Review

Inhaled corticosteroids in children: eects on bone mineral

density and growth
Anne L Fuhlbrigge, H William Kelly

Potent, topically active corticosteroids with minimum systemic activity have fewer adverse eects than do systemic Lancet Respir Med 2014;
corticosteroids, and can control both asthma and allergic rhinitis when given in recommended doses. However, 2: 48796

study ndings show that children with asthma receiving budesonide and beclometasone dipropionate have Published Online
April 9, 2014
decreased linear growth, and that children who receive long-term inhaled corticosteroid therapy for asthma have
http://dx.doi.org/10.1016/
height decits 12 years after treatment initiation that persist into adulthood. The eects of inhaled corticosteroids S2213-2600(14)70024-4
on growth seem to be dependent on both dose and duration; the degree of systemic eects is dependent on Pulmonary and Critical Care,
pharmacokinetic properties (ie, absorption, distribution, and elimination), whereas the eective dose delivered is Department of Medicine,
dependent on the delivery system and potency of the molecule. The eects of corticosteroids on bone mineral Brigham and Womens
Hospital, Boston, MA, USA
density in children seem to be more amenable to intervention; long-term therapy with inhaled corticosteroid
(A L Fuhlbrigge MD); and
therapy is safer than frequent bursts of oral corticosteroids on bone mineral accretion in this regard. Importantly, Department of Pediatrics:
adequate nutrition (particularly sucient intake of calcium and vitamin D) should prevent or blunt the eects of Pediatrics/Pulmonary,
corticosteroids on bone mineral density. The potential adverse eects of inhaled corticosteroids need to be weighed University of New Mexico,
Albuquerque, NM, USA
against the large and well established benet of these drugs to control persistent asthma. To minimise any adverse
(Prof H W Kelly PharmD)
eects, treatment with inhaled corticosteroids should always aim to reach the lowest eective dose that gives the
Correspondence to:
patient good asthma control. Dr Anne L Fuhlbrigge, Pulmonary
and Critical Care, Department of
Introduction Inhaled corticosteroids and growth Medicine, Brigham and Womens
Hospital, Boston, MA 02115,
Continued use of systemic corticosteroids causes several Eects on growth
USA
adverse systemic eects, including growth reduction in The usual decrement in growth velocity after initiation afuhlbrigge@partners.org
children and decreased bone mineral density.1,2 Potent, of continuous-use inhaled corticosteroids ranges from
topically active corticosteroids with little systemic activity 0420 cm during 12 years of treatment.18 Findings
allow regular use to control both asthma and allergic from studies6,9 with 36 year follow-ups suggested that
rhinitis without substantial debilitating adverse eects the greatest reduction in growth velocity occurred
when used in low-to-medium doses. However, ndings within 6 months; growth velocity usually returned to
from studies in the early 1990s showed reduced linear that of children receiving placebo by 2 years, resulting
growth in children with asthma receiving recommended in greater decrements in height in the rst 2 years of
doses of budesonide and beclometasone dipropionate.3,4 therapy than in later years of therapy. Whether this
The US Food and Drug Administration subsequently temporary reduction in growth velocity would eventually
received further evidence of growth reduction from oral result in a permanent decrement in adult height was
and intranasal inhaled corticosteroids, and convened a
joint meeting between the Pulmonary Allergy Drugs
Advisory Committee and the Endocrine and Metabolic Key messages
Drugs Advisory Committee in 1998.5 After the meeting, The eects of inhaled corticosteroids on growth in children seem to be both dose and
the Food and Drug Administration identied that duration dependent, with the degree of systemic eects from topical corticosteroids
diminished growth was a class eect and established dependent on pharmacokinetic properties (ie, absorption, distribution, and
standardised warning labels about the potential growth elimination) and the eective dose delivered dependent on the delivery system and
eects from all oral and intranasal inhaled corticosteroids. potency of the molecule
Additionally, the agency determined that growth studies Long-term therapy with inhaled corticosteroids seems to be safer than frequent bursts
were an important signal for systemic safety and were of oral corticosteroids in terms of bone mineral accretion in children; adequate
more sensitive than were standard tests of hypothalamic nutrition (particularly sucient intake of calcium and vitamin D) could prevent or
pituitaryadrenal axis function. The Food and Drug blunt the eects on bone mineral accretion
Administration strongly encouraged all pharmaceutical The reductions in growth reported due to initiation of therapy with inhaled
manufacturers to include growth as part of clinical corticosteroids do not progress but persist into nal adult height
development programmes, and issued a guidance The potential adverse eects of inhaled corticosteroids must be weighed against the
outlining recommendations for such studies.5 As a result large and well established benet of these drugs to control persistent asthma; however,
of this recommendation, studies of growth in children to minimise any adverse eects, treatment with inhaled corticosteroids should always
for newly developed inhaled corticosteroids and new aim to achieve the lowest eective dose that keeps the patient in good asthma control
delivery systems for older drugs are in progress. Recent Consideration should be given to inhaled corticosteroid preparations that have
trials have provided new insights into the problem of demonstrated lesser eects on growth or combination therapy for children with more
growth suppression and decreased bone mineral density moderate to severe persistent asthma
from inhaled corticosteroids.

