ORIGINAL ARTICLE

Inhaled Corticosteroids and BoneDensity of Children with Asthma

Nerin N. Bahceciler, M.D.,* Gulay Sezgin, M.D.,Mustafa A. Nursoy, M.D., Isil B. Barlan, M.D., andMujdat M. Basaran, M.D.

Marmara University Hospital, Department of Pediatrics,Division of Pediatric Allergy/Immunology, Istanbul, Turkey

ABSTRACT

In this cross-sectional study we aimed to compare anteroposterior (AP) spine andtotal body bone mineral density (BMD) measurements of children with asthmatreated with long-term inhaled budesonide (n ¼ 52, mean age 6.4� 2.2 yr,M/F ¼ 22/30) (Group I) with those of asthmatic children who had never receivedtreatment with inhaled corticosteroids (Group II) (n ¼ 22, mean age 6.8� 2.2,M/F ¼ 10/12). Boys and girls were comparable for age, weight, height, cumula-tive corticosteroid (CS) dosage, duration of disease and inhaled corticosteroid(ICS) treatment within each group. The mean total accumulated dosage ofbudesonide for children in Group I was 154.0� 135.3 mg (mean dailydosage ¼ 419� 154�g) and the mean treatment duration was 13.0� 9.8months. The two groups were comparable with respect to age, gender, weight,height, Tanner’s stage and duration of disease. There was no significant differencebetween subjects in the two groups for total (p ¼ 0.214) and (AP) spine BMDresults (p ¼ 0.661), respectively. Our results provide additional support for thesafety of ICS therapy on bone density of asthmatic children.

Key Words: Asthma; Inhaled corticosteroids; Bone mineral density; Children

*Corresponding author. Nerin N. Bahceciler, M.D., Vefa Bey Sok No 2/B, Yesil Apt D 39, Gayrettepe 80680, Istanbul,Turkey. Fax: (þ90) 216 326 80 30; E-mail: aonder@attglobal.net

Journal of Asthma, 39(2), 151–157 (2002)

151

Copyright � 2002 by Marcel Dekker, Inc. www.dekker.com

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INTRODUCTION

With the recognition that airway inflammationis a characteristic feature even in patients with mildasthma, the emphasis in the treatment has shifted toanti-inflammatory medications (1,2). This modifica-tion resulted in an improvement in all asthma out-come parameters to a greater extent with inhaledcorticosteroids than with any other anti-asthmatreatment (3). On the other hand, there is particularconcern over the possible negative effects of long-term treatment with these agents, especially in bonemetabolism of growing children.Results of a number of studies evaluating the

effects of inhaled corticosteroids on bone metabolismby measuring biochemical markers are contradic-tory. These markers of bone metabolism have vary-ing degrees of sensitivity and specificity that differbetween different assays (3–9). For this reason,changes in these biochemical markers and theireffects on final bone mass are yet to be understood.In this cross-sectional study, we measured antero-

posterior (AP) spine and total body bone mineraldensity (BMD) in children with asthma treated forat least six months with the inhaled corticosteroid(ICS) budesonide and compared these measure-ments with those of asthmatic children who hadnever received treatment with ICSs.

MATERIAL AND METHODS

Subjects

A total of 74 (32 boys, 42 girls, age range 3–10.5years) prepubertal (Tanner’s stage I) childrenattending to the Outpatient Allergy Clinic ofMarmara University Hospital with mild intermittentplus persistent mild to moderate asthma, as estab-lished by current guidelines for severity (1), wereincluded in the study.Subjects with chronic illness other than asthma,

excessive exercise programs or eccentricities in dietwere excluded. All subjects were within 10th and90th percentile for height and weight. The studywas approved by the Ethics Committee of theHospital, and parents of all patients signedinformed consent forms.The study group was divided in two groups:

. Group I (ICS group) consisted of 52 subjects [22boys, 30 girls, 6.4� 2.2 (mean� SD) years of age]

who were being treated with budesonide as MDIfor at least six months (mean� SD, 13.0� 9.8,range of 6–41 months) at a dosage range of200–800 mg/day and a mean cumulative dosageof 154.0� 135.3mg (range 18–504mg).

