Inhaled Corticosteroids (Icss) Are Established As

Long-Term Safety of Fluticasone Propionate and Nedocromil Sodium on Bone in Children With Asthma

Christian Roux, MD, PhD*; Sami Kolta, MD*; Jean-Luc Desfouge`res, MD‡; Pascal Minini, PhD‡; and Etienne Bidat, MD§

ABSTRACT. Objective. Inhaled corticosteroids are nhaled corticosteroids (ICSs) are established as recommended as first-line therapy for pediatric asthma. the most effective anti-inflammatory therapy for However, few controlled long-term studies have investi- asthma. Thus, internationally endorsed treatment gated their effect on bone mineral density (BMD) and I guidelines recommend the use of these agents for growth. Methods. Children who were aged 6 to 14 years and long-term control of asthma, in both adults and chil- 1 had persistent asthma were randomized to 24 months’ dren. treatment with fluticasone propionate (FP) 200 ␮g/d or Long-term treatment with oral corticosteroids may nedocromil sodium (NS) 8 mg/d (if uncontrolled, maxi- cause bone loss and reduce growth in children.2,3 In mum doses of 400 ␮g/d and 16 mg/d, respectively). BMD contrast, lower doses and lower systemic exposure was assessed blind and analyzed at a central facility on with ICS has been shown to minimize the risk of the basis of dual-energy x-ray absorptiometry measure- such systemic effects.4,5 Nevertheless, concerns per- ments of the lumbar spine and femoral neck at months 0, 6, 12, and 24. Height was measured at months 0, 12, and sist in relation to the potential effects of long-term 24. Efficacy parameters (lung function, asthma control, therapy on bone in adults6 and on childhood occurrence of exacerbations) were measured every 3 growth.7 Complicating this issue is the knowledge months. that asthma also has the potential to reduce child- Results. In total, 174 children were randomized to hood growth and bone mineral density (BMD) ac- treatment (87 received FP, and 87 received NS). At month crual, mainly through reduced physical activity.8 24, the adjusted mean percentage increase in lumbar spine BMD was 11.6% in the FP group compared with Optimal asthma control therefore would facilitate 10.4% in NS-treated children (95% confidence interval for normal growth and bone development, and clinical treatment difference: ؊0.7% to 3.1%). The corresponding trials investigating the effects of ICS must account for increases in femoral neck BMD were 8.9% and 8.5%, this. respectively. There was no significant difference in Inhaled fluticasone propionate (FP) has equivalent growth between the 2 groups: adjusted mean growth efficacy when used at half the dose of older-genera- rates were 6.1 cm/y with FP and 5.8 cm/y with NS. FP was tion ICS (eg, beclomethasone dipropionate, budes- significantly superior for every efficacy parameter inves- 9–11 tigated and was similarly well tolerated as NS. onide) and has a comparable safety profile. Nu- Conclusions. The long-term effects of FP and NS on merous studies have investigated the safety of FP in BMD accrual and growth are similar among children children at doses up to 400 ␮g/d by measuring bio- with asthma. The benefit:risk ratio of FP may be consid- chemical markers, most commonly relating to adre- ered superior to that of NS. Pediatrics 2003;111:e706–e713. nal function.11–15 In addition, biochemical markers of URL: http://www.pediatrics.org/cgi/content/full/111/6/e706; bone metabolism have been studied for up to 20 bone mineral density, fluticasone propionate, long-term months.13,16,17 These studies indicate that although safety, height. FP treatment may be associated with reduced cortisol levels compared with placebo, it is more favor- ABBREVIATIONS. ICS, inhaled corticosteroid; BMD, bone mineral density; FP, fluticasone propionate; NS, nedocromil sodium; able than therapeutically equivalent doses of budes- PEFR, peak expiratory flow rate; FEV1, forced expiratory volume onide or beclomethasone dipropionate and no in 1 second; BHR, bronchial hyperreactivity; DXA, dual-energy different from nonsteroidal therapy in terms of bone x-ray absorptiometry; CI, confidence interval; ITT, intention-to markers. treat. Although biochemical markers may provide a sen- sitive short-term measurement of the effects of ICS From the *Hoˆpital Cochin, Assistance Publique–Hoˆpitaux de Paris, Univer- therapy, long-term studies are required to show the site´Rene´Descartes, Paris, France; ‡GlaxoSmithKline, Marly Le Roi, France; consequences of these effects on bone and growth, and §Hoˆpital Ambroise Pare´, Assistance Publique–Hoˆpitaux de Paris, Bou- with 24 months suggested as the minimum duration logne-Billancourt, France. 