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 Review
not established by these study ndings, as shown by the
required standardised labelling of these drugs: The
long-term eects of this reduction in growth velocity
associated with [orally inhaled/intranasal] cortico-
steroids, including the impact on nal adult height, are
unknown.5 Investigators of most cross-sectional
retrospective cohort studies1014 in adults reported no
dierences in target heights between patients with
asthma who received inhaled corticosteroids as children
and age-matched and sex-matched controls (either
patients with asthma who had not received inhaled
corticosteroids, or controls without asthma). However,
ndings from one study10 showed a signicantly lower
dierence for adult height minus target height in adults
who received inhaled corticosteroids as children than
for those with asthma who had never received the drugs,
despite no dierences in mean adult height or height
standard-deviation scores.
The cross-sectional study ndings were lent support by
two important longitudinal studies.6,15 The Childhood
Asthma Management Program (CAMP) trial6 compared
budesonide, nedocromil, and placebo for 46 years in
1041 children aged 512 years with mild-to-moderate
persistent asthma; the investigators reported a mean
height decrement in the budesonide group of 13 cm at
2years and 12 cm at the end of the trial compared with
the placebo group. However, a standardised prediction
equation projected no dierences in nal adults heights
between the treatment groups. Agertoft and Pedersen15
reported no signicant dierence between actual adult
height and predicted adult height for 142 children who
received budesonide in variable daily doses (mean dose
427 g/day) for a mean of 92 years compared with
controls. In this open-label treatment study, only 15 of the
original controls not treated with inhaled corticosteroids
180 Budesonide
Placebo 12 11 12
p=0001 p=0004 p=0002
12
160 p=0004
Height (cm)
13
p<00001
140
03
p=050
120
Trial entry 2 years End of trial Adult 1 Adult 2 Adult 3
(n=729) (n=692) (n=668) (n=658) (n=693) (n=729)
Figure 1: Mean adjusted height* over time for the CAMP cohort18
Adult 1 refers to mean height at age older than 18 or 20 years, or height when growth at less than 1 cm/year. Adult 2
refers to Adult 1 supplemented by projected adult height based on bone age. Adult 3 refers to Adult 1 supplemented
by multiple imputation height. *Means adjusted for race or ethnic origin, sex, clinic, age, asthma duration and
severity, skin test reactivity, and height at trial entry.
488
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were available at adulthood, so the investigators recruited
51 healthy non-asthmatic siblings of the asthma cohort to
be controls. Thus, most evidence suggested that the
decrement in height reported in children did not aect
nal adult height.2,16 However, an additional 48-year
follow-up17 of the CAMP cohort showed a continued
signicant dierence in height of 09 cm between the
placebo and budesonide groups, despite all groups using
inhaled corticosteroids during 30% of the post-trial follow-
up. The CAMP cohort was then followed up for an
additional 8 years to a mean age of 249 years with the
same standardised stadiometer measurements 12 times
yearly.18 The investigators were able to obtain nal adult
heights in 906% of the original CAMP participants.
Adult heights in the budesonide group were 12 cm
shorter than in the placebo group, similar to the 12 cm
decrement at the end of the original trial (gure 1). This
analysis was the rst long-term follow-up of an initially
randomised treatment group into adulthood that allowed
an intention-to-treat analysis of the eect of continuous
inhaled corticosteroids in childhood on attainment of
adult height.
Formulation and devices
The systemic activity of topical corticosteroids, which
has been extensively reviewed elsewhere,1922 is depend-
ent on several factors: formulation (ie, suspension vs
solution) and pharmacokinetic properties (ie, absorption,
distribution, and elimination); constancy of dosing,
which is dependent on the delivery system or device (ie,
intrinsic airow resistance of the device, and the
dependence of drug release on the variability of
inspiratory airow); and the eective dose delivered,
which is dependent on the device or delivery system (eg,
pressurised metered-dose inhaler with or without a
spacer, breath-actuated metered-dose inhaler, dry-
powder inhaler, soft-mist inhaler, and nebulisers) and
potency of the molecule. Additionally, each of these
systems needs a dierent technique, and patients
preferences and ability to use devices correctly can
aect the dose delivered directly (through suboptimum
technique) or indirectly (through lack of adherence).
