In a 12-week, double-blind, randomized, placebo-controlled study assessing the systemic adverse effect potential of ciclesonide, 164 patients were randomized to receive fluticasone propionate (CFC propellant) 440 mcg daily, ciclesonide 320 mcg once daily, ciclesonide 320 mcg twice daily, or placebo (Lipworth et al. 2005). Serum and urine cortisol levels were measured at baseline, week 6, and week 12. HPA axis function was preserved with ciclesonide in doses of up to 640 mcg/day. After 12 weeks, changes in mean peak serum cortisol levels and 24-hour urinary free cortisol levels following both doses of ciclesonide were not significantly different from placebo, in contrast to fluticasone propionate 880 mcg/day, which was associated with significant reductions of 9–10% in peak serum cortisol levels and 60% in 24-hour urinary free cortisol levels (Lipworth et al. 2005). Other studies have also reported a lack of effect of ciclesonide therapy on serum and 24-hour urinary free cortisol corrected for creatinine (Postma et al. 2001; Pearlman et al. 2005). In a 12-week study of once-daily inhaled ciclesonide 80 mcg (n=182) or 320 mcg (n=195) compared with inhaled budesonide 200 mcg (n=177) twice daily, no relevant changes in 24-hour urinary cortisol excretion were observed in patients receiving ciclesonide. However, patients who received budesonide had a statistically significant suppression of urine cortisol (P<0.05) (Hansel et al. 2006). Sixty adult patients were randomized in a single-center, double- blind, double-dummy, parallel-group study evaluating HPA axis suppression associated with the use of ciclesonide compared to fluticasone in patients with moderate-to-severe asthma (Szefler et al. 2005). Patients received either ciclesonide 320 mcg twice daily, ciclesonide 640 mcg twice daily, fluticasone 440 mcg twice daily, fluticasone 880 mcg twice daily, or placebo for 29 days. Mean serum cortisol AUC0–24h at the end of treatment was significantly suppressed in the high-dose fluticasone group. A cosyntropin stimulation test showed no statistically significant differences among the groups. Twenty-four-hour urinary cortisol levels were significantly increased from baseline at week 4 compared with placebo in the ciclesonide 320 mcg twice-daily group (P=0.0224; 95% confidence intervals 0.0023, 0.0283); the other treatment groups did not demonstrate any change in urinary cortisol levels (Szefler et al. 2005). In addition, two abstracts report preliminary information on HPA axis suppression with ciclesonide and an active control in adults (Ukena et al. 2003) and in children (Pederson et al. 2004b). In the study comparing ciclesonide 320 mcg/day with budesonide 400 mcg/day in adults, no relevant change in laboratory parameters or urine cortisol were noted after 12 weeks of treatment (Ukena et al. 2003). In the pediatric phase III comparator study, the difference between urinary free cortisol levels in patients treated with ciclesonide 80 mcg twice daily (+1.54 nmol/mmol creatinine) versus patients treated with fluticasone propionate 88 mcg twice daily (–1.83 nmol/mmol creatinine) was statistically significant (P=0.0062) (Pedersen et al. 2004b). The lack of suppressive effect appears to be independent of dose. A study of high-dose ciclesonide 800 mcg/day substantiates the Core Evidence 2006;1(4) Ciclesonide | place in therapy review lack of suppressive effect with ciclesonide. The HPA axis function of 12 healthy volunteers was preserved after 800 mcg/day of inhaled doses of ciclesonide (400 mcg twice daily, 800 mcg in the morning, or 800 mcg in the evening) given for 7 days. The effect was independent of time of administration (Weinbrenner et al. 2002). There is further evidence for the lack of effect on HPA axis from 26 patients with asthma receiving ciclesonide 320 mcg once daily, or 640 mcg once or twice daily, or fluticasone 440 mcg or 880 mcg twice daily in randomized, double-blind fashion for 9 days (Derom et al. 2005). Although the study was short duration and involved few patients, 24-hour cortisol secretion was unaffected by ciclesonide, even at the high dose. Furthermore, there is evidence that HPA axis suppression does not appear to develop with longer-term ciclesonide treatment (Chapman et al. 2002; O'Connor et al. 2002). In these placebo- controlled ciclesonide trials, patients received an individualized dose of ciclesonide for 40 weeks following the initial 12-week study. Serum cortisol levels were increased compared with the former steroid treatment (budesonide 800–2000 mcg/day or equivalent) (O'Connor et al. 2002). There was no evidence that ciclesonide suppressed the HPA axis as evidenced by changes in serum and urine cortisol measurements (Chapman et al. 2002). Importantly, these long-term data have been replicated in 661 children aged 5–8.5 years, with ciclesonide 40 or 160 mcg/day associated with minimal changes in urinary-free cortisol levels after 1 year of treatment (Bernstein et al. 2006). Bone mineralization and growth Orally administered glucocorticoids are known to affect bone mineralization, decrease osteocalcin concentration in healthy volunteers, and decrease bone density in the lumbar spine (Jones et al. 2002; van Staa et al. 2002). In young patients, these factors impact bone growth. In adults, these effects can increase the risk of fracture. Glucocorticoids assert their effect on bone predominantly by decreasing bone formation through a negative effect on the function and lifespan of osteoblasts (Jones et al. 2002). Despite the limited systemic absorption of inhaled corticosteroids, the long-term administration of these agents is also believed to impact bone metabolism (Roland 2004; O’Connell 2005). Laboratory indices of bone formation (bone-specific alkaline phosphatase and serum osteocalcin) have been followed to quantify the impact of therapy. Over a 52-week study in patients with moderate-to-severe asthma, increased levels of serum bone-specific alkaline phosphatase and serum osteocalcin were observed in patients after receiving ciclesonide compared with the levels obtained while they were on their prestudy doses of steroid (P<0.05), suggesting that the impact of ciclesonide treatment on bone metabolism in these patients was significantly less than the effects of previously used inhaled corticosteroid therapies (O'Connor et al. 2002). Studies measuring the effect of lower leg growth in children have been reported. Twenty-four children aged 6–12 years were randomized to receive a daily dose of ciclesonide 40 mcg, 80 mcg, 160 mcg, or placebo over a 12-week period. No statistically significant differences in knemometry results, height 245