Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate

Objective. Intranasal beclomethasone dipropionate (BDP) has generally been considered to have no systemic activity at recommended doses, but the poten tial for long-term effects on growth has not previously been evaluated. Thi s study was undertaken to assess the effects of 1 year of treatment with in tranasal BDP on growth in children. Study Design. In this double-blind, randomized, parallel- group study, 100 prepubertal children 6 to 9 years old with perennial allergic rhinitis were treated with aqueous BDP 168 mu g twice daily (n = 51) or placebo (n = 49) for 1 year. Subjects' baseline heights were required to be between the 5th and 95th percentile, and skeletal age as determined by left wrist radiogra ph was required to be within 2 years of chronological age. Washout periods for medications known to affect growth, including other forms of corticoste roids, were established, and these medications were prohibited during the s tudy. However, short courses of oral prednisolone lasting no more than 7 da ys, and short courses of dermatologic corticosteroids lasting no more than 10 days, were allowed. Height was measured with a stadiometer after 1, 2, 4 , 6, 8, 10, and 12 months of treatment. The hypothalamic-pituitary-adrenoco rtical axis was assessed by measurements of 8 AM basal cortisol concentrati ons and response to .25 mg cosyntropin stimulation. The primary safety parameter was the rate of change in standing height. Sta tistical analyses were based on all randomized subjects who received at lea st 1 dose of medication (intent-to-treat principle). The rate of change in standing height was analyzed for all subjects who entered the study and for those completing the full 12 months of treatment (n = 80). The rate of cha nge in standing height over the 1-year study was calculated as the slope of a linear regression line fitted to each subject's height measurements over time. Because there was a statistically significant between-group differen ce in standing height at baseline, an analysis of covariance was performed for all analyses of standing height data. Results. Of the 100 subjects enrolled, 90 completed the study. The 2 treatm ent groups were generally comparable at baseline; however, at baseline, mea n age and mean height were significantly greater in the BDP treatment group that the in placebo treatment group. In both analyses, overall growth rate was significantly slower in BDP-treated subjects than placebo-treated subj ects. The mean change in standing height after 1 year was 5.0 cm in the BDP -treated subjects compared with 5.9 cm in the placebo-treated subjects. The difference in growth rates was evident as early as the 1-month treatment v isit, suggesting that the effect on growth occurred initially. The growth-suppressive effect of BDP remained consistent across all age and gender subgroups, and among subjects with and without a previous history o f corticosteroid use. Use of additional exogenous corticosteroids during th e study was similar in both groups and did not affect the results. Because there was a baseline imbalance in height, a supplemental analysis o f the differences in prestudy growth rates was performed. This analysis fou nd no baseline imbalance in prestudy growth rates. To determine whether the difference in growth rates during the study could be attributed to preexisting growth rates, a z score analysis was performed . The heights of both groups were normalized at baseline and at the end of the study using the US National Center for Health Statistics data for mean and standard deviations of height. This analysis confirmed that the differe nce in growth rates between the 2 groups was primarily attributable to the treatment rather than to any preexisting difference in growth. Additional a nalyses confirmed that the results were not influenced by outlier values. No significant between-group difference were found in the hypothalamic-pitu itary-adrenocortical axis assessments. No unusual adverse events were obser ved. No evidence of other systemic effects of BDP was found, including analysis for fluid and electrolyte imbalances; alterations in protein, lipid, or car bohydrate metabolism; alterations in formed elements in blood; and alterati ons in differential white blood cell counts, including eosinophils. Conclusions. Additional study is warranted to define the clinical relevance of these findings. This study suggests, however, that intranasal BDP may s low growth rate in children without suppressing basal 6 AM cortisol concent rations or the response to cosyntropin stimulation, which are commonly used clinically to test for adrenal suppression. The effect on final height is unknown. Alterative explantations for the finding of drug-induced growth suppression , including the possibility that the results were affected by either differ ences in height and age at baseline between the 2 groups or by outlier valu es, were discounted upon additional analysis. The results of this study wer e considered by the Food and Drug Administration in the development of rece ntly proposed new class labeling for all inhaled and intranasal corticoster oids, which states that these agents may cause a reduction in growth veloci ty in pediatric patients (see reference 21). However, both the Food and Dru g Administration and several professional bodies in the United States concu r that, depending on disease severity, the benefits of intranasal corticost eroid therapy may outweigh the risks (see reference 22). Because the effect , if any, on final height in not known, the height of children receiving lo ng-term therapy should be monitored periodically during treatment, and shou ld be plotted on a growth or growth-velocity chart to monitor for growth su ppression. To minimize the risks of systemic corticosteroid exposure, inclu ding growth suppresson, dose-reduction strategies should be considered. For patients who concomitantly receive exogenous corticosteroids via other rou tes for other conditions, such as inhaled corticosteroids for asthma, clini cians should consider the total corticosteroid exposure and titrate each pa tient to the lowest effective dose. Clinicians should also consider each me dication's potential for systemic effects when selecting among the various available corticosteroids.