The initial trials showing growth reduction used
beclometasone dipropionate and budesonide, which
have 2040% and 11% oral bioavailability, respectively,
from the dose portion swallowed after admini-
stration.1922 Newer drugs (eg, uticasone propionate,
mometasone furoate, and ciclesonide) have sub-
stantially decreased oral bioavailability (1%) and
improved lipophilicity, promoting an improved
therapeutic index (therapeutic-to-systemic activity
ratio).1921 Direct comparisons of uticasone propionate
with budesonide or beclometasone dipropionate have
shown this improved therapeutic index; when given in
equally eective therapeutic doses, uticasone
propionate produced signicantly less growth
suppression than did budesonide or beclometasone
www.thelancet.com/respiratory Vol 2 June 2014
 Review

dipropionate.2326 It is important to note that all of these Doseresponse eects

studies used the dry-powder inhaler formulations for
these drugs, and the delivery system can have a
substantial eect on systemic activity and therapeutic
index.19,27 Both uticasone propionate and mometasone
furoate delivered by dry-powder inhaler have little to no
eect on growth in prepubertal children at doses of
100200 g/day (dose delivered),28,29 but both drugs
aect growth at higher doses (table). By contrast, both
beclometasone dipropionate and budesonide aect
growth both at the equally eective dose of 400 g/day
dry-powder inhaler and at much lower doses (table).3,69,30
Although ciclesonide was assessed at 40 g and 160 g
once daily for 1 year in children aged 585 years, neither
of these doses had a positive therapeutic eect, rendering
the data inconclusive.35 Additionally, intranasal cortico-
steroids, generally prescribed in low doses (which could
result in low systemic absorption), are associated with
small decreases in growth velocity (table).22,3134 Finally,
the events after drug deposition on the respiratory
epithelium, the eect of lungparticle interactions on
nal dose, and how cell-level mechanisms dier between
formulations are under investigation.36
Findings from clinical trials7,28,29 in which several doses
of a given inhaled corticosteroid were compared have
shown dose-dependent eects on growth, although
most trials did not assess more than one dose in
children (table) and of the trials that did assess more
than one dose, not all doses were shown to signicantly
aect growth.29 In the CAMP trial18 there were sucient
numbers of patients to analyse doseresponse; the
results showed a signicant daily doseresponse
association during the rst 2 years of treatment, with a
01 cm decrement in height for each 1 g/kg bodyweight
increase (p=0007). Visser and colleagues36,37 compared
the ecacy and safety of two dosing strategies for
uticasone propionate dry-powder inhaler (1000 g/day
initial dose tapered by half every 2 months until
100 g/day for the rest of the 2-year study period,
compared with 200 g/day for 2 years) in 55 children
aged 610 years with mild-to-moderate persistent
asthma. Signicant reductions in growth velocity of
roughly 40% and 30% were reported for the 1000 g/day
and 500 g/day periods, respectively. These ndings
suggest that if any inhaled corticosteroid is given in a

Drug, device, dose, Duration Age range of Number receiving Growth outcome compared
and comparator participants drug with control group
(years)
Tinkelman and colleagues Beclometasone dipropionate (CFC-MDI, 1 year 617 172 10 cm/year (p<0001), all boys;
(1993)3 400 g/day, ex-valve) vs theophylline 10 cm/year (p=0004),
prepubertal boys; 10 cm/year
(p=0015), pubertal boys
Verberne and colleagues Beclometasone dipropionate (DPI, 1 year 616 33 14 cm/year (p=0007)
(1997)8 400 g/day) vs salmeterol
Allen and colleagues Fluticasone propionate (DPI, 100 g/day 1 year 411 85 (100 g/day), 021 cm/year (NS), 100 g dose;
(1998)28 and 200 g/day) vs placebo 96 (200 g/day) 042 cm/year (NS), 200 g dose
Childhood Asthma Budesonide (DPI, 400 g/day) vs 46 years 512 311 13 cm at 2 years
Management Program placebo
Research Group (2000)6
Pauwels and colleagues Budesonide (DPI, 200 g/day and 3 years 517 1000 (510 years), 045 cm/year (p<00001),
(2003)9 400 g/day) vs placebo 640 (1117 years) 200 g dose; 040 cm/year
(p=0003), 400 g dose
Skoner and colleagues Mometasone furoate (DPI; 110 g/day, 1 year 49 48 (110 g/day), 01 cm/year (NS), 070 cm/year
(2011)29 220 g/day in morning, and 220 g/day 41 (220 g/day in (p=002), 064 cm/year (NS)
divided between morning and evening; morning),
dose contained) vs placebo 49 (220 g/day
divided between morning
and evening)
Martinez and colleagues Beclometasone dipropionate 1 year 618 63 11 cm/year (p<00001)
(2011)30 (100 g/day ex-valve) vs placebo
Skoner and colleagues Intranasal beclometasone dipropionate 1 year 69 90 09 cm/year (p<001)
(2000)31 (aqueous) 336 g/day vs placebo
Schenkel and colleagues Intranasal mometasone furoate 1 year 39 82 +04 cm/year (p<005)
(2000)32 100 g/day vs placebo
Sano-Aventis Intranasal triamcinolone acetonide 1 year 39 267 045 cm/year (p<001)
201333 (aqueous) 110 g/day vs placebo
GlaxoSmithKline Intranasal uticasone furoate 1 year 585 474 027 cm/year
201234 110 g/day* vs placebo (95% CI 048 to 006)

Ex-valve refers to the dose released from the MDI valve. CFC=chlorouorocarbon-propelled. MDI=metered-dose inhaler. DPI=dry-powder inhaler. NS=non-signicant.