. Group II (control group) consisted of 22 age-matched asthmatic children (12 girls, 10 boys,mean� SD age of 6.8� 2.2 years) who havenever received ICSs.

No subject had received treatment with systemiccorticosteroids in the previous six months. All sub-jects used inhaled beta-2-agonists per needed (prn).The demographic data of both groups are presentedin Table 1.Boys and girls within each group were compared

for all measured variables. Demographic data forboth genders are presented in Table 2.Due to the large variation in cumulative CS

dosage, subjects in the ICS group were divided intotwo groups for comparison of BMD of the subjectsreceiving a high cumulative CS dosage with thosereceiving a low cumulative CS dosage or no CSs atall. Subjects in the high-dose CS group were thosewho received a cumulative CS dosage of higherthan the established median value (102mg), whereasthe low-dose CS group consisted of those whoreceived a cumulative dose of less than 102mg. Thedemographic data of these three groups are pre-sented in Table 3.

Follow-up and Therapy

Uniform therapies are initiated in line with ourasthma treatment protocol at Marmara UniversityPediatric Allergy Division. According to this proto-col, patients with intermittent asthma receive onlyinhaled beta-2-agonists on an as-needed basis.Patients with persistent asthma who are assignedfor anti-inflammatory therapy receive inhaled bude-sonide for a daily total dose of 800 mg. All subjectsare instructed to rinse the mouth after initiation ofICS therapy. At the end of one month, if animprovement is achieved, the dose is decreased to atotal daily dose of 400 mg. During the follow-upperiod, the dose of medication needed for control ofrespiratory symptoms is adjusted to find the mini-mal dose. In addition to that, all patients receiveinhaled beta-2-agonists on an as-needed basis.All the patients followed at our outpatient clinic

are asked to maintain symptom score diaries

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supplied by us and to bring them on each visit.Patients keep a diary of daily symptoms includingcough, shortness of breath, sleep disturbance,and need for additional beta-2-agonist treatment.Some patients also record peak flow measurements

daily in their diaries. Patient evaluation includeslung function tests, daily symptom scores, andpeak flow meter results on follow-up visits everytwo to three months and more frequently ifneeded.

Table 1

Patient Characteristics of Subjects in the ICS and Control Groups

Meanþ SD

ICS Group (n ¼ 52) Control Group (n ¼ 22) p value

Age (yr) 6.4� 2.2 6.8� 2.2 0.504*Gender (M/F) (n) 22/30a 10/12a 0.803**

Height (cm) 118.5� 14.5 120.9� 14.6 0.529*Weight (kg) 22.8� 7.5 24.9� 10.2 0.381*Duration of disease at referral (month) 44.6� 24.2 33.3� 23.0 0.065*ICS therapy duration (month) 13.0� 9.8 — —

Daily dose of ICS (mg) 419� 154 — —Cumulative ICS dose (mg) 154.0� 135.3 — —Total BMD (g/cm2) 0.779� 0.081 0.802� 0.056 0.244*

AP spine BMD (g/cm2) 0.593� 0.122 0.579� 0.156 0.661*

aRatio.

*Unpaired t-test.

**Chi-square test.

Table 2

Comparison of All Characteristics of Girls and Boys Within Each Group

Mean (Range)

Girls Boys p value*

Control groupa

Age (yr) 7.2 (4.5–10.5) 6.5 (3.5–10.0) 0.407Weight (kg) 27.7 (13–59) 22.2 (14–30) 0.467Height (cm) 124.5 (99–148) 117 (101–135) 0.390

Duration of asthma (month) 33.6 (12–60) 33 (1–96) 0.666Total BMD (g/cm2) 0.808 (0.711–0.919) 0.796 (0.729–0.891) 0.573AP spine BMD (g/cm2) 0.581 (0.039–0.795) 0.576 (0.481–0.692) 0.291

ICS groupb

Age (yr) 6.1 (2–9) 6.7 (1.5–10.5) 0.430Weight (kg) 22.1 (10–48) 23.3 (10–43) 0.200Height (cm) 117 (83–140) 119.7 (80–144) 0.364Duration of asthma (month) 40.4 (6–84) 47.7 (12–108) 0.342

