Pediatric Pulmonology

Inhaled Corticosteroids and

Bone Mineral Density at School Age:
A Follow-up Study After Early Childhood Wheezing
Virpi H. Sidoroff, MD,1,2* Mari K. Ylinen, MD, PhD,3 Liisa M. Kröger, MD, PhD,3
Heikki P.J. Kröger, MD, PhD,4 and Matti O. Korppi, MD, PhD1,5
Summary. Objective: The aim of the study was to evaluate the association between previous use
of ICS and bone mineral density (BMD) at school age in a cohort followed after early childhood
wheezing. Methods: As part of a prospective follow-up study after hospitalization for wheezing at
<24 months of age, BMD was measured in 89 children at 12.3 (median) years of age. Data on ICS
use were collected by interviewing the parents, and this was supplemented with data from patient
records. Cumulative doses and the duration of ICS use were calculated. Areal BMD (BMDareal, g/cm2)
was measured by dual energy X-ray absorptiometry (DXA), and apparent volumetric BMD
(aBMDvol, g/cm3) was calculated, for the lumbar spine and femoral neck. Weight, height and
pubertal stage were recorded. Findings: Age, sex, and pubertal stage were significantly
associated with BMDareal and aBMDvol of the lumbar spine and BMDareal of the femoral neck. The
regular use of ICS for >6 months at age <6 years was associated with a lower BMD of the lumbar
spine. A lower BMDareal and aBMDvol of the femoral neck were associated with higher cumulative
doses of ICS at age 0–12.3 (median) years. The results were robust to adjustment for age, sex,
pubertal stage, height, weight, and use of systemic steroids. Conclusion: ICS use during childhood
may be related to a decrease in BMD at late school age. It is important to use the lowest possible
ICS dose that maintains adequate asthma control. Pediatr Pulmonol. ß 2013 Wiley Periodicals, Inc.

Key words: asthma; bone mineral density; child; dual energy X-ray absorptiometry;
inhaled corticosteroids.

Funding source: Tampere Tuberculosis Foundation

INTRODUCTION route of administration, corticosteroids can have detri-

The prevalence of childhood asthma has increased
during the last few decades,1 and as a result, asthma is the
most common chronic disease in children.2 Inhaled
corticosteroids (ICS) are the drugs of choice for asthma in
children, improving symptom control and preventing
asthma exacerbations more effectively than cromones or
leukotriene antagonists.3,4 However, irrespective of the
mental effects on bone metabolism and mineralization.5,6
The use of ICS has been associated with temporary
growth retardation in childhood, but no, or only minor,
effect on height in adulthood.6,7 Cross-sectional or short-
term longitudinal studies have not revealed any associa-
tion between the use of ICS and bone mineral density
(BMD) or bone biomarkers.8–10 In one study, high-dose
ICS therapy reduced BMD in pre-pubertal children.11 In

1
Department of Paediatrics, School of Medicine, University of Eastern Conflict of interest: None.
Finland, Kuopio, Finland.


Correspondence to: Virpi Sidoroff, MD, Matarakatu 34, 80130 Joensuu,
2
Department of Paediatrics, North-Karelia Central Hospital, Joensuu, Finland. E-mail: vpietika@student.uef.fi
Finland.
Received 14 November 2012; Accepted 22 October 2013.
3
Department of Paediatrics, Kuopio University Hospital, Kuopio, Finland.
DOI 10.1002/ppul.22968
4
Department of Surgery, Kuopio University Hospital, Kuopio, Finland. Published online in Wiley Online Library
(wileyonlinelibrary.com).
5
Paediatric Research Centre, Tampere University and University Hospital,
Tampere, Finland.

ß 2013 Wiley Periodicals, Inc.