*Exceeds the recommended starting dose of 55 g/day.

Table: Growth eects of inhaled corticosteroids in randomised controlled clinical trials of 12 months duration or longer

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 Review
Glucocorticoid eects on growth and BMD
Linear growth Bone mineralisation
Growth hormone pulsatile secretion Sex hormone secretion
Growth hormone receptor expression Vitamin-D-associated
IGF-1 bioactivity calcium absorption
Adrenal androgen production Renal calcium reabsorption
Bone formation/osteocalcin
Growth suppression Bone resorption
Parathyroid hormone
Decreased bone mineral density
Osteoporosis
Figure 2: Eects of corticosteroids on growth and bone mineral density
BMD=bone mineral density.
suciently high dose, growth velocity will be reduced.
However, after patients in the high-initial-dose group
were tapered to 100 g/day, their growth velocity
rebounded and was signicantly higher than that of the
200 g/day group; no dierence in gain in standing
height between the two groups was reported at 2 years.37
This nding suggests that duration of decrease in
growth velocity is an important factor aecting
decrement in height. In the CAMP trial,6 the decrease
in velocity was present for roughly 2 years before
returning to the values of the patients receiving placebo.
In a 3-year early-intervention trial of budesonide in
more than 3000 children aged 517 years with mild
asthma, growth velocity was decreased in the treatment
group across all three years, but to a lesser extent
during the third year compared with the rst two years.9
Findings from a 7-month study38 of beclometasone
dipropionate 400 g/day in children aged 79 years
showed a decrement in height compared with placebo
and no catch-up growth in a 4-month washout after
treatment (table). Thus, although 4 months of sucient
doses to reduce growth velocity did not produce a
decrement in height, 7 months of treatment did.
Age and pubertal status
Baseline growth velocities in children are highly
dependent on age and pubertal status in addition to
genetics and nutrition. Normal growth consists of three
phases, the rst at age 02 years of mainly nutrition-
dependent growth, and a second phase (beginning in
the rst to second year of life and extending throughout
the rst decade) mainly dependent on growth hormone
490
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but is also dependent on nutritional status (gure 2).39
The last phase is the pubertal growth spurt that begins
roughly at the end of the rst decade, but can be quite
variable; this stage is dependent on stimulation of
growth-hormone secretion by sex hormones.2,39 The last
phase generally begins at a younger age in girls and
results in a steeper increase in growth velocity, whereas
in boys starts later and has a less steep increase but
longer duration. In the rst phase growth velocity
sharply decreases, but in the second phase growth
velocity steadily but slowly falls until puberty.2 Fairly
constant growth in the second phase is why guidance
from the US Food and Drug Administration5
recommends that growth studies are done for inhaled
corticosteroids in prepubertal children aged 411 years
to avoid the variability associated with the pubertal
growth spurt. As a result, few studies with suciently
large numbers of patients have assessed the eect of
inhaled corticosteroids on pubertal children. Addition-
ally, several studies that did include older children did
not provide Tanner staging, and adolescents are often
included in trials with adults in which growth is not
evaluated.4,16
Findings from early studies8,40 suggested that the
growth of children in their pubertal growth spurt might
not be suppressed by inhaled corticosteroids, although
these studies included 20 or fewer pubertal children. In
one of the few trials assessing pubertal status,
Tinkelman and colleagues3 reported the same mean
decrement in annual growth velocity in all boys
(10 cm/year, p<0001), prepubertal boys (10 cm/year,
p=0004), and pubertal boys (10 cm/year, p=0015)
receiving beclometasone dipropionate 400 g/day ex-
valve (ie, the dose released from the metered-dose inhaler
valve). Overall, the girls in the study did not have
signicant reductions in growth velocity (03 cm/year
for all girls, 04 cm/year for pubertal girls), but, similar
to the CAMP trial ndings, the eects of treatment on
growth did not dier signicantly by sex in regression
models, suggesting no substantial sex eect.3,18 Although
the CAMP trial ndings showed that the decrement
occurred mainly in prepubertal children, the eect was
not exclusive to them because the interaction for the age
at entry was non-signicant (19 cm for entry at
58 years vs 05 cm for entry at 913 years, p=012).13
Additionally, the interaction of Tanner stage at
enrolment into the trial was not signicant (Tanner
stage 1 vs Tanner stage 25, p=086).6 The dierence in
magnitude of eect is probably due to the confounding
of age and pubertal status to size and the known dose
response eect. This suggestion is supported by data
from a very large early-intervention trial9 which included
children aged 510 years who received budesonide
200 g/day, whereas those aged 1117 years old received
400 g/day. No signicant dierence in growth velocity
during the 3 years of treatment was recorded between the
younger group (045 cm/year, 95% CI 056 to 034)
www.thelancet.com/respiratory Vol 2 June 2014

and the older group (040 cm/year, 95% CI
066 to 014). Therefore, increasing the dose to
achieve similar weight-based doses achieves similar
reductions in growth velocity. A trial30 of low-dose
ultrane-particle beclometasone dipropionate stratied
enrolment to ensure balance between children aged
611 years and 1218 years (table); mean age of
participants was 105 years, and no dierence in growth
suppression between the two age groups was reported.
