safety of the newer inhaled corticosteroids in childhood asthma
Post on 19-Mar-2017
222 Views
Preview:
TRANSCRIPT
Pediatr Drugs 2003; 5 (7): 481-504REVIEW ARTICLE 1174-5878/03/0007-0481/$30.00/0
© Adis Data Information BV 2003. All rights reserved.
Safety of the Newer Inhaled Corticosteroids inChildhood AsthmaTabitha L. Randell,1 Kim C. Donaghue,1,2 Geoffrey R. Ambler,1 Christopher T. Cowell,1,2
Dominic A. Fitzgerald2,3,4 and Peter P. Van Asperen2,3
1 Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
2 Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
3 Department of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
4 Division of Academic and General Medicine, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
1. Pathophysiology of Asthma and Pharmacokinetics of Inhaled Corticosteroids (ICS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
1.1 Pathophysiology of Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
1.2 Mechanism of Action of ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
1.3 Pharmacokinetics of ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
1.3.1 Oral Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
1.3.2 Mode of Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
1.3.3 Systemic Bioavailability of the Newer ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
1.3.4 Comparing ICS Systemic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
2. Potential Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
2.1 Topical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
2.1.1 Dysphonia and Oral Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
2.1.2 Dental Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
2.2 Adrenal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
2.2.1 Assessment of Adrenal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
2.2.2 Biochemical Suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
2.2.3 Clinical Adrenal Suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
2.2.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
2.3 Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
2.3.1 Normal Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
2.3.2 Effect of ICS and Asthma on Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
2.3.3 Short-Term Growth (Knemometry) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
2.3.4 Linear Growth (Intermediate and Long Term) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
2.3.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
2.4 Bones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
2.4.1 Normal Bone Mineralization and the Effect of ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
2.4.2 Assessing Bone Mineralization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
2.4.3 Effect of ICS on BMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
2.4.4 ICS and Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
2.4.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
482 Randell et al.
2.5 Cataracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Inhaled corticosteroids (ICS) remain a vital part of the management of persistent asthma, but concerns haveAbstractbeen raised about their potential adverse effects in children. This review examines the safety data on three new
ICS – fluticasone propionate, mometasone, and extrafine beclomethasone in hydrofluoroalkane (HFA-134a)
propellant (QVAR®1 formulation) in relation to the older corticosteroids.
Topical adverse effects such as thrush and dysphonia are rare, but dental erosion is a possibility with powder
forms of ICS because of their low pH. Thus, it is important to stress mouth rinsing after administration and
maintaining good dental hygiene to minimize this risk.
Biochemical adrenal suppression can be readily demonstrated, particularly with high doses of all ICS. The
clinical relevance of this was uncertain in the past, but there have now been >50 reported cases of acute adrenal
crises in children receiving ICS, most of whom were on fluticasone propionate. In order to minimize the risk of
symptomatic adrenal suppression, it is important to back-titrate the ICS dose and alert families of children
receiving high-dose ICS of this potential adverse effect. A pediatric endocrine opinion should be sought if
adrenal suppression is suspected. The older ICS cause temporary slowing of growth velocity, but the limited data
available do not show any significant compromise of final adult height. The effect on growth of fluticasone
propionate may not be as great as with the older ICS, but the studies have been short term and only used low
doses of fluticasone propionate. There have been case reports of growth suppression in children receiving high
doses of fluticasone propionate. The limited studies performed on the effect of ICS on bone mineral density in
children did not show any adverse effects, but there may be an increased risk of fractures.
Hydrofluoroalkane beclomethasone (QVAR) is essentially the same drug as chlorofluorocarbon beclometha-
sone, but with double the lung deposition owing to the smaller particle size. Thus, it could be expected that any
adverse effects seen with chlorofluorocarbon beclomethasone would be the same with hydrofluoroalkane
beclomethasone. However, some of the published data, particularly in adults, suggest that hydrofluoroalkane
beclomethasone may be less systemically active than chlorofluorocarbon beclomethasone, even at equipotent
doses. As yet, there are no long-term data on mometasone, but initial studies in adults suggest there may be less
suppression of the hypothalamic-pituitary-adrenal axis, although further studies are required, particularly in
children.
ICS will remain a cornerstone in the management of persistent pediatric asthma, provided that the diagnosis
of asthma is secure. It is very important to use ICS appropriately and to ensure the lowest possible doses are used
to achieve symptom control, thus minimizing the risk of serious adverse effects.
Inhaled corticosteroid (ICS) therapy has become the corner- safety, particularly when used in high doses.[5] The main concerns
in children have focused on suppression of the hypothalamic-pitui-stone of the preventive management of childhood asthma and is
tary-adrenal (HPA) axis, growth, and potential for decreased bonecurrently recommended as an alternative first-line preventive ther-
mineral density (BMD).apy in frequent episodic or mild persistent asthma, and first-line
therapy in moderate and severe persistent asthma, in children.[1-3] In the past 10 years, newer ICS such as fluticasone propionate,
The efficacy of ICS at controlling symptoms and maintaining mometasone, and extrafine beclomethasone in hydrofluoroalkane
good health in children with asthma is well proven,[4] but more (HFA-134a) propellant (QVAR® formulation, 3M Pharmaceuti-
recently there have been increasing concerns about their overall cals) have been introduced. Fluticasone propionate in particular
1 The use of tradenames is for product identification purposes only and does not imply endorsement.
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 483
was hailed as having fewer adverse effects than the previous inflammatory effects include increasing the expression of β2-adre-
generation of ICS.[6,7] Mometasone has mainly been used as an noceptors and increasing anti-inflammatory mediators such as
intranasal preparation, although it is now being prepared for IL-10 (inhibits transcription of inflammatory cytokines), and li-
licensing as an ICS for patients with asthma. Hydrofluoroalkane pocortin-1 (inhibits production of lipid mediators). They also
beclomethasone was introduced to replace the previously used decrease the transcription of inflammatory proteins such as TNF-
chlorofluorocarbon propellant, to alleviate environmental con- α, GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-6, IL-11, and chemokines.
cerns. Thus, mast cell and eosinophil numbers are decreased and T-
lymphocyte activity inhibited, plus mucus secretion is inhibited.[9]This review examines the safety data on these three new ICS in
relation to the older corticosteroids – beclomethasone with chloro-
fluorocarbon propellant, and budesonide. 1.3 Pharmacokinetics of ICS
1. Pathophysiology of Asthma andICS are designed to have a local, topical effect. Thus, the aim is
Pharmacokinetics of Inhaled Corticosteroids (ICS)to minimize potential systemic effects, such as suppression of the
HPA axis, adverse effects on growth, and decreased bone mineral-1.1 Pathophysiology of Asthma ization. Systemic bioavailability is related to both oral and pul-
monary absorption and subsequent metabolism of the compound.Asthma is now defined as a chronic inflammatory disorder of
the airways in which many cells and cellular elements play a role,1.3.1 Oral Absorption
particularly mast cells, eosinophils, T lymphocytes, macrophages,Most of the dose of ICS leaving an inhaler device (about 80%)
neutrophils, and epithelial cells.[1] This inflammatory response iswill be deposited in the oropharynx and then swallowed. The oral
mediated by numerous cytokines, including interleukins (IL),systemic bioavailability of the drug will then depend on the
granulocyte-macrophage colony-stimulating factor (GM-CSF), tu-amount that undergoes first-pass hepatic metabolism. The older
mor necrosis factor (TNF)-α, and growth factors.[8] This inflam-compounds such as chlorofluorocarbon beclomethasone and
mation leads to a susceptibility to recurrent episodes of variablebudesonide are said to undergo 80% and 89% first-pass metabol-
airway obstruction, characterized by contraction of the airwayism, respectively, when absorbed orally, still leaving a significant
smooth muscle, mucosal edema, and mucus hypersecretion. Theseamount of the drug to have a systemic effect (table I).[10] Beclo-
episodes are usually reversible, either spontaneously or withmethasone also undergoes biotransformation to its active metabo-
bronchodilator medication. The inflammation may also contributelite, 17-beclomethasone monopropionate, which undergoes first-
to the underlying bronchial hyper-responsiveness to a variety ofpass inactivation whether it enters via the gut or the lung.[11] In
stimuli, e.g. histamine, methacholine, and exercise. It is now alsofact, a recent study on the biovailability of beclomethasone in
clear that this inflammatory process can lead to airway fibrosis andhealthy volunteers,[12] demonstrated that unchanged beclometha-
remodeling, which results in irreversible airway obstruction.[8]
sone is not absorbed orally and that 17-beclomethasone monopro-Therefore, the rationale for ICS therapy is to reduce this airway
pionate accounts for all the oral bioavailability of the drug. Fur-inflammation by providing both symptom control and a reduction
thermore, the study demonstrated that the total systemic bioavaila-in bronchial hyper-responsiveness. This will hopefully also pre-
bility of 17-beclomethasone monopropionate from an inhaled dosevent permanent airway fibrosis and remodeling.
was 62%, with the lung and the gut thought to contribute 36% and
26%, respectively, to systemic exposure.[12] This may also explain1.2 Mechanism of Action of ICS
why the systemic bioactivity of hydrofluoroalkane beclometha-
Corticosteroids are thought to diffuse across the membrane into sone is comparable to chlorofluorocarbon beclomethasone, despite
cells and then bind to receptors in the cytoplasm.[9] Intracellularly, the greater lung deposition of the hydrofluoroalkane formulation
they act by increasing the transcription of anti-inflammatory genes (which relates to smaller particle size, as discussed in section
and decreasing the transcription of inflammatory genes. Cortico- 1.3.2).[11] In contrast, both fluticasone propionate and mometasone
steroids then act either directly on the primary cell or indirectly on have <1% oral bioavailability, meaning that the majority of sys-
a secondary cell by modifying the release of mediators. The anti- temic bioavailability is via pulmonary absorption.[11]
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
484 Randell et al.
Table I. Clinical pharmacology of inhaled corticosteroids[10-14]
Corticosteroid Recommended dosage range in Hepatic first-pass elimination Plasma half-life
children (μg/day) (%) (h)
Chlorofluorocarbon beclomethasone 100–500 80 6.5a
Hydrofluoroalkane beclomethasone 50–200 80 6.5a
Budesonide 100–500 89 2.3–2.8
Fluticasone propionate 50–200 >99 3.7–14.4
Mometasone 100–400b >99 4.45
a Beclomethasone is converted in vivo to beclomethasone monopropionate, which has a half-life of 6.5h.
b Not yet licensed.