2 Sidoroff et al.
the long-term prospective CAMP study, repeated courses
of oral corticosteroids increased the risk of osteopenia and
high cumulative doses of ICS decreased BMD.12 BMD is
dependent on age, height, gender, race, pubertal stage and
physical activity,13,14 and may also be dependent on
relative weight.15
We have prospectively followed-up a group of children
hospitalized for wheezing at <24 months of age.16–18 As
published earlier the prevalence of asthma was 40.2% at
7.317 (median) and 39.5% at 12.318 (median) years of age.
For the present analysis, our hypothesis was that ICS
consumed during childhood may decrease BMD at school
age, and that the decrease may be dependent on treatment
time, age and dose. The aim of the present study was to
evaluate the association between the use of ICS during
childhood and the BMD at late school age.
MATERIAL AND METHODS
Study Design
During a 20-month surveillance period in 1992–
1993,16 100 children were hospitalized for wheezing
induced by respiratory infection at <24 months of age and
attended an intervention study. Fourteen children hospi-
talized for wheezing at same time, refused to attend the
intervention study. Children born prematurely or having
an underlying chronic lung or heart disease, were
excluded. Ninety-two children completed the 4-month
early intervention; 31 received inhaled budesonide and 61
either received disodium cromoglycate or were without
maintenance therapy.16 The budesonide dose was
1,000 mg per day for 8 weeks and 500 mg per day for a
further 8 weeks.16 Eighty-one children attended the
clinical control visit at 7.317 (median) and 12.318
(median) years of age. Fourteen children not participating
in the intervention study were invited to attend the
12 years follow-up visit. All parents of the participants
completed the questionnaire and were interviewed as part
of the clinical study. Medical records of the hospital and
health care centers were available for collecting the
records of ICS doses used, and the time periods of use,
throughout childhood. In all, 95 children attended the
follow-up visit, and among them, BMD was measured in
91 children. After excluding 2 children using cortico-
ABBREVIATIONS:
ICS inhaled corticosteroids
DXA dual-energy X-ray absorptiometry
BMD bone mineral density
BMDareal areal bone mineral density (g/cm2)
aBMDvol apparent volumetric bone mineral density (g/cm3)
BMI-SDS body mass index standard deviation score
CI confidence interval
Pediatric Pulmonology
steroids for juvenile arthritis, 89 children formed the final
study group.
Weight and height were measured using standard
methods, and the body mass index standard deviation
score (BMI-SDS) was assessed using an obesity calcula-
tor (NIBHI 2007).19 The cut-off point of >1.3 SD
(corresponding to a BMI of 25.0 at age 18 years) was used
to define overweight and that of >2.0 SD (corresponding
to a BMI of 30.0 at age 18 years) to define obesity.20
Pubertal stage was assessed using the Tanner classifica-
tion21,22; stages M/G1-2 were regarded as pre-pubertal/
early pubertal and stages M/G3-5 as pubertal. Two boys
refused the pubertal stage examination, and they were
excluded from the analyses adjusted for puberty.
Data on vitamin-D consumption or physical activity
were not systemically collected, but at that time, vitamin
D supplementation was not recommended for school-
aged children. Two children had an allergy to cow’s milk,
and they were on regular calcium substitution.
Bone Mineral Density Measurement
DXA measurements were performed by trained nurses,
using the same scanner for all 89 children (Lunar
Radiation Corp., Madison, WI). Measurements were
obtained from the lumbar spine at the L2–4 level and from
the femoral neck region. Quality assurance tests using the
Lunar DPX scanner have shown an inter-assay variation
ranging between 0.08% (for lumbar spine) and 2.3% (for
femoral neck) in children.23 DXA measures the areal
BMD (BMDareal in g/cm2), which is dependent on bone
size.24,25 To minimize this error, we calculated apparent
volumetric BMD values (aBMDvol in g/cm3).24 Femoral
neck aBMDvol was calculated according to the equation:
aBMDvol ¼ BMD  [(4/p)  (height for measurement
area/measurement area for femoral neck)], and lumbar
spine aBMDvol according to the equation: aBMDvol ¼
BMD  [4/(p  width of measurement area in lumbar
spine).23 Finnish and international reference values are
available for both BMDareal and aBMDvol, expressed as Z-
scores.23,26 However, there are no specific cut-off points
in the Z-scores for an increased risk of clinical
manifestations such as fractures. We thus decided to
use both BMDareal and aBMDvol as continuous variables
with no need for reference-based classifications.
Corticosteroid Consumption History
As described previously,16 none of the children had
been treated for asthma before hospitalization for
wheezing at age <24 months in 1992–1993, and 31
children received budesonide for 16 weeks immediately
after hospitalization and completed an early intervention
study. Thereafter, ICS were prescribed when required on
clinical grounds. Data on asthma medication were
collected in 2004 by interviewing the parents using