Infants and children aged 14 years present another
challenge; inhaled corticosteroids are dicult to
administer and the need for continuous treatment can be
dicult to establish. However, various guidelines
recommend regular therapy with inhaled corticosteroids
for patients who meet specic criteria (eg, two or more
exacerbations in 6 months or four or more wheezing
episodes in a year, and a positive asthma predictive
index).16 In a placebo-controlled 2-year trial of asthma
prevention in children aged 23 years with a positive
asthma predictive index, uticasone propionate 176 g/day
ex-actuator (ie, the dose delivered from the mouthpiece;
equivalent to 200 g/day ex-valve) was given by chloro-
uorocarbon-propelled metered-dose inhaler with a valved
holding chamber and facemask (Aerochamber, Monaghan
Medical, Plattsburgh, NY, USA).41 Participants in the
treatment group were 17 cm shorter than were those in
the placebo group after 2 years of treatment (p<0001),
and 07 cm shorter after a 1-year washout follow-up
(p=0008). A follow-up report of 204 participants from the
original cohort of 285 showed a non-signicant 02
cm dierence (95% CI 11 to 06) between the treatment
and placebo groups, except for a subgroup of children
aged 2 years and weighing less than 15 kg at enrolment
(16 cm, 95% CI 28 to 04, p=0009).42 However,
whether this dierence was dose related was not clear,
because older children weighing less than 15 kg at
enrolment did not have this dierence in height. The
dose used in this study was based partly on ndings from
two previous studies in infants aged 1247 months, which
showed improved ecacy for 200 g/day ex-valve of
uticasone propionate given with a valved holding
chamber plus facemask (Babyhaler, GlaxoSmithKline,
Stevenage, UK) without a signicant eect on growth at
1-year follow-up compared with sodium cromoglycate.43,44
The disparate eects on growth reported in these studies
are probably due to dose dierences; ndings from a
pharmacokinetic and bioavailability study45 comparing
delivery of uticasone propionate by Aerochamber and
Babyhaler in infants aged 13 years showed that the
Aerochamber delivered a two times higher dose than
did the Babyhaler.45 These dierences in delivery of
inhaled corticosteroids in infants might be even larger
with the use of antistatic valved holding chambers; a
recent study showed signicantly increased steady-state
concentrations of uticasone propionate for use with an
antistatic Aerochamber with facemask compared with
labelling claims.46
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Review
Daily versus intermittent use of inhaled corticosteroids
Two studies47,48 assessed the use of intermittent high-
dose inhaled corticosteroids for infants who had a
history of severe exacerbations needing oral
corticosteroids associated with upper-respiratory-tract
infections but were asymptomatic between episodes.
The rst47 compared very-high-dose uticasone
propionate (750 g twice daily given by metered-dose
inhaler and Aerochamber) with placebo at the start of
respiratory illness for up to 10 days in children aged
16 years. Although this therapy decreased oral
corticosteroid use by 50%, high-dose uticasone
propionate was associated with signicantly reduced
height and weight gain compared with placebo after a
median follow-up of 40 weeks. The second trial48
assessed the use of nebulised budesonide (05 mg daily)
compared with intermittent budesonide (1 mg twice
daily for 7 days) at the start of a respiratory illness
usually associated with exacerbations in children aged
1253 months with a positive modied asthma
predictive index. At the end of the 1-year trial, no
dierence was recorded in the rate of asthma
exacerbation (as dened by use of oral corticosteroids)
or in linear growth. Although 2 mg/day of budesonide
is a high dose, nebulisers deliver only 8% of the nominal
dose, whereas the use of uticasone propionate with an
Aerochamber can deliver 22% of the nominal dose to an
infants mouth.19,49 In view of the two-to-four times
increased potency of uticasone propionate, a sub-
stantially larger dose of inhaled corticosteroid was used
in the rst study than in the second.19,47,48 Whether the
decrease in growth for infants receiving inhaled
corticosteroids aects adult height is unknown, but
ndings from this 2-year trial with 2-year follow-up
provide some reassurance that many of these young
children are able to catch up.42
Asthma and allergies
Asthma and allergies can reduce growth in children.5053
Findings from the CAMP study18 showed that atopic status
and increased duration of asthma before enrolment were
independent risk factors for decreased adult height. The
decrease in growth associated with asthma had been
associated with a delay in bone maturation similar to that
reported with inhaled corticosteroid therapy, and was not
thought to aect nal adult height.2,53 However, the CAMP
data suggested that this decrement could persist into
adulthood. Because most studies into the eect of inhaled
corticosteroids are done in patients with mild disease to
isolate the eect to the inhaled corticosteroid, whether
control of more moderate-to-severe disease could
counterbalance the adverse eect of disease severity on
growth is not clear. Findings from some early studies2,4 in
small numbers of patients with severe disease suggest
this counterbalancing might occur. Thus, clinicians must
weigh the risks and benets of inhaled corticosteroids to
treat infants and children with asthma and allergic
491
 Review
rhinitis. More studies evaluating appropriate dosing of
inhaled corticosteroids and dierences in growth in this
population are warranted.