1.3.2 Mode of Delivery recent study comparing chlorofluorocarbon beclomethasoneThe method of delivery will affect how much ICS is deposited 200–400 μg/day delivered via MDI + spacer with hydrofluoro-
in the lungs, compared with how much is ingested. There is alkane beclomethasone 100–200 μg/day via Autohaler® (smallerconsiderable variability in the amount of drug delivered to the particle size) in 300 children with asthma aged between 5 and 11lungs when different dry powder devices are used. Undoubtedly, years, showed similar efficacy, growth, and systemic safety over asome of this is attributable to the way in which a patient uses the 12-month period when one-half the dose of hydrofluoroalkanedevice, the current state of their asthma (ability to generate ade- beclomethasone compared with chlorofluorocarbon beclometha-quate inspiratory flow rates), and familiarity with the device. In a sone was used.[20]
study comparing fluticasone propionate with budesonide delivered Overall, when considering different ICS and delivery systems,via dry powder inhalers (DPIs), similar amounts of ICS reached it is important to be mindful of four factors that will significantlythe airways.[7] The choice of device, essentially between metered influence the efficacy of treatment:dose inhaler (MDI) + spacer and dry powder devices, is important
• the drugin children. The age of the child/adolescent and the individual’s
• the delivery deviceability to use a device will directly influence the likely adherence• the age of the patientwith therapy,[15,16] and may well be the predominant arbiter of drug
• the preference of the patient (for older children).effect. Generally speaking, an MDI + spacer is the preferred
delivery method for young children, switching to dry powder1.3.3 Systemic Bioavailability of the Newer ICSdelivery devices during the school years (table II).[3]
Interestingly, the amount of ICS or bronchodilator delivered to The systemic bioavailability of hydrofluoroalkane beclometha-
the lungs by MDI may be increased by as much as 50–100% when sone depends on both the oral deposition of beclomethasone (with
a spacer device is used.[17] Again, patient factors, as well as 80% first-pass metabolism) and its pulmonary deposition. How-
differences between devices, will influence this result. Moreover, ever, as highlighted previously, beclomethasone undergoes con-
the particle size of the delivered medication is also important in version to its active metabolite, 17-beclomethasone monopropion-
dose responsiveness. This is often described in terms of the ate, and beclomethasone itself contributes only about 2% to sys-
‘respirable dose’, derived from the proportion of smaller sized temic bioavailability through pulmonary absorption.[12] In
particles delivered to the distal airways.[18] Hydrofluoroalkane addition, the total systemic bioavailability of 17-beclomethasone
beclomethasone, which was introduced because of environmental monopropionate from an inhaled dose has been estimated to be
concerns of chlorofluorocarbons, is a solution which results in 62%, with the lung and the gut thought to contribute 36% and
smaller particle size. This has clinical correlates in that the smaller 26%, respectively, to systemic exposure.[12] This may help to
particle size in hydrofluoroalkane beclomethasone, compared with explain why there does not appear to be increased systemic ac-
its predecessor chlorofluorocarbon beclomethasone, will allow tivity with hydrofluoroalkane beclomethasone compared with
more drug to be deposited into the lung periphery, and presumably chlorofluorocarbon beclomethasone, despite the increased lung
allow for a reduced dose of ICS to maintain symptom control.[19] A deposition.[11]
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 485
In contrast, the other newer ICS, such fluticasone propionate in assessing the significance of studies comparing different ICS,
we have chosen to include comparative data, particularly for theand mometasone, have <1% bioavailability when taken orally as
newer ICS, where pediatric data is limited. At the same time wethey are eliminated by first-pass metabolism (fluticasone propion-
have attempted to point out the limitations of these studies, as wellate)[13] or minimally absorbed from the gut (mometasone).[14]
as highlight the need for further well-designed comparative studiesThus, the main determinant of systemic bioavailability is direct
in children.absorption from the lungs, where there is no first-pass inactivation.
Fluticasone propionate and mometasone are highly lipophilic and2. Potential Adverse Effectswill preferentially partition into the systemic tissue compartment.
At steady state, there is consequently a large volume of distribu-
tion, acting as a reservoir to be slowly released.[11] This may 2.1 Topicalaccount for the greater adverse effects on growth and adrenal
function seen when fluticasone propionate has been given to 2.1.1 Dysphonia and Oral Candidiasispeople with mild or no asthma.[21,22] If the airways are less con- There have previously been concerns about dysphonia and oralstricted or inflamed, more of the drug may be absorbed from the thrush developing in people using ICS. These symptoms havelungs, and thus be systemically available. Initially, a high dose of been described in adults,[24] but subsequent systematic reviews onICS may be needed to control the asthma. If the drug is effective, their use in children have shown these to be uncommon prob-local inflammation will be reduced and airway obstruction will lems.[4,25] The reasons for this are unclear, but may in part beimprove so the amount of drug absorbed through the lungs may because of the greater use of spacer devices in children. There areincrease. This emphasizes the importance of using the lowest no specific data on topical adverse effects with the newer ICS suchpossible dose of ICS for symptom control. as fluticasone propionate or mometasone.
2.1.2 Dental Health1.3.4 Comparing ICS Systemic Activity
ICS may also have an adverse effect on dental health. ChildrenThe difficulties of comparing both the efficacy and safety ofwith asthma have been shown to have a higher incidence of toothICS in asthma have been discussed in detail elsewhere.[23] In brief,decay and dental erosion of both deciduous and permanent teethsystemic activity of ICS will depend on both the potency of thethan those who have never had asthma.[26,27] One possible reasonparticular ICS, and, perhaps more importantly, the pulmonaryfor this is a reported higher prevalence of gastro-esophageal refluxdeposition of the ICS. Pulmonary deposition is still the majorin the children with asthma.[26] However, the pH of the asthmadeterminant of systemic bioavailability, even when there is somemedication could be contributory. Powdered forms of many of theoral bioavailability, as this is usually minimized by using a spacercommon asthma drugs, including bronchodilators and ICS, have aor having the patient rinse and spit after use. In turn, pulmonarypH of <5.5, and tooth substance is known to begin to dissolve atdeposition will depend on factors related to the individual ICS, aspH 5.5.[28] This may be a potential complication with mometasone,well as patient-related factors. As already discussed, factors suchas a dry powder form is being introduced for lung deliveryas the delivery device and the particle size will have a significant
influence on pulmonary drug deposition. In addition patient fac-
tors, particularly inhaler technique and degree of airway obstruc-
tion, will also affect pulmonary deposition. The latter issue is
highlighted by the recent observation that systemic availability of
fluticasone propionate was significantly less in patients with asth-
ma compared with healthy volunteers,[21,22] although interestingly,
systemic availability of budesonide was similar in patients with
asthma and in healthy volunteers.[22] Given the above issues, it is
obviously difficult to compare the relative systemic activity of
different ICS or to determine a ‘threshold’ dose above which
systemic activity is apparent. While these issues are also important
Table II. Choice of inhaler device in children according to age[3]
Route of Age
administration <2y 2–5y 5–8y ≥8y
MDI + small volume spacer + Yes Yes No No
mask
MDI + spacer No Yes Yes Yes
Dry powder device No No Possible Yes
Breath activated device No No Possible Yes
MDI (alone) No No No Yes
MDI = metered dose inhaler.
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
486 Randell et al.
(Twisthaler®), and the dry powder form of fluticasone propionate cemia, in particular, can be hazardous, with two fatalities in
(Accuhaler™). Aerosol forms have a pH of between 7 and 9.3, children in the UK in the 1980s[35] (resulting from inappropriate
therefore hydrofluoroalkane beclomethasone and fluticasone pro- treatment of the hypoglycemia), although a more recent paper
pionate pressurized MDI should not have the same adverse effect describes its safe use in more than 500 children.[36] The short
on dental enamel, particularly if spacers are used to ensure the synthetic corticotropin stimulation test is usually the investigation
dose is delivered to the back of the mouth. of choice, but debate even surrounds how best to perform this. The
standard test uses supraphysiological doses (250μg intramuscular-2.2 Adrenal Function ly) of synthetic corticotropin (Synacthen®), and thus it has been
argued that this could give false normal results when secondary2.2.1 Assessment of Adrenal Function adrenal failure is suspected. A low dose, i.e. 10μg or even 0.5 μg/
1.73m2, of Synacthen® may be more sensitive.[37] Others haveSuppression of the Hypothalamic-Pituitary-Adrenal Axiscontradicted this finding[38] and, in the case reports of adrenalSuppression of the HPA axis and the risk of adrenal crises areinsufficiency, standard-dose Synacthen® tests have demonstratedpotentially the most serious adverse effects of exogenous cortico-inadequate cortisol responses whenever they were performed.[31-33]
steroid use. Synthetic glucocorticoids down-regulate corticotropin
(adrenocorticotropic hormone; ACTH) production by the same 2.2.2 Biochemical Suppressionfeedback-inhibition loops that control endogenous glucocorticoid
General Effects of ICSproduction, thus causing adrenal suppression. It is well recognizedMost studies have used early morning blood cortisol levels as athat oral glucocorticoids can cause this,[29] hence the recommenda-
measure of HPA function and, generally, suppression was not seention that any patient on long-term treatment with oral corticoster-until high doses of ICS were used (table III). A recent systematicoids carry a corticosteroid alert card. ICS have been known toreview of the systemic adverse effects of ICS therapy concludedcause biochemical HPA suppression for many years, even at dosesthat marked adrenal suppression occurs with high dosages of ICSconsidered to be moderate or low.[30] The effects of ICS on theabove 1500 μg/day (750 μg/day for fluticasone propionate), al-HPA axis can be assessed by various means, with some debatethough there was a considerable degree of interindividual suscepti-regarding the best method of doing so. Since effects of ICS on thebility.[39] The measurements used as an assessment of adrenalHPA axis are generally mild, sensitive methods are required tofunction were 24-hour or overnight urinary cortisol levels, ordetect suppression.8.00am plasma cortisol levels. Studies included healthy adult
Screening for Adrenal Insufficiencyvolunteers, and both children and adults with asthma.