structured questionnaires. The data were supplemented
by information collected from the medical records at the
hospital and health-care centres. Since the children
attended a prospective follow-up study, patient card
data on ICS-use were available in all cases. The data
collected on corticosteroid treatment were as follows:
continuous and intermittent ICS (daily doses and
treatment times in months/weeks); and on-demand
emergency treatments with oral or parenteral cortico-
steroids (daily doses and treatment times in days).
Fluticasone propionate doses were transformed to
budesonide equivalents by multiplying the dose by two.
Doses of beclomethasone propionate were not trans-
formed. The total cumulative doses and the duration of
ICS-use were calculated separately in two age groups: 0–
6 years and 6–12.3 (median) years. Use of ICS for
6 months or longer during the 6-year period was defined
as regular use. Six months has been a common time for
evaluating the effect of ICS to BMD in short-term trials.27
The cumulative doses of systemic corticosteroids (in-
cluding intravenous, intramuscular and oral administra-
tion) were calculated for the whole follow-up period and
divided into four categories using 10th, 50th, and 90th
percentiles as cut-off points.
Statistics
The data were analysed using SPSS 17.0 software
(SPSS Inc., Chicago, IL). Student’s t-test was used for
continuous variables in univariate analyses, and analysis
of variance (ANOVA) in multivariate analyses, with
adjustments for systemic corticosteroids, age, gender,
BMI-SDS and pubertal stage. Height was also included in
the model when BMDareal was the outcome. The results
are expressed as means and 95% confidence intervals
(95% CI). Pearson’s correlation coefficients (r, r2) were
used for correlations.
TABLE 1— The Association Between Bone Mineral Density, Gender and Pubertal Stage at the Median Age of 12.3 Years in 89
Children After Early Childhood Wheezing
Gender
Bone mineral density (mean, 95% CI)3 Female, N ¼ 24
BMDareal1
Lumbar spine L2–4 0.95 (0.88–1.02)

Femoral neck 0.91 (0.84–0.98)
aBMDvol2
Lumbar spine L2–4 0.33 (0.31–0.35)

Femoral neck 0.41 (0.39–0.44)
1
Areal BMD (g/cm2) measured by dual energy X-ray absorptiometry (DXA).
2
Apparent volumetric BMD(g/cm3) calculated from DXA measurements.
3
95% Confidence interval.
4
Tanner stage M1–2 and G1–2 as pre- and early pubertal, M3–5 and G3–5 pubertal.