Cumulative CS dosage (mg) 171.9 (18–501) 140.9 (24–504) 0.243ICS therapy duration (month) 16.2 (6–33) 12.1 (6–41) 0.222Total BMD (g/cm2) 0.763 (0.567–0.954) 0.789 (0.60–1.002) 0.162

AP spine BMD (g/cm2) 0.577 (0.325–0.845) 0.606 (0.327–0.899) 0.270

a10 girls, 12 boys.b22 girls, 30 boys.

*Mann–Whitney U-test.

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Bone Density Measurements

Bone density measurements were performed on allsubjects. Total body and AP spine (L2–L4) BMDswere measured by dual energy photon absorbtiome-try (DEXA), using a Lunar DP3 densitometer(Lunar Corp., Madison, WI). The results arereported as absolute densities (in grams per squarecentimeter).

Statistical Analysis

Statistical analysis was performed by t-test,ANOVA, Mann–Whitney U-test, and chi-squaretest for independent samples. A p value of less than0.05 was considered significant. Linear correlationwas performed by Pearson’s correlation coefficientwhen indicated.

RESULTS

Boys and girls within each group (ICS group,n ¼ 52 and control group, n ¼ 22) were comparedfor age, height, weight, duration of disease at refer-ral, cumulative CS dosage, duration of ICS therapy,and total and AP spine bone density. No statisti-cally significant difference was detected betweenboys and girls within each group for all measuredvariables (Table 2). Therefore, we analyzed boysand girls pooled together in each group. The twogroups were comparable with respect to age,

gender, height, weight, and duration of disease.Also, there was no significant difference betweensubjects in the two groups for total and AP spinebone density results (Table 1).Due to the very large variation in the cumulative

CS dosage, subjects in the ICS group were dividedinto two groups for further comparison. Subjects inthe high-dose CS (n ¼ 27), low-dose CS (n ¼ 25),and control groups (n ¼ 22) were comparable withrespect to age, gender, weight, and height; whereasduration of disease at referral was found to be sig-nificantly longer in the high-dose CS group com-pared to the control group ( p ¼ 0.0034). There wasno significant difference between subjects in thethree groups for total and AP spine bone densitymeasurements (Table 3).The mean accumulated dose of budesonide for

children in the ICS group was 154.0� 135.3mg(range 18–504mg) and the mean treatment dura-tion was 13.0� 9.8 months (range 2–41 months).Anteroposterior and total BMD were not correlatedwith the mean total accumulated dose or with meantreatment duration of budesonide (data not shown),whereas both AP spine and total body BMD werepositively correlated with body height and weight(Figs. 1 and 2).

DISCUSSION

In this study we have demonstrated thattotal body and AP spine BMD measurements of the

Table 3

Comparison of Characteristics of Patients in the High-Dose CS, Low-Dose CS, and Control Groups

Mean (Range)

High Dose(�102mg) (n ¼ 27)

Low Dose(<102mg) (n ¼ 25)

Control(n ¼ 22) p value*

Age (yr) 7 (3–105) 5.8 (1.5–10.5) 6.8 (3.5–10.5) 0.352

Weight (kg) 25.2 (12–48) 20.2 (10–36) 24.7 (13–59) 0.109Height (cm) 122.7 (94–144) 114.1 (80–142) 12.9 (99–148) 0.08Duration of disease (month)** 50.4 (18–108) 38.3 (6–84) 33.3 (1–96) 0.034Cumulative CS dosage (mg) 243.9 (102–504) 56.9 (18–96) — 0.000

Duration of ICS therapy (month) 18.6 (7–41) 6.9 (6–14) — 0.000Total BMD (g/cm2) 0.794 (0.567–1.002) 0.762 (0.600–0.917) 0.802 (0.711–0.919) 0.155AP spine BMD (g/cm2) 0.616 (0.325–0.845) 0.568 (0.327–0.899) 0.579 (0.039–0.795) 0.389

*ANOVA. Statistically significant values in bold.