Clinical indicators of systemic effects, such as poor growth orA further study examined the effects of ICS by dose, rather than
Cushingoid features, are not always present in children withtype of ICS.[40] Forty-five children with asthma who were taking
documented biochemical adrenal insufficiency secondary toregular ICS were investigated and analyzed according to whether
ICS.[31-33] As a basic screening tool, early morning serum orthey were receiving <600 μg/m2/day (n = 23, group 1) or >600 μg/
salivary cortisol concentrations can be reassuring if they are highm2/day (n = 22, group 2). Thirteen children were taking beclo-
normal, but lower levels can be indeterminate.[29] In a study on themethasone, 27 budesonide, and 5 had very recently changed to
effects of high-dosage inhaled chlorofluorocarbon beclometha-fluticasone propionate. In those children receiving fluticasone
sone (2 mg/day) in healthy adult volunteers, 24-hour urinarypropionate, the previous dose of beclomethasone or budesonide
cortisol levels were reduced after only 4 days of treatment.[34]
was used to calculate the amount of ICS administered. The chil-However, this may simply be a result of negative feedback, which
dren were aged between 5 and 15 years and had been taking ICSdoes not indicate significant adrenal suppression. Also, collecting
for a mean of 5.59 (range 1.59–10.18) years. They were at various24-hour urine samples from children is frequently impractical.
stages of puberty. An ultra-low-dose short Synacthen® test (SST)Dynamic Testing was performed (0.5 μg/1.73m2): 48% of group 1 and 68% of group
Dynamic testing is used to formally assess adrenal function, 2 had abnormal responses (60-minute cortisol value <500 nmol/
with the ‘gold-standards’ being the metyrapone suppression or L), with no significant difference between the groups. However,
insulin-induced hypoglycemia tests.[29] Insulin-induced hypogly- the 5 children receiving >900 μg/m2/day all had peak cortisol
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the New
er Inhaled C
orticosteroids in C
hildhood
Asthm
a487
© A
dis D
ata
Info
rma
tion
BV 2003. A
ll righ
ts rese
rved
.P
ed
iatr D
rug
s 2003; 5 (7)
Table III. Summary of studies examining biochemical adrenal suppression with inhaled corticosteroids
Study Population studied Drug and dosage Investigation used Results
Clavano et al.[40] 45 children with asthma Beclomethasone/budesonide Ultra-low-dose SST (0.5 μg/ Maximum cortisol <500 nmol/L in
<600 μg/m2/day (I) or >600 μg/ 1.73m2) 48% (I), 68% (II) [no significant
m2/day (II) difference]
Fitzgerald et al.[41] 34 children with asthma Fluticasone propionate 750 μg/ Ultra-low-dose SST (0.5 μg/ Maximum cortisol <500 nmol/L in
day or beclomethasone 1500 μg/ 1.73m2) 70% of children in both groups
day, for 12 weeks each
Kannisto et al.[42] 75 children with asthma Fluticasone propionate 500 μg/ Ultra-low-dose SST (0.5 μg/ 23% abnormal SST, more children
day then 200 μg/day vs 1.73m2) receiving budesonide than
budesonide 800 μg/day then 400 fluticasone propionate affected at
μg/day vs cromones lower dosages
Lipworth et al.[43] 8 children with asthma Fluticasone propionate 200 and Overnight urinary cortisol No suppression of cortisol in any
400 μg/day, or budesonide 200 of the groups
and 400 μg/day, for 4 days each
Lipworth[39] Meta-analysis of 27 studies of Fluticasone propionate 500–2000 24h or overnight urinary cortisol Greater suppression of cortisol
healthy adults, and adults and μg/day; beclomethasone and/or morning plasma cortisol with fluticasone propionate than
children with asthmaa 200–2000 μg/day; budesonide others (exact values not given)
400–2000 μg/day; flunisolide
1000–4000 μg/day; triamcinolone
400–1600 μg/day
Barnes et al.[44] Meta-analysis of 14 studies, two Fluticasone propionate 200–1000 Morning plasma cortisol At presumed equipotent doses
in children μg/day; budesonide 400–1600 less suppression with fluticasone
μg/day; beclomethasone propionate than with budesonide;
400–2000 μg/day similar suppression with fluticasone
propionate and beclomethasone
Continued next page
488R
andell et al.
© A
dis D
ata
Info
rma
tion
BV 2003. A
ll righ
ts rese
rved
.P
ed
iatr D
rug
s 2003; 5 (7)
Table III. Contd
Study Population studied Drug and dosage Investigation used Results
Fowler et al.[45] 16 healthy adults Hydrofluoroalkane fluticasone Overnight urinary cortisol and Dose-related suppression, more
propionate 500–2000 μg/day and morning serum cortisol with hydrofluoroalkane
hydrofluoroalkane beclomethasone than
beclomethasone 500–2000 μg/ hydrofluoroalkane fluticasone
day propionate
Pedersen et al.[20] 35 children with asthma (out of Hydrofluoroalkane Low-dose Synacthen® test (1 μg/ 4/24 hydrofluoroalkane
300 enrolled) beclomethasone 100–200 μg/day 1.73m2) beclomethasone recipients and 1/
or chlorofluorocarbon 11 chlorofluorocarbon
beclomethasone + spacer beclomethasone recipients had
200–400 μg/day cortisol <500 nmol/L
Davies et al.[46] 233 adults with asthma Hydrofluoroalkane Morning plasma cortisol Less suppression with
beclomethasone 800 μg/day or hydrofluoroalkane beclomethasone
chlorofluorocarbon (cortisol <193 nmol/L)
beclomethasone 1500 μg/day
Gross et al.[47] 347 adults with asthma Hydrofluoroalkane Morning plasma cortisol >96% of patients in both groups
beclomethasone 400 μg/day or had normal cortisol (193–690
chlorofluorocarbon nmol/L)
beclomethasone 800 μg/day
Fireman et al.[48] 354 adults with asthma Hydrofluoroalkane Morning plasma cortisol No suppression with
beclomethasone 200–800 μg/day hydrofluoroalkane
or chlorofluorocarbon beclomethasone, even at 800 μg/
beclomethasone 400-1600 μg/ day
day
Affrime et al.[49] 3 groups, 60–64 adults with Mometasone 400–1600 μg/day Standard-dose Synacthen® test No suppression seen until
asthma in each vs prednisone 10 mg/day, (250μg) mometasone dosage of 1600 μg/
fluticasone propionate 1760 μg/ day (peak cortisol <500 nmol/L)
day or placebo
a Studies involving children used only beclomethasone or budesonide as inhaled corticosteroids.
SST = short Synacthen® test.
Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 489
levels of <500 nmol/L. Urine specimens for 24-hour urinary free = 12) or changed to cromones (n = 18). The third group of 15
cortisol (UFC) were collected prior to the SST, and early morning received cromones for 4 months, and then either continued with
serum cortisol and corticotropin levels were also checked. The them (n = 9) or changed to ICS (budesonide or fluticasone pro-24-hour UFC did not predict those children who had an abnormal pionate [n = 6]). An ultra-low-dose SST was performed at thelow-dose SST. beginning of the study, and at 2, 4, and 6 months. The authors
defined an abnormal result as a stimulated cortisol level of more
than 2 standard deviations below the mean baseline measurement,Fluticasone Propionate
which was calculated before starting treatment (<330 nmol/L).The above-mentioned systematic review concluded that thereUsing this criterion, 23% of children receiving ICS had an abnor-was a significantly steeper dose-related adrenal suppression slopemal SST response at 2 months (no difference between fluticasonewith fluticasone propionate compared with beclomethasone orpropionate or budesonide), with a similar percentage at 4 months,budesonide, even allowing for its greater potency.[39] However, abut with more children receiving budesonide (n = 9) than receivingmeta-analysis of systemic activity of fluticasone propionate at
fluticasone propionate (n = 5) affected (p < 0.05). At 6 months, 4presumed equipotent doses compared with beclomethasone and
children receiving ICS still had an abnormal response but allbudesonide in both children and adults with asthma concluded
there was no greater adrenal suppression with fluticasone propion- cromone users (including those previously on ICS) had a normal
ate.[44] These apparently opposing conclusions may relate to differ- SST.
ent patient groups (healthy individuals or patients with asthma of Fitzgerald et al.[41] studied 34 children who had been on high-different severity),[21,22] differing individual susceptibility, differ-
dosage ICS (budesonide 1200–1600 μg/day or chlorofluorocarbonent ways of measuring HPA suppression, and/or measurements
beclomethasone 1000–2000 μg/day) for at least 12 months andmade at different parts of the adrenal suppression dose-response
were switched to either fluticasone propionate 750 μg/day orcurve.
chlorofluorocarbon beclomethasone 1500 μg/day, via a large vol-There have been limited comparative studies of biochemical
ume spacer. They spent 12 weeks taking the first ICS and thenadrenal suppression in children. Lipworth et al.[43] measured over-
switched to the second ICS for 12 weeks, with both patients andnight urinary cortisol, as a measure of adrenal suppression, in a
observers blinded to the order in which they were given. Twenty-crossover study in 8 children with asthma, comparing fluticasone
four-hour UFC levels did not change during the study period,propionate and budesonide at dosages of 200 and 400 μg/day
regardless of whether the patients were taking fluticasone propion-given over a 4-day period. There was no evidence of significant
ate or beclomethasone. Ultra-low-dose Synacthen® tests wereadrenal suppression with either fluticasone propionate or budeso-
performed at the end of each treatment phase and in both groups;nide at the dosages studied, and the investigators concluded that
>60% of patients showed biochemical evidence of adrenal sup-the results emphasized the good safety profile of these ICS at
pression. Thus, these data suggest that high dosages of fluticasoneconventional dosage levels. These results should be interpreted
propionate do cause biochemical adrenal suppression which is nowith caution as the study was performed over a very short period
greater than equipotent dosages of chlorofluorocarbon beclo-of time and the relevance of overnight urinary cortisol measure-
methasone, supporting the conclusions of the Barnes meta-ana-ments is uncertain.
lysis.[44]
A Finnish study compared 75 children with asthma in whomFigure 1 summarizes the dose effect of fluticasone propionatethe diagnosis had been newly made (n = 62), or who had only
on biochemical adrenal suppression, with the effects of differingpreviously received bronchodilators (n = 9) or cromone medica-doses of fluticasone propionate on the ultra-low-dose SST (com-tions (n = 4).[42] The children were divided into three groups. Thepared with clinical efficacy of the same doses of fluticasonefirst group of 30 children received fluticasone propionate 500 μg/propionate). This figure serves to highlight that increasing theday for 2 months, then 200 μg/day for 2 months, and then eitherdosage of fluticasone propionate above 200 μg/day results in acontinued with that dosage of fluticasone propionate (n = 11) or
significant increase in biochemical adrenal suppression, withoutchanged to cromones (n = 19). The second group of 30 received
any significant increase in clinical benefit. While the clinicalbudesonide 800 μg/day for 2 months, then 400 μg/day for 2
months, and then either continued on that dosage of budesonide (n relevance of this biochemical suppression was uncertain, there are
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
490 Randell et al.
included in the analysis. No differences between the 24-hour UFC
levels in the two groups was found, and 4 out of 24 children in the
hydrofluoroalkane beclomethasone group had subnormal
Synacthen® responses, compared with 1 out of 11 in the chloro-
fluorocarbon beclomethasone group.