Two independent samples t-test P < 0.05, between males and females or pre-/early pubertal and pubertal children.
Inhaled Steroids and Bone Density 3
Ethics
The study was approved by the joint Research Ethics
Committee of Kuopio University and Kuopio University
Hospital. Informed written consent was obtained from the
parents of the children, including the approval of the use
of the charts of the hospital and health care centres.
RESULTS
The study group comprised 65 boys and 24 girls.
Thirty-three (37.1%) were overweight with a BMI-SDS
>1.3 SD and 21 (23.6%) were obese with a BMI-SDS
>2.0 SD. Fifteen (23.1%) boys and 9 (37.5%) girls were
at puberty (M/G3-5). In the lumbar spine, BMDareal and
aBMDvol were lower in boys than in girls and lower in pre-
pubertal than in pubertal children (Table 1). In the femoral
neck, BMDareal was lower in pre-pubertal children than in
pubertal children (Table 1).
There were no statistically significant differences
between the BMD of obese, overweight and normal
weight (BMI-SDS < 1.3) children (data not shown). The
mean cumulative dose of systemic corticosteroids during
the follow-up period was 161 mg. Systemic cortico-
steroids were analysed as continuous and categorized
parameters (at the 10th, 50th, and 90th percentiles) and
had no significant association with BMD (data not
shown).
The mean cumulative dose of ICS expressed as
budesonide equivalents during the whole follow-up
period was 517 mg (SD 424, range 31–1,813) in those
68 children who have received ICS medication. Twenty
one of the children did not receive any ICS medication
during the follow-up. There was a significant association
between increasing cumulative ICS dose and decreasing
BMDareal (adjusted P ¼ 0.000) and decreasing aBMDvol
(adjusted P ¼ 0.006) in the femoral neck. However, the
correlation was weak: for BMDareal r ¼ 0.32, r2 ¼ 0.10,
Pubertal stage
Pre- and early pubertal4,
Male, N ¼ 65 N ¼ 63 Pubertal,4 N ¼ 24
0.83 (0.80–0.85) 0.82 (0.80–0.85)
0.97 (0.91–1.03)
0.91 (0.89–0.94) 0.88 (0.86–0.91)
1.00 (0.95–1.06)
0.29 (0.28–0.30) 0.29 (0.28–0.30)
0.32 (0.30–0.34)
0.39 (0.38–0.41) 0.40 (0.38–0.41) 0.42 (0.39–0.44)
Pediatric Pulmonology
4 Sidoroff et al.

and for aBMDvol r ¼ 0.28, r2 ¼ 0.08 (Fig. 1A and B).

There was no association between the cumulative ICS
dose and BMD in the lumbar spine (Fig. 2A and B).
Both BMDareal and aBMDvol in lumbar spine were
significantly lower in the 12 children who had used
regular ICS medication only at <6 years of age than in
those 21 who had never used ICS (Table 2). The findings
were robust to adjustments for age, gender, pubertal
stage, weight status and the use of systemic cortico-
steroids, and in the case of BMDareal for the additional
adjustment for height. In the femoral neck, the findings
were similar but statistically significant only for
aBMDvol (Table 2). Twelve children had used ICS
regularly between 6.0 and 12.3 years of age, and there
was no significant association with BMD at age 12.3
years (Table 2).

Fig. 2. The distributions of areal BMD values (g/cm2) (A) and

apparent volumetric BMD values (g/cm3) (B) in the lumbar spine
at the median age of 12.3 years of age in relation to the
cumulative dose of inhaled corticosteroids (ICS) used between 0
and 12.3 years of age. (A) Pearson’s correlation coefficient,
r (r2) ¼ 0.173 (0.03); analysis of variance, adjusted P ¼ 0.076. (B)
Pearson’s correlation coefficient, r (r2) ¼ 0.032 (0.001); analysis
of variance, adjusted P ¼ 0.418.

Fig. 1. The distributions of areal BMD values (g/cm2) (A) and
apparent volumetric BMD values (g/cm3) (B) in the femoral neck
at the median age of 12.3 years of age in relation to the
cumulative dose of inhaled corticosteroids (ICS) used between 0
and 12.3 years of age. (A) Pearson’s correlation coefficient,
r (r2) ¼ 0.315 (0.10); analysis of variance, adjusted P ¼ 0.000. (B)
Pearson’s correlation coefficient, r (r2) ¼ 0.282 (0.08); analysis
of variance, adjusted P ¼ 0.006.
Pediatric Pulmonology
DISCUSSION
The results reveal that the use of ICS medication during
childhood was associated with reduced BMD docu-
mented by DXA at the median age of 12.3 years in
children hospitalized for wheezing in infancy. High
cumulative ICS doses were associated with reduced BMD
in the femoral neck. Reduced BMD emerged in the
lumbar spine when ICS were used for >6 months before
6 years of age. The results were robust to adjustments for
known confounding factors, such as age, gender, pubertal
stage, height and weight status, and the use of systemic
corticosteroids. However, no definitive conclusions can
be drawn regarding the clinical impact of the findings.
On the other hand, the clinical complications associated
with decreased BMD in childhood may not arise until
adulthood.