Inhaled corticosteroids and bone mineral density
Eects on bone mineral density
High-dose inhaled corticosteroids and oral corticosteroids
have been associated with decreased bone mineral density,
osteoporosis, and a dose-dependent increased risk of
fracture in adult patients with other high-risk factors.5456
Additionally, ndings from a large case-control study57 of
children aged 417 years suggested an increased risk of
fracture associated with 4 or more courses of oral
corticosteroids per year, although residual confounding by
severity of illness could not be excluded. However,
ndings from previous cross-sectional studies5862 in
children with asthma showed no negative eect of inhaled
corticosteroids on bone mineral density. Similarly, no
dierences in bone mineral density between patients
treated with inhaled corticosteroids and those given
placebo, and no dierences in risk of osteoporosis or time
to rst fracture between patients treated with inhaled
corticosteroids and those not treated, have been shown in
prospective cohort studies and randomised trials in
paediatric populations.6,6365 However, all four studies used
low-to-medium doses of inhaled corticosteroids; the eect
of high doses on bone health in children has not been
adequately studied.
The cumulative eect of both inhaled and oral doses of
corticosteroids for acute exacerbations on mean bone
mineral accretion was studied in the CAMP cohort.66 Bone
mineral density was measured by dual-energy x-ray
absorptiometry scans of the lumbar spine at baseline and
at least one follow-up at a median duration of 7 years from
877 children (93% of participants). A signicant dose-
dependent eect was reported for oral corticosteroid bursts
on bone mineral accretion with an associated increased
risk of osteopenia in boys but not girls. Although a small
reduction of bone mineral accretion from inhaled
corticosteroid use in boys was reported, no increased risk
of osteopenia was noted. Findings from a recent follow-
up67 to this study showed that the dose-dependent eect of
oral corticosteroids on decreased bone mineral
accretion was modied by serum concentrations of
25-hydroxyvitamin D; only patients with insucient
vitamin D concentrations (7488 nmol/L) had decreased
bone mineral accretion with increased use of oral
corticosteroids. This nding suggests that vitamin D, in
addition to reducing the risk of severe exacerbations (ie,
those needing courses of prednisone), could also prevent
mineral resorption from the bone due to oral corticosteroids
when used in the treatment of asthma.
By contrast, secondary analysis68 of the Helsinki Early
Intervention Childhood Asthma Study suggested that
daily budesonide treatment in prepubertal children could
aect bone mineral density. In a double-blind randomised
study,68 children were randomly assigned to one of three
492
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treatment groups: medium-dose budesonide (800 g/day
for 1 month and 400 g/day for 5 months) followed by
low-dose budesonide (200 g/day); the same medium-
dose budesonide regimen followed by placebo; or sodium
cromoglycate. Asthma exacerbations were treated with
budesonide for 2 weeks at a dose of 400 g twice daily in
all groups. Bone mineral density increased in all treatment
groups during the 18-month study. However, the regular
use of budesonide resulted in a statistically signicantly
smaller increment in bone mineral density (calculated as
g/cm and Z score) than did use of sodium cromoglycate
at the end of the study. Periodic treatment did not aect
bone mineral density; the increase in bone mineral
density (calculated as g/cm) in the group receiving only
intermittent budesonide after the rst 6 months did not
dier signicantly from that of the other two groups.
The reason for the dierence in ndings between the
CAMP and Helsinki studies is not clear.68 Data suggest the
eect of inhaled corticosteroids is more profound during
the rst 612 months of treatment. The investigators of
the Helsinki cohort initiated treatment with a higher dose
of budesonide than did those of the CAMP cohort, but
only for the rst month of therapy. The Helsinki trial
ndings are also inconsistent with the results of a similar
2-year trial37 with uticasone propionate in 55 children
aged 610 years. Participants received uticasone
propionate that was reduced every 2 months from an
initial high dose (initially 1000 g/day, then 500 g/day,
200 g/day, and nally 100 g/day for the remainder of
the study), whereas controls received a low dose
(200 g/day) for the entire study. Despite signicant
reductions in growth velocity during the rst 4 months in
the high-dose group, no dierences in Z scores for bone
mineral density were recorded at 1 year or 2 years.
