Click Here

Two studies investigating ICS effects on bone mineral density and fractures were not included in the systematic review. A study from 1998 examined the effect of ICS on bone mineral density in 34 female and 19 male patients with persistent asthma who had received high-dose ICS (inhaled BDP or BUD at doses > 1,500 ^g/d) for at least 12 months, with or without a history of maintenance therapy with oral corticosteroids (> 1 month). The investi-gators found that lumbar spine and proximal femur bone mineral density was 1 SD lower than normal in men and women receiving oral corticosteroids or high-dose ICS, equal to a doubling of the risk of fracture at these sites. In women, prior exposure to oral corticosteroids was also associated with lower lumbar spine and proximal femur bone mineral density than normal, while men were more sensitive to the side effects of ICS on bone mineral density at the lumbar spine and the Ward triangle. All patients had evidence of suppression of both endogenous cortisol and adrenal androgen production, indicating hypothalamic-pituitary-adrenal axis suppression; this study therefore supports an effect of high-dose ICS on bone mineral density.

A retrospective cohort study conducted in the United Kingdom after the systematic review described above was compiled investigated the fracture risk with ICS. Patients who were using systemic corticosteroids were excluded from this study, leaving 170,818 ICS users, 108,786 bronchodilator users, and 170,818 control patients. During ICS therapy, there was an increased relative risk (RR) for nonver-tebral fractures (RR, 1.15; 95% confidence interval [CI], 1.10 to 1.20), hip (RR, 1.22; 95% CI, 1.04 to 1.43), and vertebral fractures (RR, 1.5; 95% CI, 1.22 to 1.85). The RR of fractures was similar for BUD, FP, and BDP. However, there were no differences in fracture risk between the ICS group and the bronchodilator groups, and the authors suggested that the excess risk of fractures with ICS may be related to the underlying respiratory disease. Further prospective data are required on fracture risk with ICS therapy in order to clarify these findings.

Table 2—Conclusions of an Expert Panel Systematic Review of Side Effects With ICS Therapy

EvidenceGradej Effect on: Conclusion
A Bone mineral density, children ICS use is not associated with a reduction in bone density in children with asthma.
C Bone mineral density, adults Adult asthma patients generally do not sustain a significant reduction in bone mineral density in response to ICS treatment, although the effect may become clinically important in patients receiving high-dose ICS for many years.
C Cataracts The risk of subcapsular and nuclear cataracts associated with ICS use is negligible in young asthma patients, however, it may be elevated in older patients.
F Cataracts There is insufficient information regarding differences in the risk of cataract formation between various ICS formulations.
F Cataracts The dose-effect relationship between ICS use and cataract formation is poorly understood.
F Glaucoma The risk of glaucoma associated with ICS use is likely to be small; however, further study is warranted.
F Glaucoma There is insufficient information regarding differences in the risk of glaucoma between various ICS formulations.
F Glaucoma There is an apparent, although poorly studied, dose-effect relationship between ICS use and glaucoma.
A Growth Therapy with ICS is associated with a decrease in short-term growth rates in children, but the overall effect is small and may not be sustained with long-term therapy.
C Growth The adult height attained by asthmatic children treated with ICS is not different from that of nonasthmatic adults.
C Growth There is insufficient information on the difference between steroid formulations to derive definitive conclusions regarding their effects on growth.
B Skin The risk of skin thinning and easy bruising is elevated in patients receiving ICS. Dose, duration of use, and patient gender are important variables affecting overall risk.
F Skin There is insufficient information regarding differences in the risk of skin thinning/bruising between various ICS formulations.
B Skin There is an apparent dose-effect relationship between ICS use and skin thinning/bruising.