TABLE 2— Bone Mineral Density at the Median Age of 12.3 Years in Children Who Had Regularily Used Inhaled
Corticosteroids (ICS) Before School Age and at School Age, Compared to Children Who Had Never Used ICSs
BMDareal1 (mean, 95% CI)3
Regular use of ICS Lumbar spine
during childhood4 L2–4 P-value4 Femoral neck
Only at 0–6 years
of age
N ¼ 12 0.81 (0.74–0.90) 0.010 0.91 (0.83–1.00)
Only at 6–12.3 years
of age
N ¼ 12 0.88 (0.77–0.99) 0.514 0.96 (0.86–1.05)
No ICS use during
the 12.3 years
follow-up
N ¼ 21 0.85 (0.82–0.93) 0.94 (0.90–0.98)
1
BMD measured by dual energy X-ray absorptiometry (DXA), apparent volumetric BMD calculated.
2
Regular use; over 6 months use of ICS during the 6-year age period.
3
95% Confidence interval.
4
The analysis of variance adjusted for the cumulative dose of systemic corticosteroids (mg) classified with cut-off points at the 10th, 50th, and
90th percentiles), gender, pubertal stage (Tanner stage M1–2 and G1–2 as pre- and early pubertal, M3–5 and G3–5 pubertal), age and weight as
BMI-SDS (normal, overweight, obesity). Height (cm) was included in the model for analysis of areal BMD.
Preliminary evidence indicated that the critical age for
the emergence of reduced BMD may be between 0 and
6 years, seen more prominently in the lumbar spine. The
lumbar spine consists mainly of trabecular bone that has a
rapid turnover, and the femoral neck consists mainly of
cortical bone that has a slower turnover; in addition,
trabecular bone is more susceptible to hormonal and
metabolic effects.25 Most previous studies of children
have focused on the lumbar spine or whole body BMD,
thus mainly reflecting the effects on trabecular bone.3,9,12
Earlier long-term studies have not revealed any
significant differences in areal BMD between children
treated and not treated with ICS.3,9,12 In the CAMP study,
1,041 children aged 5–12 years with mild to moderate
asthma were randomized to receive budesonide 200 mg,
nedocromil or a placebo twice a day.12 Lumbar spine
BMD was measured recurrently with DXA, and annual
bone mineral accretion was calculated. The use of ICS
had no detrimental effect on the mineral accretion in girls
during a follow-up of 4–7 years. However, the cumulative
ICS dose was associated with decreased bone mineral
accretion in boys.12 Oral corticosteroids were allowed
when necessary and produced a dose-dependent reduction
in bone mineral accretion in boys but not in girls.12 In a
Danish study, 157 asthmatic children with and 111
without ICS were monitored for 3–6 years. Total body
BMD was measured by DXA, and no significant
differences were observed in BMD, bone mineral content,
or total body calcium between the groups.9 In a French
study, 174 children aged 6–14 years with persistent
asthma were randomized to receive or not to receive
inhaled fluticasone propionate.3 BMD was measured by
DXA in the lumbar spine and femoral neck at baseline and
Inhaled Steroids and Bone Density 5
2
aBMDvol1 (mean, 95% CI)3
Lumbar spine
P-value4 L2–4 P-value4 Femoral neck P-value4
0.059 0.27 (0.25–0.30) 0.006 0.38 (0.36–0.40) 0.031
0.784 0.31 (0.28–0.35) 0.454 0.42 (0.38–0.46) 0.886
0.30 (0.28–0.31) 0.41 (0.39–0.44)
at 12 and 24 months later, and no significant differences
were found between the groups.3
However, ICS therapy with an average daily dose of
670 mg for 9–20 months reduced BMD in pre-pubertal
children compared to controls in an Australian study,11
suggesting a potentially harmful role for regular treatment
with high ICS doses. Unfortunately, long-term follow-up
results were not available. The results are in line with the
observations of the present long-term study that high
cumulative ICS doses were associated with reduced BMD.
In the randomized, controlled, double-blind study from
Helsinki, Finland, including 136 children aged 5–10 years
with recently diagnosed asthma,28 the intervention was