18 Received for publication Oct 8, 2002; accepted Jan 30, 2003. for bone density studies. Few such data showing Reprint requests to (C.R.) Service de Rhumatologie, Hoˆpital Cochin, Assis- the effects of FP on BMD and growth in children tance Publique–Hoˆpitaux de Paris, Universite´ Rene´ Descartes, 27 rue du have been published. The present study was under- Faubourg Saint Jacques, 75014 Paris, France. E-mail: [email protected] taken to compare the increase in BMD among chil- hop-paris.fr PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Acad- dren with asthma treated with FP or nedocromil emy of Pediatrics. sodium (NS). e706 PEDIATRICS Vol.Downloaded 111 No. 6 from June www.aappublications.org/news 2003 http://www.pediatrics.org/cgi/content/full/111/6/ by guest on September 24, 2021 e706 METHODS in Table 1) was judged over the last 2 weeks before each clinic visit: a patient was declared as controlled if he or she was receiv- This was a randomized, open, multicenter, parallel-group, ing FP 200 ␮ 2-year comparison of the safety and efficacy of FP and NS. All g/d or NS 8 mg/d and if all the criteria were fulfilled. assessments of the main safety criterion (BMD) were performed Height was measured at the end of the run-in period and at blind. The study protocol was designed in accordance with the months 12 and 24, using the standard methods in place at each Declaration of Helsinki and was approved by a French ethics center. Adverse events were recorded at each clinic visit. committee (Consultative Committee for the Protection of Persons Enrolled in Biomedical Research of Boulogne Ambroise-Pare´). The Statistical Methods parents of every child who participated in the study provided The primary endpoint was the percentage change from baseline written informed consent; the consent of the patient was also in lumbar spine BMD, and the sample size was calculated to sought when he or she was old enough to express his or her establish noninferiority of FP compared with NS. Noninferiority opinion. Respiratory care clinicians from 52 specialist clinics in was declared when the lower bound of the 90% confidence inter- France recruited study participants. val (CI) for treatment difference (FP Ϫ NS) was greater than or equal to Ϫ2%, a threshold chosen according to our opinions on the Patients basis of clinical practice and relevant literature. Assuming a stan- Children who were aged 6 to 14 years, weighed at least 13 kg, dard deviation for the percentage change from baseline of 4%, the and experienced persistent asthma that was treated with a short- required sample size was 53 assessable patients in each treatment ␤ group (90% power). The analysis was originally based on 90% CIs. acting 2-agonist were eligible for inclusion. The defining criteria for persistent asthma were exacerbations occurring at least once a However, as 95% CIs have since become preferential for express- week but less often than daily, or chronic symptoms requiring ing noninferiority results, the data were reanalyzed accordingly. daily treatment. The main exclusion criteria were treatment dur- Primary analysis of BMD outcomes was based on the intention- ing the previous month with an oral, inhaled, or intranasal corti- to-treat (ITT) population, defined as all patients who were ran- ␤ domized and received at least 1 dose of study medication. Sec- costeroid, a chromone theophylline, or a long-acting 2-agonist; or an uncontrolled serious concurrent disease. ondary analysis was performed on the per-protocol population (ie, The study included a run-in period of 1 to 4 weeks, during the ITT population, excluding patients with serious protocol vio- which previous bronchodilator therapy was replaced as required lations). Efficacy analyses were performed on the ITT population. by salbutamol and patients completed daily record cards. Peak Adverse events were described for all patients who received at expiratory flow rate (PEFR) was measured twice daily using a least 1 dose of study medication. Mini-Wright peak flow meter. Patients entered the study if the For patients with missing BMD or growth data, predicted val- following 3 criteria were fulfilled: 1) clinic forced expiratory vol- ues were derived from a linear regression model based on predic- tive covariates, baseline, and subsequent values. This was used ume in 1 second (FEV1) or PEFR was at least 80% predicted; 2) FEV or PEFR reversibility was at least 15% from baseline (at clinic instead of last observation carried forward, as last observation 1 carried forward assumes that measurements remain constant over visit or during the previous year) or bronchial hyperresponsive- 19 ness (BHR) during the previous year; and 3) daily variability of time