Studies in adults comparing equipotent doses of hydrofluoro-
alkane beclomethasone and chlorofluorocarbon beclomethasone
have demonstrated no difference in HPA axis suppression,[46-48]
with one showing less suppression of morning plasma cortisol
levels on high-dosage hydrofluoroalkane beclomethasone (800
μg/day) than on high-dosage chlorofluorocarbon beclomethasone
(1500 μg/day).[11,46]
Mometasone
Mometasone is in the process of being introduced for the
treatment of asthma in adolescents and adults. There have been no
studies of its safety or efficacy in children younger than 12 years of
age, although its pharmacokinetics appear to be similar to those of
0
20
40
60
80
100
120
Daily dose of inhaled fluticasone propionate (μg)
Per
cent
age
affe
cted
Asthma controlledAbnormal LDSST
0 100 200 500 750
aa
b
Fig. 1. Schematic diagram comparing the efficacy of fluticasone propionateat different doses (clinical benefit based on percentage of children control-led on varying doses of fluticasone propionate)[42,50] with the effect of differ-ent doses of fluticasone propionate on the low-dose short Synacthen® test(LDSST). Data from Kannisto et al.[42] (a) and Fitzgerald et al.[41] (b).
fluticasone propionate.[14] The effect of mometasone on the HPA
axis has only been evaluated in adults with mild to moderatenow more than 50 case reports of adrenal crises with high-dose
asthma.[49] The authors claimed that there were no adverse effectsfluticasone propionate (see section 2.2.3).
seen until dosages of 1600 μg/day (double the highest recommen-
ded clinical dosage) were used.[49] However, others have criticizedHydrofluoroalkane Beclomethasone
the interpretation of these data, suggesting that suppression wasThe effect of hydrofluoroalkane beclomethasone on adrenal
demonstrable at most time points with both the 800 and 1600 μg/function was compared with identical doses of hydrofluoroalkane
day dosages, when compared with placebo, and questioning thefluticasone propionate in 16 healthy adult volunteers by measuring
authors’ conclusions that the systemic bioavailability of mometa-early morning cortisol and urinary cortisol/creatinine excretion.
sone was negligible.[11] No data are currently available on theHydrofluoroalkane beclomethasone caused significantly greater
effects on children and, clearly, more studies are required to assesssuppression of the overnight urinary cortisol/creatinine ratio than
the potential of mometasone for adrenal suppression, particularlyfluticasone propionate at dosages ≥1000 μg/day.[45] This was felt
given its high lipophilicity.to be a result of the greater lung deposition of hydrofluoroalkane
Clinical Relevancebeclomethasone offsetting the greater glucocorticoid potency of
The clinical relevance of this degree of adrenal suppression isfluticasone propionate.
uncertain, and until recently it was felt that the risk of symptomaticHydrofluoroalkane beclomethasone has also been comparedacute adrenal insufficiency from the use of ICS alone was verydirectly with chlorofluorocarbon beclomethasone with regard tosmall.its effect on the HPA axis.[20] In a multicenter, international, open-
label comparison, children were randomized to either hydrofluoro-2.2.3 Clinical Adrenal Suppression
alkane beclomethasone 100–200 μg/day or chlorofluorocarbonAdrenal Crisesbeclomethasone 200–400 μg/day. At 12 months, the children had
24-hour UFC assessments and/or a low-dose (1 μg/1.73m2) Acute adrenal insufficiency has been rarely reported as a com-
Synacthen® test performed to assess suppression of the HPA axis. plication of ICS therapy until recently. In 1992, Wong and
Children who had been taking dosages higher than those detailed Black[51] reported an adult on high-dosage budesonide (1.6–6.4
above (hydrofluoroalkane beclomethasone up to 400 μg/day or mg/day) who developed acute adrenal insufficiency following
chlorofluorocarbon beclomethasone up to 800 μg/day) were not dosage reduction. In the same year, Zwaan et al.[52] reported a child
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 491
on low-dosage budesonide (500 μg/day, inhaled and nasal), who
presented with an adrenal crisis following sudden cessation of ICS
because of concern about systemic adverse effects. Over the past
few years, there have been increasing numbers of case reports of
children receiving ICS who have presented with adrenal crises
(table IV). In 1999, a 9-year-old girl who had been receiving
fluticasone propionate 550 μg/day for severe labile asthma was
described. She was clinically Cushingoid and developed orthosta-
tic hypotension and moderate dehydration following a mild viral
illness. Hypoglycemia was not mentioned. Her 8.00am cortisol
was undetectable and her corticotropin level was inappropriately
low at 21 ng/L (4.62 pmol/L, normal 2.0–10.0 pmol/L).[53] No
other cause for her adrenal insufficiency was found.
A series of eight children with symptomatic adrenal insuffi-
ciency was published in November 2001.[31] Two of these children
presented with altered consciousness as a result of hypoglycemia,
consistent with an adrenal crisis. The rest had a more insidious
course, with poor growth being the main symptom.[31] The two
children with adrenal crises had been on high-dosage fluticasone
propionate (500 μg/day) for at least 4 months before presentation;
however, the dosages did not exceed the recommended dosages
detailed in the British Thoracic Society guidelines.[56,57] Further-
more, four other children who presented with hypoglycemia and
altered consciousness (one of whom had had recurrent hypoglyce-
mic seizures during intercurrent illnesses) were all receiving high-
dosage fluticasone propionate (500–1500 μg/day).[32] None were
Cushingoid, and two of the four had normal growth velocities. All
had inappropriately low cortisol levels on testing with standard
SST.
Three other case series have reported similar presenta-
tions,[33,54,55] the largest being a national survey in the UK in which
33 cases of acute adrenal insufficiency were reported.[54] Twenty-
eight of the 33 were children, and in 28 patients, fluticasone
propionate in dosages of 500–2000 μg/day was the only ICS used.
Of the 33 patients, three were felt not to have asthma. Five were
described as having probable asthma that was being overtreated
with ICS because of concurrent lung diseases simulating asthma
symptoms. Six had moderate asthma as per the British Thoracic
Society guidelines,[56,57] and no information was available on 5
patients. The remainder (1 adult, 13 children) were described as
having severe asthma.[54] In all reported case series, no other
causes of adrenal insufficiency were found. In the UK, fluticasone
propionate accounts for only 15% of all ICS prescriptions and yet
in this case series, 31 out of 33 patients (94%) were taking it.
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Tab
le I
V.
Sum
mar
y of
rep
orts
of
adre
nal c
rises
in p
atie
nts
rece
ivin
g in
hale
d co
rtic
oste
roid
s
Rep
ort
Age
(no
. of
pat
ient
s)D
rug
and
dosa
geP
rese
ntin
g sy
mpt
oms
Cor
tisol
leve
l
Tay
lor
et a
l.[53]
9y (
1)F
lutic
ason
e pr
opio
nate
550
μg/
Cus
hing
oid,
hyp
oten
sion
Und
etec
tabl
e at
8.0
0am
day
Pat
el e
t al
.[31]
4.5–
10y
(2/8
a )F
lutic
ason
e pr
opio
nate
500
μg/
Hyp
ogly
cem
ia,
impa
ired
cons
ciou
snes
s<
500
nmol
/L p
ost-
Syn
acth
en®
or
mor
ning
day
(in t
he c
hild
ren
with
cort
isol
<20
0 nm
ol/L
adre
nal c
rises
)
Dra
ke e
t al
.[32]
4–8y
(4)
Flu
ticas
one
prop
iona
teH
ypog
lyce
mia
, un
cons
ciou
snes
s<
500
nmol
/L p
ost-
Syn
acth
en®
500–
1500
μg/
day
Tod
d et
al.[3
3]7–
9y (
3)F
lutic
ason
e pr
opio
nate
Hyp
ogly
cem
ic s
eizu
res
<50
0 nm
ol/L
pos
t-S
ynac
then
®
500–
2000
μg/
day
Tod
d et
al.[5
4]C
hild
ren
3.3–
10y
(28)
Flu
ticas
one
prop
iona
teH
ypog
lyce
mic
sei
zure
s or
com
a (2
3/33
);<
500
nmol
/L p
ost-
Syn
acth
en®
, co
rtis
olA
dults
(5)
500–
2000
μg/
day
(30/
33);
hypo
tens
ion,
fat
igue
, na
usea
(9/
33);
fat
al<
500
nmol
/L a
t tim
e of
acu
te il
lnes
s, o
rbe
clom
etha
sone
dos
age
NR
(2/
seps
is w
ith h
ypog
lyce
mia
(1/
33)
cort
isol
<50
0 nm
ol/L
pos
t-gl
ucag
on33
); f
lutic
ason
e pr
opio
nate
+st
imul
atio
nbu
deso
nide
, do
sage
NR
(1/
33)
Mac
dess
i et
al.[5
5]4–
11y
(3)
Flu
ticas
one
prop
iona
teH
ypog
lyce
mia
, se
izur
es<
500
nmol
/L p
ost-
Syn
acth
en®
, or
<20
010
00–1
500
μg/d
aynm
ol/L
at
time
of h
ypog
lyce
mia
aN
umbe
r of
pat
ient
s w
ith a
cute
adr
enal
cris
es w
as 2
out
of
8 pa
tient
s in
tot
al r
epor
ted
with
any
end
ocrin
e ad
vers
e ef
fect
s of
IC
S.
NR
= n
ot r
epor
ted.
492 Randell et al.
While there have been suggestions that adrenal suppression is absorbed through the lungs, or whether it is a reflection of
more likely to occur with fluticasone propionate,[32,54] perhaps prescribing practices. However, in the UK survey where 94%
because of its greater lipophilicity,[54] it is clear that other ICS can of patients with adrenal crises were taking fluticasone propion-
also be responsible. It is also apparent that individual susceptibility ate, it accounted for only 15% of all ICS prescriptions.[54]
plays a significant role. The other explanation for the preponder- • It is important to be aware of this potentially very seriousance of fluticasone propionate-related cases is the generally very adverse effect in children who require high doses of ICS, andhigh dosages of fluticasone propionate that have been used in the ‘back-titrate’ doses as soon as adequate control is achieved.patients described. Parents of these children should also be counseled regarding
There have, as yet, been no reports of symptomatic adrenal this risk.