budesonide 200 mg daily for 18 months or budesonide
200 mg daily as required or disodium cromoglycate daily
for 18 months. Areal BMD in the lumbar spine was
measured by DXA before and after intervention. Daily
treatment with budesonide, but not treatment on-demand,
reduced both BMD and height growth velocity when
compared with the group treated with daily disodium
cromoglycate. However, the findings were not robust to
adjustment for height. The authors concluded that changes
in BMD interact with changes in height, which means that
monitoring children’s heights gives an approximation of
the effects of ICS on bone.28 The most recent cross-
sectional study including retrospective follow-up time did
not find a difference in lumbar BMD in pre-pubertal
children using intermitted fluticasone with 200 mg mean
daily dose for 5 years compared with newly diagnosed
asthmatic children with no history of ICS medication.29
Due to the long follow-up time, the median cumulative
ICS dose in the present study was higher than in two
previous French and Finnish studies.3,28 In the CAMP
Pediatric Pulmonology
6 Sidoroff et al.
study, Danish study and recent Turkish study the ICS dose
was higher than the median dose of this study.9,12,29 The
high accrual dose up to 1,800 mg of ICS and long follow-
up time might be the reason for positive results in the
present study compared with other studies. In the early
years of the study, used ICS doses were higher than the
doses currently recommended for childhood asthma,
which might have influenced the results concerning ICS
use before school age.
DXA scanners, as used in the present and previous
studies, measure areal BMD (in g/cm2), and thus the size
of the bone influences the BMD values obtained; smaller
bones have a lower areal BMD than larger ones.
Calculated volumetric BMD values are similar in large
and small bones.30 The interaction between height and
BMD requires special attention in long-term follow-up
studies, since measured areal BMD increases with the
growth of the bones without any actual increase in
BMD.25 The calculation of volumetric BMD values has
been used to counteract this artificial increase in areal
BMD values. In the present study, aBMDvol confirmed the
changes in femoral neck associated with ICS-use in early
childhood.
The main strengths of the present study are the long
prospective follow-up time from infancy to school age
and a high participation rate. Though data on the use of
ICS were collected retrospectively, they were recorded
relatively accurately, due to participation in the prospec-
tive follow-up study. Age, gender and pubertal stage were
significant confounding factors, and the analyses were
adjusted for all of them and additionally for systemic
corticosteroids. However, bone age was not studied by
radiology, and since the Tanner classification is not
sufficiently exact in the estimation of pubertal stage in
growth studies, we were not able to evaluate the effects of
ICS on growth in height. In addition, physical activities
and diets were not systematically recorded, which is a
clear shortcoming of the study.
In conclusion, the use of ICS during childhood may
reduce the BMD measured at late school age. High
cumulative doses during childhood were associated with
changes in the femoral neck. There might be a critical
period for changes in the BMD, and this critical period
seems to be before 6 years of age. These preliminary
results emphasize the importance of using the lowest
possible ICS dose that maintains adequate asthma
control.
ACKNOWLEDGMENTS
Kuopio University Hospital, Kuopio, and North-
Karelia Central Hospital, Joensuu, Finland, The National
Graduation School of Clinical Investigations and Tam-
pere Tuberculosis Foundation are acknowledged for
financial support.
Pediatric Pulmonology
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