and therefore would not be a conservative approach. A PEFR was 20%–30% on at least 2 days, salbutamol was required sensitivity analysis using alternative methods was performed to Ͼ3 times during the previous week, or nocturnal symptoms were give robustness to the conclusion. noted more than twice during run-in. Menstrual status was as- Percentage change in BMD was analyzed by analysis of covari- sessed at inclusion and at subsequent clinic visits, allowing clas- ance, with treatment as the main effect; adjustments were made sification of subjects according to whether menstruation com- for age, height, weight, and BMD at baseline, as well as gender menced before, during, or later than the study. and the make of device used to measure BMD (Hologic or Lunar). Interaction of treatment with these covariates was assessed sepa- Treatment rately. Secondary analyses were performed to assess the impact of systemic corticosteroid use and menstruation status. Growth Eligible children received 24 months’ treatment with FP at an (cm/y) was also analyzed by analysis of covariance, with adjust- initial dose of 200 ␮g/d (100 ␮g twice daily, via the Diskus/ ments for age, gender, and baseline measurement. Lung function Accuhaler dry powder inhaler; Glaxo-Wellcome CSU, Ware, parameters and asthma control at each visit were analyzed using United Kingdom) or NS at an initial dose of 8 mg/d (two 2-mg a repeated measures model. inhalations twice daily, via a metered-dose inhaler). Treatment was allocated by balanced, block randomization with gender strat- RESULTS ification; investigators dialed into a central voice mail system to ensure correct synchronization. All patients used salbutamol as A total of 207 children were screened, 174 of whom required throughout the study; persistent inadequately controlled were randomized to treatment: 87 with FP and 87 asthma (defined below) was treated by doubling the dose of study with NS (Fig 1). One additional patient received FP ␮ medication, then by adding salmeterol (50 g twice daily), and, but was not randomized and was included in the when necessary, systemic corticosteroids. Previously used H1 an- tihistamines and ketotifen were permitted throughout the study. adverse event but not in the ITT population. Baseline Use of vitamin D was limited to a maximum of 1000 UI/d, and characteristics of the 2 treatment groups were well- treatments known as having an impact on bone metabolism were matched (Table 2); 94% were white in both groups. not allowed. When used, they had to be reported in the case report Forty-one patients withdrew early from the study, form. 13 from the FP group and 28 from the NS group (Fig Bone Safety 1). Adverse events caused 1 discontinuation in the FP Dual-energy x-ray absorptiometry (DXA) examinations were group and 4 in the NS group, whereas lack of efficacy performed at clinic visits during the run-in period and at months led to 0 and 8 discontinuations, respectively. The 6, 12, and 24. The lumbar spine and femoral neck were examined, proportion of female patients who reported menstru- with strict adherence to the equipment manufacturer’s recommen- dations for positioning the patient. Every patient was scanned using the same device (Hologic [Hologic, Waltham, MA] or Lunar TABLE 1. Definition of Asthma Control [Lunar GE, Madison, WI]) throughout the study. Cross-calibration was achieved by scanning a European Spine Phantom 10 times on During the last 2 weeks before each clinic visit each device, whereas device stability was evaluated regularly No occurrence of asthma symptoms during the study using the manufacturer-supplied phantom. All Salbutamol use Ͻ4 times a week patient scans were analyzed blind in a central facility. No hospitalization or emergency visit as a result of asthma No limitation of physical activity Secondary Endpoints Daily PEF variability Ͻ20% (data from diary, first 3 mo only) PEF Ͼ80% predicted Lung function was assessed at clinic visits every 3 months, with No drug-related adverse event measurements of FEV1 and PEFR. Asthma control (see definition