insufficiency with hydrofluoroalkane beclomethasone or mometa- • If an adrenal crisis is suspected, the blood sugar and cortisolsone. level should be checked. If abnormal, the child should be
referred to a pediatric endocrinologist for formal adrenal func-Preventing Adrenal Crises
tion testing.An adrenal crisis can be a life-threatening event, therefore it is
very important to warn parents of children receiving high-dose 2.3 GrowthICS of this potential risk. Any doctor who sees a child in whom an
adrenal crisis is suspected should check the blood glucose and 2.3.1 Normal Growthcollect blood to determine the cortisol level at the same time. It is Growth rate varies considerably during childhood. It can bealso crucial to administer parenteral hydrocortisone (intravenously typically characterized by a rapid growth velocity during infancy,or intramuscularly) as soon as possible if adrenal crisis is suspect- slow deceleration during the prepubertal years to reach a nadired. If the blood glucose level or cortisol level is abnormal, the prior to the onset of puberty, followed by the growth spurt andchild should be urgently referred to a pediatric endocrinologist for attainment of final height. Catch-up and catch-down growth mayformal assessment of adrenal function. As it is difficult to be sure also be seen in infants, and occasionally in children, as program-of the clinical relevance of biochemical evidence of adrenal sup- med by their genetic potential. A potential problem exists whenpression, it may be more appropriate to advise the parents of interpreting the growth data of children receiving ICS as the meanchildren receiving high-dose ICS to seek urgent medical advice ages in many of the studies often overlap with the natural decelera-should their child become significantly unwell. This is particularly tion in growth velocity prior to the onset of puberty.[58]
important with vomiting or diarrheal illnesses, or with high fever2.3.2 Effect of ICS and Asthma on Growth
(temperature >39ºC).[55]
It is postulated that the adverse effects of ICS on growth areIt should also be noted that in several of the case reports, the
caused by potential suppression of growth hormone secretion andchildren were subsequently found not to have asthma or to have
decreasing circulating insulin-like growth factor-1 levels.[59] Corti-asthma of a significantly milder degree than previously as-
costeroids may also have a direct effect on the growth plate,sessed.[54,55] It is recommended that a pediatric respiratory physi-
restricting growth by their effects on the hypertrophic chondro-cian should review any child thought to have asthma who does not
cytes within the cartilage.[60]respond to conventional doses of ICS before increasing the dose
Untreated asthma itself has an adverse effect on growth, espe-further.[2,55]
cially if it is severe.[61,62] Asthma has also been shown to delay2.2.4 Summary puberty, and hence the growth spurt.[63] The effects of ICS on
• Biochemical evidence of adrenal suppression can be commonly growth in children have been of concern for some time. It has,found in children receiving ICS, particularly on high doses. The however, been difficult to ascertain their precise effects. The firstclinical relevance of such adrenal suppression is uncertain. evidence suggesting that ICS could cause growth attenuation was
• While uncommon, there are now reports of adrenal crises in based on retrospective studies, with wide variations in ages of the
children. The majority of these have been on high-dose fluti- children and doses of corticosteroids.[64] Later studies tried to
casone propionate, but it is not clear whether this relates to the control for these factors. While these studies confirmed a slowing
greater potency of fluticasone propionate, particularly when of growth in some children with asthma receiving ICS therapy,[64]
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 493
the authors indicated that no firm conclusion could be reached on
final adult height. However, a subsequent study has suggested that
ICS therapy does not reduce final adult height[65] and this issue
will be discussed in more detail in section 2.3.4.
2.3.3 Short-Term Growth (Knemometry)
Growth has been evaluated in two different ways. Knemometry
measures changes in lower leg length as an index for short-term
growth and is generally used in studies to measure growth over a
2–4 week period, with washout periods employed between differ-
ing dose or drug comparisons. However, as has already been
stated, growth in children is not a constant progression, but rather
occurs episodically. Short-term changes in lower leg length veloc-
ity are not predictive of long-term growth,[66] but rather appear to
reflect short-term suppressive effects on collagen turnover.[67]
Other studies have followed children for longer periods of time
and measured their linear growth, comparing it with either healthy
children without asthma, or children with asthma not using ICS, as
controls.
Much of the research using knemometry as a measurement of
growth velocity has been on the older ICS, in particular budeso-
nide. A few have compared fluticasone propionate with either
budesonide or chlorofluorocarbon beclomethasone.[23]
Fluticasone Propionate
In one randomized, crossover, double-blind study, 17 children
were treated with fluticasone propionate and beclomethasone in
three active treatment periods of 15 days, with a washout period in
between each one (table V).[67] Each child acted as his or her own
control and was given either fluticasone propionate 200 μg/day, or
beclomethasone 400 or 800 μg/day via Diskhaler® as a dry pow-
der. Knemometry and other markers of growth were measured
regularly throughout and a greater effect on growth suppression
with beclomethasone than with fluticasone propionate was
found.[67]
Fluticasone propionate was compared with budesonide in an-
other study in which 48 children were assigned to either low-
dosage (200 μg/day) fluticasone propionate or budesonide or
placebo (24 children), or higher-dosage (400 μg/day) fluticasone
propionate or budesonide or placebo (24 children).[68] Each child
again acted as his or her own control and was randomized in a
double-blind fashion to either active drug or placebo given via a
DPI for 15–18 days. There was a 2-week washout period between
each treatment arm, and the same observer performed knemometry
twice weekly throughout. Again fluticasone propionate was shown
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Tab
le V
. S
umm
ary
of e
ffect
s of
inha
led
cort
icos
tero
ids
on k
nem
omet
ry
Stu
dyA
geD
rug
and
dosa
geP
uber
tal s
tatu
sLe
ngth
of
stud
yF
inal
res
ult
(no.
of
child
ren)
Wol
ther
s et
al.[6
7]7–
14y
(17)
Flu
ticas
one
prop
iona
te 2
00 μ
g/da
y vs
16 p
repu
bert
al,
112
wks
(2w
ks o
nB
eclo
met
haso
ne,
but
not
flutic
ason
e
becl
omet
haso
ne 4
00 μ
g/da
y vs
Tan
ner
IIea
ch d
osag
e)pr
opio
nate
, af
fect
ed k
nem
omet
ry
becl
omet
haso
ne 8
00 μ
g/da
y
Age
rtof
t an
d6–
12y
(48)
Flu
ticas
one
prop
iona
te 2
00 μ
g/da
y vs
Pre
pube
rtal
12w
ks (
15–1
8B
udes
onid
e, b
ut n
ot f
lutic
ason
e
Ped
erse
n[68]
bude
soni
de 2
00 μ
g/da
y vs
bud
eson
ide
days
on
each
prop
iona
te,
affe
cted
kne
mom
etry
400
μg/d
aydo
sage
)
Vis
ser
et a
l.[69]
6–10
y (2
1)F
lutic
ason
e pr
opio
nate
200
μg/
day
vsP
repu
bert
al6w
ks f
lutic
ason
eF
lutic
ason
e pr
opio
nate
had
no
effe
ct o
n
bron
chod
ilato
rpr
opio
nate
, 2w
kskn
emom
etry
bron
chod
ilato
r
Anh
oj e
t al
.[70]
1–3y
(25
)F
lutic
ason
e pr
opio
nate
400
μg/
day
vsP
repu
bert
al4w
ks c
ross
over
Flu
ticas
one
prop
iona
te a
nd b
udes
onid
e
bude
soni
de 4
00 μ
g/da
y vs
pla
cebo
affe
cted
kne
mom
etry
to
a si
mila
r
degr
ee
Age
rtof
t an
d7–
12y
(22)
Intr
anas
al m
omet
ason
e 10
0 or
200
μg/
Var
iabl
e pu
bert
y14
wks
(2w
ks o
nM
omet
ason
e an
d bu
deso
nide
had
no
Ped
erse
n[71]
day
vs b
udes
onid
e 40
0 μg
/day
vs
each
dos
age)
adve
rse
effe
ct o
n kn
emom
etry
plac
ebo
494 Randell et al.
to have no adverse effect on short-term growth compared with was used, and confirmed an overall decrease in linear growth
placebo, but high-dosage (400 μg/day) budesonide attenuated velocity of 1.51 cm/year (95% CI 1.15–1.87).[73]
growth. This is despite the fact that fluticasone propionate may Subsequently, a Cochrane review has looked specifically at thehave up to double the potency of budesonide.[68] effect of beclomethasone (given by dry powder Diskhaler® or
A further study examined the effect of fluticasone propionate MDI) on growth. Three randomized, controlled, double-blindalone on knemometry.[69] Twenty-one prepubertal boys with asth- trials examining children aged <18 years of age who were notma were given fluticasone propionate 200 μg/day for 6 weeks, taking any corticosteroids for a minimum of 3 months prior to thefollowed by a 2-week period on bronchodilators alone (washout study were included. The control groups were children with asth-period). Prior to starting fluticasone propionate, the boys had been ma matched for age, pubertal status, and gender, and receivedtaking between 100 and 400 μg/day of ICS (type not specified). either salmeterol or placebo as medication. It was found that inKnemometry was measured at 2-weekly intervals and no differ- children with mild to moderate asthma, a dosage of 400 μg/dayence was found between growth while on fluticasone propionate caused a decrease in linear growth of –1.54 cm/year. However, theor on bronchodilators alone.[69] authors point out that none of the analyzed studies lasted beyond
A recently published study compared the effect of fluticasone 54 weeks, therefore it was not possible to comment on whether this
propionate and budesonide on knemometry in children aged be- decrease in growth was sustained.[74]
tween 1 and 3 years with mild asthma.[70] The study compared The Childhood Asthma Management Program (CAMP) study,fluticasone propionate 400 μg/day, budesonide 400 μg/day, and comparing budesonide 400 μg/day with nedocromil 16 mg/day orplacebo given via an MDI and spacer over a 4-week period, in a placebo, showed a slowing of growth rate by 1cm in the first yearrandomized, double-blind, double-dummy, three-way, crossover in patients receiving budesonide compared with those receivingdesign. They enrolled 40 children, and 25 completed all three nedocromil or placebo. There was no difference in growth rate intreatments. Both fluticasone propionate 400 μg/day and budeso- subsequent years, but the lost 1cm was not regained at the end ofnide 400 μg/day caused a significant slowing of lower leg length the study (mean duration 4.3 years). In spite of this, the predictedgrowth compared with placebo (fluticasone propionate 34 μm/day, final adult height (based on bone age) was within the target geneticbudesonide 45 μm/day, placebo 85 μm/day). predicted height. Also, this study did not comment on pubertal
status of children prior to commencement of treatment, althoughMometasone and Hydrofluoroalkane Beclomethasonepubertal staging at the end of the study was not different betweenThere are no published data on the effect of inhaled mometa-the three groups. Again, asthma control was significantly better insone on knemometry, but no adverse effect was found on short-the budesonide-treated group, compared with patients receivingterm growth when intranasal mometasone was compared withnedocromil or placebo (see figure 2).[75]
intranasal budesonide and placebo.[71] The effect of hydrofluoro-One study followed a cohort of children treated with budeso-alkane beclomethasone on knemometry has not been evaluated.
nide, 142 of whom had reached adult height at follow-up.[76] The2.3.4 Linear Growth (Intermediate and Long Term)
mean duration of asthma was 14 (range 5–23) years, and the mean
Beclomethasone and Budesonide duration of budesonide treatment was 9.2 (range 3–13) years.