**Control group vs. low-dose CS group p ¼ 0.742; control group vs. high-dose CS group p ¼ 0.034; low-dose CS vs. high-dose CS groupp ¼ 0.157.

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children treated for a mean of 13 months with con-tinuous inhaled budesonide at a mean daily dosageof 419 mg (range 200–800 mg) was not different fromthe measurements of those who have never beentreated with ICSs. We have also demonstrated thattotal and AP spine bone density measurements werenot different between subjects receiving high-doseCSs, low-dose CSs, and no CSs at all. Furthermore,total body and AP spine BMD were not correlatedwith the accumulated dosage and treatment dura-tion of budesonide. The study groups were compar-able with respect to age, gender, height, weight, andTanner’s stage.Children with chronic asthma often demonstrate

a growth pattern different from that of healthy chil-dren. Many asthmatic children experience a pre-pubertal growth retardation and delayed onset ofpuberty, resulting in a Tanner stage behind their

chronological age when compared with healthy con-trol children (10–12). As growth and puberty arevery important for increase in BMD, comparison ofchildren with similar growth patterns and pubertalgrowth is of importance (13). For this reason, weincluded a control group of children with asthmanot treated with ICSs in order to allow a more rele-vant comparison than a comparison with healthychildren.Although little is known about the extent to

which duration of asthma affects BMD, it is sug-gested that longer duration of disease could have anadverse effect on BMD. In the present study, dura-tion of asthma of subjects in the high CS group wassignificantly longer than the subjects in the controlgroup, whereas there was no significant difference inthe BMD measurements of the three groups (highCS, low CS, and control groups). Duration of dis-ease seemed to have no effect on total and AP spineBMD in our study group.Agertoft and Pedersen compared total body

BMD of 157 asthmatic children treated with inhaledbudesonide at a mean daily dosage of 504 mg

0.200

0.400

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75 100 125 150

He

(a)

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ight (cm)

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Figure 1. The linear correlations between body heightwith (a) total and (b) AP spine BMD measurements.(*Pearson correlation coefficient.)

0.400

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Figure 2. The linear correlations between body weightwith (a) total and (b) AP spine BMD measurements.

(*Pearson correlation coefficient.)

Corticosteroids and Bone Density of Children 155

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(range 189–1322 mg) for three to six years with thoseof 111 age-matched asthmatic children who hadnever received ICSs. There was no statistically sig-nificant difference between the two groups in BMDand no correlation was detected between total bodyBMD and duration of or accumulated dosage ofbudesonide treatment (14).On the other hand, in the study of Boot et al. in

which the control group consisted of healthy age-matched children, total body BMD of 40 prepuber-tal asthmatic children who had used ICSs (25 ofthem budesonide and 14 of them beclomethasonedipropionate, BDP) daily for three to eight yearswith a minimal daily dosage of 400 mg was signifi-cantly lower than controls. Furthermore, in thisstudy, duration of ICS therapy negatively correlatedwith total body BMD (15).In another cross-sectional study, lumbar spine

BMD of prepubertal asthmatic children (n ¼ 44)receiving inhaled BDP for 6.7 months with a doserange of 150–600 mg/day was not significantly differ-ent than age-matched asthmatic controls treatedwith cromolyn sodium (16).Moreover, results of two longitudinal studies

assessing the development of trabecular and corticalBMD over a period of 7.4 months in 49 prepubertalasthmatic children (38 treated with BDP, mean dose276 mg/day, and 11 with cromolyn sodium) and sixmonths in 48 asthmatic children (24 treated withBDP, mean dose 400 mg/day, and 24 never treatedwith ICSs) demonstrated normal growth of BMDduring treatment with ICSs (17,18).Taken together, results of these studies are in

accordance with ours, providing evidence that long-term treatment with ICSs is unlikely to adverselyeffect BMD in children with asthma.We concluded that a mean of 13 months of treat-

ment with inhaled budesonide at an average dailydosage of 419 mg is not associated with a detectablenegative effect on total body and AP spine BMD inchildren with asthma.

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