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/111/6/ by guest on September 24, 2021 e706 e707 Fig 1. Flow chart showing patients’ progress through the study. ation onset during the study (additional to baseline) baseline BMD, and device used to measure BMD. was 23% in the FP group and 27% in the NS group. However, none of these covariates had a significant Only 3 patients (2 in the FP group) used vitamin D interaction with treatment effect and hence did not during the study. affect the noninferiority of FP compared with NS. The secondary analysis showed that after adjust- Bone Safety ment on baseline characteristics, the use of systemic At month 24, the adjusted mean increase in lumbar corticosteroids had no significant impact on BMD spine BMD from baseline (Ϯstandard error) was (P ϭ .778). Furthermore, the treatment effect was 11.6 Ϯ 0.7% among children who received FP com- similar whether patients received corticosteroids or pared with 10.4 Ϯ 0.7% among NS-treated patients. not, as showed by the lack of interaction between The treatment difference (FP Ϫ NS) was 1.2% (95% systemic corticosteroids and study treatment (P ϭ CI: Ϫ0.7% to 3.1%), indicating that FP was noninfe- .847). Onset of menstruation was associated with rior to NS. This finding was supported by the in- increased BMD (P Ͻ .001) but did not interfere with crease in lumbar spine BMD in the per-protocol pop- treatment effect (P ϭ .544). ulation (95% CI for treatment difference: Ϫ0.7% to Femoral neck BMD outcomes were similar to those 3.5%). observed for lumbar spine (Fig 2). At month 24, the Gender-specific increases in lumbar spine BMD adjusted mean increase from baseline was 8.9 Ϯ 0.6% are shown in Fig 2; larger increases were reported among children who were treated with FP and 8.5 Ϯ among female patients in both treatment groups. In 0.6% among children who were treated with NS (ITT addition to gender, the increase in lumbar spine population). The treatment difference was 0.5% (95% BMD was significantly affected by baseline height, CI: Ϫ1.2% to 2.1%). e708 LONG-TERM BONEDownloaded SAFETY from IN www.aappublications.org/news CHILDHOOD ASTHMA by guest on September 24, 2021 TABLE 2. Baseline Characteristics (ITT Population) FP (n ϭ 87) NS (n ϭ 87) Age (ys; mean [SD]) 9.1 (2.5) 9.4 (2.4) Gender (%) Male 64 66 Female 36 34 Menstruation (proportion of females, %) 16 17 Height (cm; mean [SD]) 136.1 (12.5) 135.7 (14.2) Weight (kg; mean [SD]) 33.1 (9.6) 34.1 (12.5) Duration of asthma (y; mean [SD]) 4.9 (2.8) 4.8 (2.9) FEV1 (% predicted; mean [SD]) 88.9 (12.4) 88.5 (14.1) PEFR (% predicted; mean [SD]) 96.1 (22.3) 92.9 (22.2) Lumbar spine BMD (mean [SD]; g/cm2) Hologic (n ϭ 148) 0.655 (0.092) 0.666 (0.117) Lunar (n ϭ 26) 0.749 (0.116) 0.717 (0.123) Femoral neck BMD (mean [SD]; g/cm2) Hologic (n ϭ 147) 0.698 (0.089) 0.699 (0.102) Lunar (n ϭ 25) 0.781 (0.123) 0.795 (0.148)

Secondary Safety Outcomes and Tolerability FP, compared with 43% of those in the NS group. Height increased throughout the study in both The overall requirement for systemic corticosteroids groups, with no significant treatment effect (Table 3). to treat exacerbations was significantly lower in the The adjusted mean growth velocity over 2 years in FP group (P Ͻ .001), and just 3% of patients in this the FP group was 6.1 cm/y, compared with 5.8 cm/y group required 3 or more courses (compared with in the NS group (95% CI for treatment difference: 16% in the NS group). Mean cumulative doses of Ϫ0.2 to 0.8 cm/y). During the first 12 months, the systemic corticosteroids were 193 mg in the FP group mean growth velocities in the 2 groups were 6.0 and and 330 mg in the NS group, and the mean course 6.2 cm/y, respectively (95% CI for treatment differ- durations were 3.9 days and 5.0 days, respectively. ence: Ϫ0.9 to 0.5 cm/y). Both FP and NS were well tolerated, with drug- DISCUSSION related adverse events affecting 23% and 20% of This constitutes the largest controlled study yet patients, respectively. The most common adverse reported to assess skeletal development in children events are shown in Table 4; asthma was the most who have asthma and are treated with ICS. Patients common drug-related adverse event in both treat- who received FP for 2 years demonstrated lumbar ment groups. Serious adverse events occurred in 4 spine BMD increases that were no different from patients in the FP group (5%) and 5 children in the those of patients who were treated with NS. This was NS group (6%); 1 of these was a traumatic fracture, supported by the lack of between-group differences occurring in the FP group. All of these events were in femoral neck BMD and growth and, although not resolved and considered unrelated to study medica- presented in this article, also by analyses using dif- tion. ferent imputation methods for missing data. More- over, lung function and symptom control during Efficacy treatment with FP were significantly superior to NS. More patients in the FP group had well-controlled Owing to its speed, precision, and low radiation asthma throughout the study: the mean proportion dose, DXA is widely accepted as the method of of patients with asthma controlled at initial dosage choice for measuring BMD, assuming that steps are was 82% in the FP group, compared with 51% in the taken