These children were compared with their healthy siblings and aA number of studies examining the effects of beclomethasone
control group of children with asthma who did not use ICS. Theiron linear growth have found it was decreased in those children
target adult height was estimated from parental height data. Nousing ICS (table VI).[72-74] In a Canadian study, those children
difference in final adult height was found between any of thereceiving beclomethasone showed a reduction of growth of around
groups, with over 95% of children in each group achieving an1.5 cm/year when treated with 400 μg/day, compared with those
adult height within 9cm of their target height.receiving either salmeterol or placebo. However, they also had
significantly decreased airway hyper-responsiveness and the needHydrofluoroalkane Beclomethasonefor salbutamol (albuterol) rescue therapy.[72] The beclomethasone
preparation used in this study was dry powder via Diskhaler®. A Only one study has so far been published looking specifically at
meta-analysis of the effect of ICS on growth in children found four the effects of hydrofluoroalkane beclomethasone on growth. This
studies in which beclomethasone (dosage range 328–440 μg/day) compared hydrofluoroalkane beclomethasone (100–200 μg/day,
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the New
er Inhaled C
orticosteroids in C
hildhood
Asthm
a495
© A
dis D
ata
Info
rma
tion
BV 2003. A
ll righ
ts rese
rved
.P
ed
iatr D
rug
s 2003; 5 (7)
Table VI. Summary of linear growth studies in patients receiving inhaled corticosteroids
Study Age Drug and dosage Pubertal status Length of study Final result
(no. of children)
Sharek et al.[74] 6–16y (633) Beclomethasone 400 μg/day via All stages of 7–12mo Overall loss of 1.54cm height compared
Diskhaler® (three study analysis) puberty with controls
CAMP study[75] 7–11y (941) Budesonide 400 μg/day vs nedocromil Prepubertal (at 4.3 (±0.7)y 1cm height loss in first year with
16 mg/day vs placebo start of study) budesonide, not regained
Agertoft and 3–13y (142) Budesonide, mean dosage 412 (range NR at start of Until adulthood (up Slowed growth rate initially, normal
Pedersen[76] 110–877) μg/day vs no ICS study, post- to 12y) adult height
pubertal at end
Pedersen et al.[20] 5–11y (247) Chlorofluorocarbon beclomethasone Prepubertal (at 12mo Growth velocity the same in both
200–400 μg/day vs hydrofluoroalkane start of study) groups at 12mo
beclomethasone 100–200 μg/day
de Benedictis et al.[65] 4–11y (277) Fluticasone propionate 400 μg/day vs Prepubertal 12mo Growth velocity with fluticasone
beclomethasone 400 μg/day propionate better than with
beclomethasone
Allen et al.[50] 4–11y (325) Fluticasone propionate 100 or 200 μg/ Prepubertal 12mo Growth velocity the same in all three
day vs placebo groups
Todd et al.[77]a 7–10y (6) Fluticasone propionate 1000–2250 μg/ NR 1–3y Poor growth in all six patients
day
Patel et al.[31]a 8y (2) Fluticasone propionate 500–1000 μg/ NR 12mo and 4.5y Poor growth for 1 and 2y
day
Schenkel et al.[78] 3–9y (82) Intranasal mometasone 100 μg/day vs Prepubertal 12mo Growth velocity the same in both
placebo groups
a Case reports.
ICS = inhaled corticosteroids; NR = not reported.
496 Randell et al.
0
1
2
3
4
5
6
7
CAMP
Study
Gro
wth
vel
ocity
(cm
/yea
r)
Allen et al. Pedersen et al. de Benedictis et al.Sharek et al.
p < 0.01 p < 0.005 NS NS p < 0.01
Treated with ICSControl groups or lower dose/less potent ICS
Fig. 2. Comparison of different dosages of ICS on growth velocity. Sharek et al.:[74] beclomethasone 400 μg/day vs no ICS; Childhood AsthmaManagement Program (CAMP) study:[75] budesonide 400 μg/day vs no ICS; Allen et al.:[50] fluticasone propionate 100–200 μg/day vs no ICS; Pedersen etal.:[20] chlorofluorocarbon beclomethasone 200–400 μg/day vs hydrofluoroalkane beclomethasone 100–200 μg/day; de Benedictis et al.:[65] chlorofluorocar-bon beclomethasone 400 μg/day vs fluticasone propionate 400 μg/day. ICS = inhaled corticosteroids; NS = not significant.
Fluticasone Propionateusing up to 400 μg/day) with chlorofluorocarbon beclomethasone
+ spacer (200–400 μg/day, using up to 800 μg/day) in an open- Fluticasone propionate appears to cause less effect on growth,
although only low doses have been used in controlled studies. Alabel study in prepubescent children with stable, mild to moderatemulticenter, randomized, blinded, controlled trial compared fluti-asthma.[20] The children were enrolled from 56 multinational sitescasone propionate 200μg twice daily with beclomethasone 200μgand were followed for 6–12 months. It was found that at 6 months,twice daily, both given via DPI.[65] The children enrolled in the
growth velocity was significantly greater in the chlorofluorocar-study were all prepubertal and were treated for 1 year – only those
bon beclomethasone group than in the hydrofluoroalkane beclo- children who were still prepubertal at the end of the study, did notmethasone group, but by 12 months there was no difference. In the require oral corticosteroids, and who were compliant with thehydrofluoroalkane beclomethasone group at month 12, the mean medication, were included in the final analysis (n = 277). The
growth rate in the fluticasone propionate group was 0.7 cm/yearincrease in height from baseline was 5.67cm in the 100 μg/day(95% CI 0.13–1.26 cm/year) greater than in the beclomethasonegroup, compared with only 4.45cm in the 400 μg/day group. Agroup. This was despite fluticasone propionate theoretically hav-similar pattern was seen in the children receiving chlorofluorocar-ing double the potency of beclomethasone.
bon beclomethasone + spacer group: there was an increase inAnother study compared fluticasone propionate at dosages ofheight of 6.13cm in those receiving 200 μg/day versus 5.05cm in
50 or 100μg given twice daily for 1 year by breath-actuated drythose receiving 800 μg/day. However, children receiving the
powder device with placebo in prepubescent children with persis-higher dosages of ICS (hydrofluoroalkane beclomethasone
tent asthma.[50] The final height data showed no difference be-300–400 μg/day or chlorofluorocarbon beclomethasone 600–800 tween the three groups, although only 66% of children in theμg/day) were not included in the statistical analysis (as there were placebo group completed the study compared with more than 80%
in the two fluticasone propionate-treated groups. While theseonly small numbers in each group).
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 497
studies are reassuring, low dosages of fluticasone propionate were • Fluticasone propionate appears to have less of an effect on
height than the older ICS, when used in low doses, but there areused and there are now several case reports of marked growth
reports of marked growth suppression at high doses.retardation and adrenal suppression with fluticasone propionate,
particularly when used at higher than recommended dosages.[31,77] • There are, as yet, no data on mometasone in an ICS preparation,
but the intranasal preparation at recommended doses does notMometasone have any adverse effect on growth.
The only data available on the effect of mometasone on growth2.4 Bonesis that which assesses the intranasal preparation. Prepubertal chil-
dren were randomized to either mometasone 100 μg/day or place-2.4.1 Normal Bone Mineralization and the Effect of ICSbo to treat allergic rhinitis for 1 year. There were no differencesThe mineralization of bone in children occurs in three phases,between the two groups in either height at the end of the trial, or in
paralleling linear growth rate. Rapid accretion of bone mass hap-growth velocity.[78] Whether this data can be extrapolated to thepens over the first few years, slows during childhood, and thenpulmonary version of mometasone remains to be seen.accelerates again during puberty and early adulthood. Environ-
mental factors such as diet, exposure to sunlight, and exercise areCompliance Effects
very important in ensuring optimal mineralization, with inade-A final factor which needs to be taken into consideration whenquate bone accretion potentially having lifelong consequences.evaluating the effects of ICS on long-term growth is complianceExcess exogenous corticosteroids are known to disrupt normalwith treatment, something which none of the studies on the newerbone metabolism and their long-term use is well known to causeICS have addressed. The few long-term studies on the effects ofosteoporosis. Glucocorticoids reduce bone formation and increaseICS and growth show a decrease in growth rate during the firstbone resorption by their direct action on osteoblasts and osteo-year of treatment, which is not sustained in the long term.[75,76] Itclasts. They can also lead to increased urinary calcium losses andhas been shown that adherence to treatment inevitably decreasesdecreased gut vitamin D-mediated calcium absorption, resulting inwith time,[79] therefore it has been suggested that the normalizationdecreased total body stores of calcium and secondary hyperpara-
of growth seen after the initial slowing may simply reflect reduc-thyroidism.[5,81] Thus, it could be postulated that ICS use during
tion of the dose of ICS to below growth-suppressive amounts.[80]
these vital periods of bone mineralization could have adverseAn alternative possibility is that some adaptive mechanism devel-
effects on bone mass, and potentially lead to osteoporosis in theops over time to overcome the growth-suppressive effects of the
future.ICS therapy.
2.4.2 Assessing Bone Mineralization2.3.5 Summary
Areal Bone Mineral Density (BMD) and Dual-Energy• The older ICS (budesonide and chlorofluorocarbon beclo-
X-Ray Absorptiometrymethasone) have been shown to cause a reduction in short-term
One of the big problems in assessing the effects of ICS on BMDgrowth velocity that does not appear to be sustained in the long
is the difficulty in accurately measuring BMD in children. Theterm, as final adult height appears to be preserved. The reasons
most commonly used method is dual-energy x-ray absorptiometryfor this are unclear, but may be a reflection of adherence issues (DXA). This measures areal BMD (aBMD [mg/cm2]), which isor adaptive mechanisms. calculated by dividing the total (cortical and trabecular) bone
• Hydrofluoroalkane beclomethasone, when compared with mineral content by the projected area (not volume) of the part ofequipotent doses of chlorofluorocarbon beclomethasone, does the skeleton scanned. aBMD is highly dependent on growth andnot have any additional adverse effects on growth. However, cannot distinguish between changes in the mineral density and sizewhen chlorofluorocarbon beclomethasone was compared with of the bone in growing children.[82,83] This is important as chronicplacebo, it was found to cause a significant decrease in growth severe asthma itself may cause pubertal and growth delay,[63] andvelocity, therefore hydrofluoroalkane beclomethasone may be high doses of ICS have been definitely shown to impair
found to have a similar effect. growth.[31,72,73,77] DXA measures the whole bone mineral content
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
498 Randell et al.
Volumetric BMDand does not allow selective measurement of the trabecular bone,
which is more likely to be adversely affected by corticosteroid In one study, 20 prepubertal children with asthma on moderate
excess than cortical bone. If DXA is to be used as a method of to high doses of ICS (as defined by current British Thoracic
assessment of BMD in children, it is important that results are Society guidelines[56,57]) had the volumetric trabecular BMD
compared with height-matched normative data to minimize the (vTBMD) of their lumbar spine, and distal radial trabecular BMD
confounding effects of possible short stature. (rTBMD) measured.[62] The children were taking either beclo-
methasone, budesonide, or fluticasone propionate in dosages >400Volumetric BMD
μg/day (beclomethasone or budesonide) or >200 μg/day (fluti-It has been argued that a more appropriate method of assessing
casone propionate) for at least 1 year. All but 4 children had alsothe mineral content of bone is to use volumetric BMD (vBMD).