Age and dose eects
An important concern about the eect of inhaled
corticosteroids on bone mineral density is whether
decreases in bone mineral accretion during childhood
lead to reduced peak bone mass in adulthood. Reduced
peak bone mass could place patients at risk for
osteoporosis and fractures later in life. Bone mineral
accretion in childhood is triphasic, similar to growth; it is
rapid in the rst 3 years of life, then slows, but rapidly
increases during puberty where 50% of adult bone
mineral is accumulated.39 However, despite similar
patterns of change in accretion and growth, the
mechanisms dier substantially. Nutrition is an important
factor for both growth and bone metabolism, particularly
adequate absorption of vitamin D and calcium for bone
metabolism (gure 2).39 Weight-bearing exercise also has
a substantial eect on bone mineral accretion in
childhood.68 Corticosteroids aect bone mineral density
through several mechanisms, including decreased
calcium absorption and bone formation, increased bone
resorption, and decreased secretion of sex hormones; that
dierent corticosteroids do not present similar
www.thelancet.com/respiratory Vol 2 June 2014

characteristics clinically (eg, greater eect of intermittent
oral corticosteroids on bone mineral density and greater
eect of continuous inhaled corticosteroids on growth) is
not surprising.22,39 Additionally, transient changes in bone
mineral density during childhood might not persist into
adulthood.69 Gafni and Baron69 proposed that bone mass is
regulated by a homoeostatic system that returns to a set
point after any perturbation, and that bone mass depends
mainly on recent conditions, not those in the distant past.
They reported that, in animals, bone mass acquisition in
early life had no eect on bone mass in adulthood.
Importantly, no increased risk of fractures has been
associated with use of inhaled corticosteroids. However,
the number of fractures recorded in any of the published
cohorts was small and probably insucient to accurately
assess this outcome. Additionally, investigators of
previous studies have documented that asthma and
allergies could have independent eects on growth and
bone health in children, complicating the interpretation
of studies that investigate the eects of treatment on
these outcomes. The dose of corticosteroids used is
associated with severity of asthma; separation of the
eect of increased severity of disease from the eect of
increased steroid use on bone health is dicult.
Asthma and level of control
Poorly controlled asthma can aect growth, and both
lung function and asthma control are correlated with
growth.15,7072 The routine use of low-to-medium doses of
inhaled corticosteroids is associated with decreased
asthma severity and risk of severe asthma exacerbations
needing oral corticosteroids. The combination of these
two eects means that further reduction in the risk of
corticosteroid-induced osteopenia can probably be
expected with long-term use of low-to-medium doses of
corticosteroids, which seems to be safer than frequent
bursts of oral corticosteroids in terms of bone mineral
accretion in children. Importantly, to minimise any
adverse eects, treatment with inhaled corticosteroids
should always aim to achieve the lowest eective dose
that gives patients good asthma control.
Conclusions
New evidence reported in the past 7 years increased
knowledge about the benet-to-risk ratio for use of long-
term inhaled corticosteroids in children with asthma and
rhinitis, particularly the risks of growth suppression and
decreased bone mineral density. Each of these risks is
mediated by dierent mechanisms and responds
dierently to corticosteroids. Long-term regular treatment
with inhaled corticosteroids has a greater eect on growth,
whereas bone mineral density seems to be more sensitive
to several courses of systemic corticosteroids (so-called
bursts) for exacerbations. Therefore, dierent approaches
are needed to minimise each potential risk (panel).
If patients receive inhaled corticosteroids in suciently
high doses for 712 months and have a growth reduction,
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Review
Panel: Recommendations to mitigate the risks of corticosteroid therapy in children
with asthma
Children aged 5 years or older
Begin inhaled corticosteroids at lowest dose suggested by guidelines*
Use inhaled corticosteroids with higher therapeutic indexes (ie, uticasone propionate
[dry-powder inhaler], mometasone furoate, and ciclesonide)
Measure heights of children receiving inhaled corticosteroids every six months
Consider addition of long-acting -adrenoreceptor agonists instead of increased doses
of corticosteroids if asthma is uncontrolled on low-dose inhaled corticosteroids alone
Assess status of vitamin D in children with persistent asthma or several
exacerbations yearly
Encourage weight-bearing exercise
Children aged 14 years
Use low-dose budesonide given as solution for inhalation via a nebuliser or metered-
dose inhaler with spacer
Consider use of intermittent high-dose inhaled corticosteroids for infants with
intermittent asthma
*Beclometasone dipropionate (metered-dose inhaler) 80160 g/day; budesonide (dry-powder inhaler)
180360 g/day; budesonide respiratory solution capsules 500 g/day; ciclesonide 60160 g/day; uticasone
furoate (metered-dose inhaler) 160 g/day; uticasone propionate (metered-dose inhaler) 88176 g/day;
uticasone propionate (dry-powder inhaler) 100200 g/day; mometasone furoate (dry-powder inhaler)
110 g/day (dose contained).73
it will probably persist and aect nal adult height.