to ensure correct positioning of patients and NS group (P Ͻ .001). No medication change was rigorous calibration of the DXA device.20 With such required in 45% of FP-treated patients compared a quality control, the precision of the BMD measure- with 34% of patients who received NS. ments in children is 1% on average.21 BMD measure- Figure 3 shows the difference between the 2 treatment provides the only direct measure of fracture ment groups for a number of efficacy parameters risk relating to bone fragility, although this relation- during the study. The mean proportion of children ship is not as well-established in children as in who experienced asthma exacerbations during the adults. study was 8% in the FP group, compared with 16% in The gender-specific increases in lumbar spine Ͻ the NS group (P .001). Both PEFR and FEV1 (per- BMD with FP were comparable with increases pre- centage predicted) were significantly higher among viously observed among healthy children of a similar children who received FP (between-group differ- age. In the FP group (mean age: 9.1 year), the 24- ences of 6.9% and 4.1%, respectively). month increase in lumbar spine BMD was 16.0% in Doubling of medication for patients with insuffi- female patients and 9.5% in male patients. In healthy cient control was required by 38% of patients who children, the 2-year increase from 9 years onward were treated with FP compared with 61% of patients has been reported as 10.5% in girls and 7.7% in who were treated with NS and addition of a long- boys.22 The likely reason for the higher increase in ␤ acting 2-agonist was required by 15% and 39% of the present study was the wide age range of our patients, respectively. Systemic corticosteroids were subjects and the inclusion of pubertal subjects, in required by 26% of patients who were treated with whom BMD increases at a faster rate (ϳ12.5%/y for

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/111/6/ by guest on September 24, 2021 e706 e709 Fig 2. Mean gender-specific increase from baseline in lumbar spine (A) and femoral neck (B) BMD among children who were treated with FP or NS (ITT population).

TABLE 3. Gender-Specific Height Change During the Study TABLE 4. Incidence of Drug-Related Adverse Events Affect- (ITT Population, Missing Data Imputed by Expected Values) ing at Least 2% of Children Who Were Treated With Either FP or NS Time Mean Increase in Height Height From Baseline (cm) FP NS (cm) (n ϭ 87)* (n ϭ 88)† Mean (SD) Range Lower respiratory FP ϭ Asthma 8 (9%) 15 (17%) Females (n 31) Baseline 138.3 —— Bronchitis 6 (7%) 1 (1%) Month 12 143.8 5.5 (2.4) 0–9 Lower respiratory infection 2 (2%) 1 (1%) Month 24 149.8 11.5 (4.5) 2–20 ϭ Ear, nose, and throat Males (n 56) Baseline 134.9 —— Nasal inflammation 4 (5%) 3 (3%) Month 12 141.2 6.3 (2.7) 2–16 Throat and tonsil pain/discomfort 4 (5%) 2 (2%) Month 24 147.5 12.6 (3.1) 8–24 Ear, nose, and throat infection 2 (2%) 0 (0%) NS ϭ Laryngitis 2 (2%) 1 (1%) Females (n 30) Baseline 138.4 —— Pharyngitis 1 (1%) 3 (3%) Month 12 143.8 5.4 (2.3) 1–13 Upper respiratory inflammation 1 (1%) 2 (2%) Month 24 148.3 9.9 (3.5) 2–18 ϭ Gastrointestinal Males (n 57) Baseline 134.4 —— Gastroenteritis 2 (2%) 1 (1%) Month 12 140.9 6.5 (2.1) 1–15 Skin Month 24 146.7 12.4 (3.1) 6–20 Eczema 2 (2%) 0 (0%) Any drug-related adverse event 20 (23%) 18 (20%)

23 * Includes 1 patient who was not randomized but received FP. 14- to 16-year-olds ). Although the inclusion criteria † Includes 1 patient who was randomized to FP but received NS. would ideally have been limited to prepubertal children, this would have led to recruitment difficulties and perhaps reduced the overall clinical impact and term pediatric safety studies of anti-asthma medica- relevance. However, close matching of patients’ age tion. For example, a 20-month comparison of FP 200 and the proportion of girls beginning menstruation ␮g/d with beclomethasone dipropionate 400 ␮g/d in the 2 treatment groups indicates that similar pro- indicated that BMD increased at normal rates in both portions of patients reached puberty, minimizing treatment groups.16 In terms of growth, FP has pre- any potential effect on the comparison the study was viously been shown to have no significant inhibitory intended to perform. effect compared with placebo or chromones24 and to These findings are also consistent with other long- be more favorable than therapeutically equivalent e710 LONG-TERM BONEDownloaded SAFETY from IN www.aappublications.org/news CHILDHOOD ASTHMA by guest on September 24, 2021 Fig 3. Efficacy differences between FP and NS. A, Percentage of patients with asthma controlled at initial dosage. B, Mean FEV1. C, Mean PEFR.