had at least one course of oral corticosteroids in the previous year.vBMD can be measured directly using quantitative computed
The BMD results were compared with in-house data on healthytomography (QCT), a technique that is able to distinguish between
White children and with published values from the US, matchingthe cortical and trabecular component of bone. Studies have dem-
for age and gender. It was found that the vTBMD and rTBMD inonstrated that QCT measurement of vBMD at the mid-femur of
all three groups were within the normal range, although thehealthy children is independent of age and height, but that a
standard deviation scores between the budesonide- and fluticasonemodest increase is observed at the lumbar spine at puberty.[84]
propionate-treated groups were significantly different, suggestingPeripheral QCT is a relatively new technique that measures vBMD
that fluticasone propionate had a lesser effect on TBMD thanat peripheral sites in the upper and lower limbs. It has the advan-
budesonide. It should be noted, however, that the numbers in eachtages of precision, relatively low radiation, and excellent norma-
group were very small.[82]tive data.[85]
In another study, 45 children with asthma had their BMD (bothVolume assumptions have been applied to calculate a vBMDareal and volumetric) evaluated, along with adrenal function and(g/cm3) for regional DXA techniques at the spine, hip, and mid-serum markers of bone metabolism.[40] The children were dividedfemur.[86-89] Calculated vBMD is not altered by bone size andinto two groups according to dosage, as previously described (seeremains more or less constant with age in prepubertal chil-section 2.2.2). The mean standard deviation scores for aBMD indren.[82,86] Because of these potential differences, studies usingboth groups were significantly lower than the population means ofvBMD and aBMD DXA are discussed separately in section 2.4.3.zero (p < 0.01), whereas vBMD values were normal. There were
Biochemical Markers no differences in aBMD and vBMD between the two groupsSome other studies on the effect of ICS on bone metabolism in (figure 3). The authors noted that their population was shorter than
children have looked at biochemical markers of bone turnover.[90]normal and they concluded that this would explain the lower
These include urinary hydroxyproline, creatinine and calcium, aBMD values.creatinine ratios, serum osteocalcin, and serum alkaline phospha-
tase levels.[90] However, these markers can be affected by numer- Areal BMDous variables, including recent physical activity, current growth
Chlorofluorocarbon beclomethasone and budesonide: Onevelocity, intercurrent illness, and even the assay used to measure
study compared 14 children with asthma who had taken chloro-them. There is also a paucity of data on normal age- and gender-
fluorocarbon beclomethasone at dosages of 300–400 μg/day forspecific values. Finally, there is a lack of data to validate the
the previous 6 months, with 16 age-, height-, and gender-matchedconnection between bone marker levels and subsequent growth
control individuals with asthma who were not treated with ICS.[93]
and eventual osteoporosis risk.[66] These issues limit our ability toThree children in each group (one girl and two boys) were clinical-
draw useful conclusions on the effects of ICS on bone in childrenly in early puberty. All the others were prepubertal. DXA was used
from studies using these markers.to assess BMD and the results were compared with age-matched
2.4.3 Effect of ICS on BMD (but not height-matched) reference values. The children were
ICS dose-related reduction of BMD has been well established reassessed 6 months after the initial measurements were taken and
in adult patients with asthma,[91,92] but there is limited pediatric there were no differences in BMD between the two groups. During
literature available, particularly on vBMD (table VII). the period of the study, the BMD in the control group increased by
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the New
er Inhaled C
orticosteroids in C
hildhood
Asthm
a499
© A
dis D
ata
Info
rma
tion
BV 2003. A
ll righ
ts rese
rved
.P
ed
iatr D
rug
s 2003; 5 (7)
Table VII. Summary of studies on effects of inhaled corticosteroids on bone mineral density and fractures
Study Population studied Drug and dosage Outcome measured Result
Reilly et al.[82] 20 prepubertal children Beclomethasone/budesonide >400 μg/day vBMD No difference from healthy
or fluticasone propionate >200 μg/day controls
Clavano et al.[40] 23 (group I), 22 (group II), all Beclomethasone/budesonide <600 μg/m2/ vBMD and aBMD Decreased aBMD, normal vBMD
stages of puberty day (I) or >600 μg/m2/day (II) in both
Pedersen et al.[20] 19 children (prepubertal at Chlorofluorocarbon beclomethasone aBMD (DXA scan) No change from baseline
start of study) 200–400 μg/day vs hydrofluoroalkane
beclomethasone 100–200 μg/day
Baraldi et al.[93] 30 children, variable puberty Chlorofluorocarbon beclomethasone aBMD (DXA scan) No difference between groups
300–400 μg/day vs no ICS
Harris et al.[94] 76 prepubertal children No ICS vs MIC, HIC, or HIC + O aBMD (DXA scan) Lower BMD in HIC + O than MIC
or no ICS groups
Gregson et al.[95] 23 prepubertal children Fluticasone propionate 200 μg/day vs aBMD (DXA scan) No difference from healthy
chlorofluorocarbon beclomethasone 400 μg/ controls
day
van Staa et al.[96] >500 000 adults on ICS, Fluticasone propionate, beclomethasone or Incidence of fractures Increased risk of fractures with
bronchodilators only, or no budesonide, varying dosages ICS, especially high dosages
chest disease
Ma and Jones[97] 324 prepubertal children ICS vs no ICS (drug and dosage not Incidence of fractures Increased risk of fractures with
identified) and BMD ICS, BMD normal
aBMD = areal bone mineral density; BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; HIC = high-dosage ICS; ICS = inhaled corticosteroids; MIC = moderate-
dosage ICS; O = oral corticosteroids; vBMD = volumetric bone mineral density.
500 Randell et al.
Hydrofluoroalkane beclomethasone: In a multicenter, random-
ized, open-label study, chlorofluorocarbon beclomethasone (via
spacer) and hydrofluoroalkane beclomethasone (administered by
Autohaler®) were directly compared.[20] 256 prepubertal children
with well-controlled asthma were changed from their usual ICS to
equivalent dosages of either chlorofluorocarbon beclomethasone
via spacer (dosage range 200–800 μg/day) or hydrofluoroalkane
beclomethasone (100–400 μg/day). Bone markers (serum osteo-
calcin, carboxy propeptide of procollagen type 1, 1-collagen
telopeptide, and urine deoxypyridinoline) and BMD using DXA
were assessed at the beginning and end of the study (12 months
later) in a subgroup of patients. There were no differences in either
bone markers or BMD on completion of the study compared with
baseline values. However, no comparisons were made with normal
values for children without asthma, and only 19 children out of the
initial 256 enrolled had BMD measured. These only included
children taking either a maximum of hydrofluoroalkane beclo-
methasone 200 μg/day or chlorofluorocarbon beclomethasone 400
μg/day; children receiving higher dosages did not have their BMD
Z s
core
s w
ith 9
5% c
onfid
ence
inte
rval
s
−1.5
−1.0
−0.5
0.0
0.5
1.0
Right femoral neck aBMD Right femoral neck vBMD
Group 1 Group 2
Fig. 3. Comparison of aBMD and vBMD in children receiving <600 μg/m2/day (group 1; n = 23) or >600 μg/m2/day (group 2; n = 22) of ICS.[40] aBMDwas significantly lower than normal in both groups, but vBMD was normalin both groups. There was no significant difference in the aBMD betweengroup 1 and group 2, or in vBMD between the two groups. aBMD = arealbone mineral density; ICS = inhaled corticosteroids; vBMD = volumetricbone mineral density.
reported. In addition, although the children had to be prepubertal at
the start of the study, there is no comment as to whether they were4%, compared with only 2.3% in the beclomethasone group, butexcluded from the final analysis if they started puberty during theanalysis of variance did not show any significant difference be-study.[20]
tween the groups.Fluticasone propionate and mometasone: One study has direct-
Another study examined the effects of different dosages of ICSly compared aBMD in children taking fluticasone propionate or
on the BMD of prepubertal children with asthma. Seventy-sixchlorofluorocarbon beclomethasone.[95] Twenty-three corticoster-
children with asthma who had had no changes to their treatment inoid-naive, prepubertal children were randomized to either fluti-
the previous 6 months were enrolled, all of whom were prepubert-casone propionate 200 μg/day or chlorofluorocarbon beclometha-
al. They were then divided according to whether they had received sone 400 μg/day, and followed for 20 months with regular DXAno ICS, moderate-dosage ICS (400–800 μg/day), high-dosage ICS scans. BMD increased over time, following normal patterns of(>800 μg/day), or high-dosage ICS (>800 μg/day) plus at least one growth, with no difference between the two groups.course of oral corticosteroids. Children were either taking fluti- There are as yet no published data on the effects of mometasonecasone propionate, budesonide, or chlorofluorocarbon beclo- on BMD.methasone, but were allocated to groups according to the dosage
2.4.4 ICS and Fracturesof corticosteroid taken rather than the type. Their lumbar spine
BMD was then assessed using DXA and it was found that, when Fractures in Adultsadjusted for weight, it was lower in those children who had If there are adverse effects on bone mineralization, a potentialreceived high-dosage ICS + oral corticosteroids, compared with adverse effect could be an increased risk of fractures. A recentthose who were in the moderate-dosage ICS, or no ICS groups. very large epidemiological study from the UK looked at theWhen the high-dosage ICS and high-dosage ICS + oral cortico- incidence of fractures in adults (children excluded) who used ICS,steroids groups were combined, the lumbar spine BMD was still compared with two control groups – a matched control group and alower than the moderate-dosage ICS group and it was postulated group of non-corticosteroid bronchodilator users. Patients usingthat long-term high dosages of ICS alone could be associated with oral corticosteroids were excluded from the analysis.[96] It was
reduced bone mass.[94] found that in the ICS-treated group, the relative risks of
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 501
nonvertebral, hip, and vertebral fractures were 1.15 (95% CI • Taking into consideration the above limitations, studies to date
1.10–1.20), 1.22 (95% CI 1.04–1.43), and 1.51 (95% CI have not suggested a significant effect of ICS on aBMD or
1.22–1.85) respectively, when compared with control individuals vBMD.
without respiratory disease. There were no differences between the • There does appear to be an increased risk of fractures inICS- and bronchodilator-treated groups. When the types of ICS children who use ICS, although the numbers reported so far arewere analyzed separately (fluticasone propionate, beclometha- small.sone, or budesonide) there were no differences between them.