Methods to minimise this eect include use of the
lowest dose needed to control the patients asthma, and
if medium-to-high doses are needed consideration of
add-on therapy with long-acting bronchodilators and use
of inhaled corticosteroid preparations with a high
therapeutic index and few eects on growth. Guideline
recommendations suggest that that after control is
established, attempts should be made to reduce therapy
to minimise the risk of side-eects. Caudri and
colleagues74 reported that overtreatment of asthma is
common among children; up to 50% of children
receiving inhaled corticosteroids for at least 2 years did
not report any wheezing during the same 2-year interval.
In mild persistent asthma, use of inhaled corticosteroids
(either as needed with rescue bronchodilators or
intermittent use of high-dose inhaled corticosteroids)
for children aged 14 years with mainly intermittent
wheezing has been successful.30,48 The use of intermittent
inhaled corticosteroids has been recommended to
reduce therapy in patients with well-controlled mild
persistent disease.75 As summarised in a recent Cochrane
review,76 studies have been inconsistent about the eects
of therapy with intermittent inhaled corticosteroids in
children.76 The investigators reported increased ecacy
of daily use for control of the impairment domain but
noted mixed eects for prevention of exacerbations
needing oral corticosteroids. They concluded that the
clinician should carefully weigh the potential benets
and harm of each treatment option, taking into account
the unknown long-term (>1 year) impact of intermittent
therapy on lung growth and lung function decline.
493
 Review
Search strategy and selection criteria
The safety of inhaled corticosteroids in children was
extensively reviewed in 2006 by Pedersen.2 New studies have
been published which alter some of the conclusions of that
review, specically with regards to dose dependency,
pubertal status, and eect on nal adult height. We searched
PubMed for articles published between 2005 and 2013 with
the terms inhaled corticosteroids, glucocorticoids,
children, growth, and bone mineral density, and 5 US Department of Health and Human Services Food, Drug
reviewed all randomised, prospective, controlled trials
identied by this search. We identied additional articles
from our own les and references from Pederson (2006).2
We focused on studies of at least 6 months duration
because of the time course of eects on growth and
bone health.
Fortunately, the eects of corticosteroids on bone
mineral density seem to be easily aected and amenable
to intervention. Inhaled corticosteroids mainly increase
bone loss at high daily doses, so strategies to reduce
doses (eg, add-on therapy or use of inhaled corticosteroid
preparations with high therapeutic indices) should be
used. Long-term therapy with inhaled corticosteroids
seems to be safer than frequent oral corticosteroid
bursts in terms of bone mineral accretion in children.
Importantly, assurance of adequate nutrition, parti-
cularly sucient intake of calcium and vitamin D,
should prevent or blunt the response. In a study77 of
adults with adequate concentrations of vitamin D on
enrolment who received supplements containing
calcium and vitamin D throughout the trial, treatment
for up to 1 year with mometasone furoate (a drug with
an improved therapeutic index) had no detrimental
eects on bone mineral density. Finally, routine weight-
bearing exercise improves bone formation and might
mitigate the potential adverse eects of therapy.
Contributors
HWK and ALF both participated in the literature search, preparation of
gures, and writing of this Review.
Declaration of interests
HWK is a member of the steering committees for safety trials of long-
acting inhaled -2 agonist/inhaled corticosteroid combinations that were
mandated by the US Food and Drug Administration. These trials are to
assess the risk of death, intubations, and hospital admissions from
asthma associated with LABA use and whether inhaled corticosteroids
mitigate those risks and do not assess growth, bone mineral density, and
other inhaled corticosteroid adverse eects. He is compensated for his
time and eort by AstraZeneca, GlaxoSmithKline, Merck, and Novartis.
ALF has served as a consultant for the design and analysis of
epidemiological studies for Merck and GSK. She has served on a
respiratory specialist advisory panel for Merck and GSK and is a member
of the Joint Adjudication Committee for ICON Medical Imaging. She has
received funding from the Agency for Healthcare Research and Quality
and the National Institutes of Health. She has held two positions that
were uncompensated: cochair for the Asthma Exacerbations
subcommittee for the Asthma Outcomes Workshop sponsored by the
NHLBI, and member of the Respiratory Measurement Advisory Panel for
the AHRQ. She also serves on the Respiratory Measurement Advisory
Panel for the National Committee for Quality Assurance.
494
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