Editor—Burge et al in the ISOLDE study have shown a small but significant improvement in clinical outcomes with high dose inhaled fluticasone in patients with chronic obstructive pulmonary disease, without influencing the decline in lung function.1 Their recommendation for using high dose inhaled steroids needs to be tempered on the basis of their potential for producing systemic adverse effects, especially in susceptible elderly patients.
In the ISOLDE study there was a significant but small degree of adrenal suppression, as shown by 11% and 14% falls in serum concentrations of cortisol measured at 8-10 am after six and 24 months of fluticasone compared with no change in the placebo group. Spot measurement of cortisol concentrations at 8-10 am is extremely insensitive at detecting adrenal suppression,2 which makes the finding of any significant fall even more relevant as a surrogate marker for potential systemic bioactivity in these patients. This is supported by the fact that there are more patients with bruising after taking fluticasone than placebo: 7% compared with 4% of patients. As bruising is a visible marker of altered collagen turnover in skin, similar collagen adverse effects might conceivably have also occurred in bone tissue. A recent study of asthmatic patients found a significant inverse relation between cumulative inhaled steroid dose and lumbar bone density.3
Consequently, the modest efficacy gains with high dose fluticasone should be balanced against the long term potential for systemic adverse effects. Without long term data on bone mineral density it is difficult to make rational recommendations for the use of high dose fluticasone in elderly patients with chronic obstructive pulmonary disease who may be at risk of developing steroid induced osteoporosis.
This may particularly be the case for fluticasone, which, because of its high lipophilicity, has a large volume of distribution and consequently a large reservoir of drug at steady state residing in systemic fat tissues, which equilibrates with the blood.4 An analogy is to consider a wet sponge with the constant drip representing the low plasma levels of fluticasone and the total body exposure as the amount which comes out when the sponge is squeezed. This is supported by meta-analysis of 21 studies where fluticasone exhibited significantly greater dose related adrenal suppression than other inhaled steroids—for example, 4.3-fold (P<0.001) greater than budesonide.5