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/111/6/ by guest on September 24, 2021 e706 e711 doses of budesonide and beclomethasone dipropi- and growth were prohibited, and investigators were onate.16,25,26 Although growth was a secondary pa- asked to check carefully their possible use and to rameter in the present study, no differences in report it in the case report form. Use of vitamin D growth rates between FP and NS were found during was limited to a maximum of 1000 UI/d; only 3 2 years of therapy, and there was no evidence of an patients took vitamin D during the study. early transient effect. This is in contrast to the con- ICSs are recognized in international treatment trolled comparison of budesonide with NS, which guidelines as a highly effective mainstay of asthma showed significantly reduced growth with budes- prophylaxis. Our study has demonstrated that FP onide during the first year of treatment, although the treatment for up to 2 years had a similar effect on effect was not sustained during subsequent years.27 BMD and growth as a chromone, while providing a Only 1 previous bone safety trial with an ICS was of greater degree of disease control. Consequently, it a longer duration and contained a larger number of may be possible to conclude that the long-term ben- patients than the present study, but this was neither efit:risk ratio of FP is superior to that of NS. randomized nor blinded.28 That study found no significant differences in BMD between patients who ACKNOWLEDGMENTS were treated with inhaled budesonide for 3 to 6 years This study was funded by GlaxoSmithKline France and was and age-matched, steroid-naı¨ve control subjects; sponsored by GSK France (protocol reference FLPB0256/ however, lack of randomization could have con- FMS40175), and all study medications were provided by GSK. We thank the following investigators and their coinvestigators founded the results for reasons such as poorly who participated in the study: M. Anton, T.H. Arfi, J.C. Arnal, C. matched disease severity. Auge´, H. Balloul, T. Barane`s, D. Berman, V. Boisserie-Lacroix, P.A. Comparison of FP with a chromone can be consid- Braun, J. Brouard, T.H. Bureau, M.C. Castelain, Y. Caubet, A. ered more ethical than administering placebo as a Chace´, D. Chateau-Waquet, G. Chatte´, M.T. Chauvin-Lie´bard, P. Couturier, J. De Casamyor, P.H. De Cornie`re, L. Courtois-Delair, control, while still providing a true measure of the M.C. Delsaux, A. Deschildre, Y. Dirrheimer, B. Douay, F. Duboeuf, effect of the ICS because chromones have no direct A. Ducolone´, M. Epstein, J.L. Fauquert, P. Franc¸ois, M. Gro- effect on BMD or childhood growth. The choice of sclaude, J. Goudard, J. Goudin, C. Guillaume, I. Hodouin, P. Huin, NS as a comparator is also compatible with interna- P. Hyvernat, M. Irisson, A. Isnard, M.P. Lafourcade, P.H. Laurent, tional treatment guidelines for asthma, as chromones J.C. Lebeau, M. Legendre, D. Lesbros, D. Llewelyn, F. Marmouz, Y. Martinat, H. Masson, P. Meunier, L. Miro, A. Napoly, A.P. are a recognized treatment option for mild persistent Nathan, P. Nouilhan, D. Ortolan, E. Paty, J.C. Pautard, F. Payot, C. asthma in children.1 The allowance of an increase in Peton, B. Pigearias, J. Plot, G. Poylecot, C. Ribot, J. Robert, P. the dose of study medication (up to the maximum Romberg, F. Saint-Martin, and R. Sanchez. licensed doses of FP and NS) for patients with uncontrolled asthma increases the clinical relevance of REFERENCES this study: as in clinical practice, systemic corticoste- 1. Global Initiative for Asthma. Global Strategy for Asthma Management and roids were administered only after the failure of the Prevention. Bethesda, MD: National Institutes of Health; 1995 (NIH higher dose of FP or NS combined with a long-acting publication No. 02-3659) ␤ 2. 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Downloaded from www.aappublications.org/news by guest on September 24, 2021 Long-Term Safety of Fluticasone Propionate and Nedocromil Sodium on Bone in Children With Asthma Christian Roux, Sami Kolta, Jean-Luc Desfougères, Pascal Minini and Etienne Bidat Pediatrics 2003;111;e706 DOI: 10.1542/peds.111.6.e706

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