2.5 CataractsHowever, there was an increased risk of hip and vertebral fracture
in the group treated with high-dosage ICS (>700 μg/day), com-There have been no reported cases of cataracts in children
pared with those treated with medium to low dosages or broncho-receiving ICS alone. One child in the CAMP study was found to
dilators only. This risk disappeared on cessation of treatment. Thehave a questionable posterior subcapsular cataract on slit-lamp
authors conclude that ICS use may increase the risk of fractures,examination, 5 months after initially being assessed as having no
but that the underlying respiratory disease may also have a part toproblems. Vision in that eye was normal and he had been on high
play.doses of budesonide and beclomethasone, oral corticosteroids, and
Fractures in Children also intranasal corticosteroids.[75] There appears to be no risk of
A recent Australian study has looked at the clinical risk factors cataracts in children from ICS alone.
and BMD in children with fractures.[97] A cohort of children has3. Conclusionsbeen followed since birth, and 324 of the original 696 volunteers
were reassessed at the age of 8 years. Thirty-two children had• ICS remain a vital part of the management of persistent asthma,
sustained a fracture (23 boys, 9 girls), and it was found that theybut concerns have been raised about their potential adverse
were older, were less likely to have been breast-fed, had highereffects in children.
levels of sports participation, and higher ICS use in the previous• Topical adverse effects such as thrush and dysphonia are rare,
year than those children who had not had a fracture. Nineteen of 32but dental erosion with powder forms of ICS is a possibility
children with a fracture had used ICS versus 9 out of 292 who hadbecause of their low pH. It is, thus, important to stress mouth
had no fracture. There were no differences in BMD between thoserinsing after administration and maintaining good dental hy-
children with or without fractures. The type and doses of ICS weregiene to minimize this risk.
not specified.• Adverse systemic effects have been recognized for many years
2.4.5 Summary and the newer ICS, particularly fluticasone propionate, were
• The effect of the newer ICS on BMD is difficult to assess initially introduced as being safer than the older ICS. Theoreti-because of the technical problems in measuring it. cally, there would be less systemic availability, as any drug that
• Biochemical markers of bone turnover cannot be recommended was swallowed would be eliminated by the first-pass mecha-
as a measure of bone physiology in children as they are subject nism. However, time has shown this not to be the case, because
to too much day-to-day variability, based on activity levels, of direct absorption from the lungs, particularly in the context
growth rate, etc. of mild asthma.
• aBMD measured using DXA scans is the most commonly used • Biochemical adrenal suppression can be readily demonstrated,
method of assessing BMD, but is highly dependent on the particularly with high doses of ICS. The clinical relevance of
growth of children and does not assess trabecular bone, which this was uncertain in the past, but there have now been >50
is more likely to be affected by ICS. It is important that if it is reported cases of acute adrenal crises in children receiving ICS,
used as an assessment tool, values are matched for height and most of whom were on fluticasone propionate.
not just age. • Screening all children who are on ICS for adrenal insufficiency
• vBMD may be a more accurate way of assessing the actual would be impractical, and while many of the children who
mineral content of bone in children, but very few studies have experienced adrenal crises were on high doses of corticoster-
used it as a tool. oids, others were on doses within the recommended treatment
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
502 Randell et al.
References of relevant studies were sought from the manufacturers of therange. This suggests that the risk of adrenal crisis is idiosyn-ICS. No sources of funding were used to assist in the preparation of thiscratic and not necessarily possible to predict.manuscript. The authors believe that there are no potential conflicts of interest
• In order to minimize the risk of symptomatic adrenal suppres- that are directly relevant to the content of this manuscript.sion, it is very important to back-titrate the ICS dose once
symptom control is achieved, and alert families of childrenReferencesreceiving high-dose ICS of this potential adverse effect. A
1. National Institutes of Health. National asthma education and prevention programpediatric endocrine opinion should be sought if adrenal sup-
expert panel report 2: guidelines for the diagnosis and management of asthma.pression is suspected. Bethesda (MD): National Institutes of Health, 1997. Publication no. 97-4051
2. Van Asperen PP, Mellis CM, Sly PD. The role of corticosteroids in the manage-• The older ICS cause temporary slowing of growth velocity, butment of childhood asthma. The Thoracic Society of Australia and New Zealand.
the limited data available do not show any significant compro- Med J Aust 1992; 156 (1): 48-52
3. National Asthma Council. Asthma management handbook [online]. Availablemise on final adult height. The effect on growth of fluticasonefrom URL: www.NationalAsthma.org.au [Accessed 2003 Jun 11]
propionate may not be as great as with the older ICS, but the4. Calpin C, Macarthur C, Stephens D, et al. Effectiveness of prophylactic inhaled
studies have been short term and only using low doses of steroids in childhood asthma: a systemic review of the literature. J Allergy ClinImmunol 1997; 100 (4): 452-7fluticasone propionate. There have been case reports of growth
5. Allen DB. Safety of inhaled corticosteroids in children. Pediatr Pulmonol 2002; 33suppression in children receiving high doses of fluticasone (3): 208-20
6. Fabbri L, Burge PS, Croonenborgh L, et al. Comparison of fluticasone propionatepropionate.with beclomethasone dipropionate in moderate to severe asthma treated for one• The limited studies performed on the effect of ICS on BMD inyear. International Study Group. Thorax 1993; 48 (8): 817-23
children do not show any adverse effects, but there may be an 7. Ferguson AC, Spier S, Manjra A, et al. Efficacy and safety of high-dose inhaledsteroids in children with asthma: a comparison of fluticasone propionate withincreased risk of fractures in children receiving ICS.budesonide. J Pediatr 1999; 134 (4): 422-7
• Hydrofluoroalkane beclomethasone is essentially the same 8. Hamid QA, Minshall EM. Molecular pathology of allergic disease (I): lowerairway disease. J Allergy Clin Immunol 2000; 105 (1 Pt 1): 20-36drug as chlorofluorocarbon beclomethasone, but with double
9. Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids:the lung deposition owing to the smaller particle size with thenew developments. Am J Respir Crit Care Med 1998; 157 (3 Pt 2): S1-53
new propellant. Thus, it could be expected that any adverse 10. Lipworth BJ. New perspectives on inhaled drug delivery and systemic bioactivity.Thorax 1995; 50 (2): 105-10effects seen with chlorofluorocarbon beclomethasone on
11. Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids: lessonsgrowth or BMD would be the same with hydrofluoroalkane
for the new millennium. Drug Saf 2000; 23 (1): 11-33beclomethasone. However, some of the published data, partic- 12. Daley-Yates PT, Price AC, Sisson JR, et al. Beclomethasone dipropionate:
absolute bioavailability, pharmacokinetics and metabolism following intrave-ularly in adults, suggest that hydrofluoroalkane beclometha-nous, oral, intranasal and inhaled administration in man. Br J Clin Pharmacol
sone may be less systemically active than chlorofluorocarbon 2001; 51 (5): 400-9
13. Holliday SM, Faulds D, Sorkin EM. Inhaled fluticasone propionate: a review of itsbeclomethasone, at equipotent doses.pharmacodynamic and pharmacokinetic properties, and therapeutic use in asth-• There are no long-term data as yet on mometasone, but initialma. Drugs 1994; 47 (2): 318-31
studies in adults suggest there may be less suppression of the 14. Sharpe M, Jarvis B. Inhaled mometasone furoate: a review of its use in adults andadolescents with persistent asthma. Drugs 2001; 61 (9): 1325-50HPA axis with this agent than with other ICS. The intranasal
15. Fitzgerald D. Non-compliance in adolescents with chronic lung disease: causativepreparation has no adverse effect on growth in clinically recom- factors and practical approach. Paediatr Respir Rev 2001; 2 (3): 260-7
16. Couriel J. Asthma in adolescence. Paediatr Respir Rev 2003; 4 (1): 47-54mended doses.17. Newman SP, Millar AB, Lennard-Jones TR, et al. Improvement of pressurised• ICS will remain a cornerstone in the management of persistent
aerosol deposition with Nebuhaler spacer device. Thorax 1984; 39 (12): 935-41pediatric asthma, provided that the diagnosis of asthma is 18. Feddah MR, Davies NM, Gipps EM, et al. Influence of respiratory spacer devices
on aerodynamic particle size distribution and fine particle mass of beclometha-secure. It is very important to use ICS appropriately and tosone from metered-dose inhalers. J Aerosol Med 2001; 14 (4): 477-85
ensure that the lowest possible doses are used to achieve19. Lipworth BJ, Jackson CM. Pharmacokinetics of chlorofluorocarbon and hydro-
symptom control, and thus minimize the risk of serious adverse fluoroalkane metered-dose inhaler formulations of beclomethasone dipropion-ate. Br J Clin Pharmacol 1999; 48 (6): 866-8effects.
20. Pedersen S, Warner J, Wahn U, et al. Growth, systemic safety, and efficacy during1 year of asthma treatment with different beclomethasone dipropionate formu-
Acknowledgements lations: an open-label, randomized comparison of extrafine and conventionalaerosols in children. Pediatrics 2002; 109 (6): E92
The authors wish to thank Dr Amabel Clavano for allowing us to repro- 21. Brutsche MH, Brutsche IC, Munawar M, et al. Comparison of pharmacokineticsduce her data on bone mineral density. and systemic effects of inhaled fluticasone propionate in patients with asthma
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 503
and healthy volunteers: a randomised crossover study. Lancet 2000; 356 44. Barnes NC, Hallett C, Harris TA. Clinical experience with fluticasone propionate(9229): 556-61 in asthma: a meta- analysis of efficacy and systemic activity compared with
budesonide and beclomethasone dipropionate at half the microgram dose or22. Harrison TW, Wisniewski A, Honour J, et al. Comparison of the systemic effectsless. Respir Med 1998; 92 (1): 95-104of fluticasone propionate and budesonide given by dry powder inhaler in
healthy and asthmatic subjects. Thorax 2001; 56 (3): 186-91 45. Fowler SJ, Orr LC, Wilson AM, et al. Dose-response for adrenal suppression withhydrofluoroalkane formulations of fluticasone propionate and beclomethasone23. Pedersen S, O’Byrne P. A comparison of the efficacy and safety of inhaleddipropionate. Br J Clin Pharmacol 2001; 52 (1): 93-5corticosteroids in asthma. Allergy 1997; 52 (39 Suppl.): 1-34
46. Davies RJ, Stampone P, O’Connor BJ. Hydrofluoroalkane-134a beclomethasone24. Toogood JH, Jennings B, Greenway RW, et al. Candidiasis and dysphoniadipropionate extrafine aerosol provides equivalent asthma control to chloro-complicating beclomethasone treatment of asthma. J Allergy Clin Immunolfluorocarbon beclomethasone dipropionate at approximately half the total daily1980; 65 (2): 145-53dose. Respir Med 1998; 92 Suppl. A: 23-3125. Agertoft L, Larsen FE, Pedersen S. Posterior subcapsular cataracts, bruises and
47. Gross G, Thompson PJ, Chervinsky P, et al. Hydrofluoroalkane-134a beclometha-hoarseness in children with asthma receiving long-term treatment with inhaledsone dipropionate, 400 microg, is as effective as chlorofluorocarbon beclo-budesonide. Eur Respir J 1998; 12 (1): 130-5methasone dipropionate, 800 microg, for the treatment of moderate asthma.26. Al Dlaigan YH, Shaw L, Smith AJ. Is there a relationship between asthma andChest 1999; 115 (2): 343-51dental erosion: a case control study. Int J Paediatr Dent 2002; 12 (3): 189-200
48. Fireman P, Prenner BM, Vincken W, et al. Long-term safety and efficacy of a27. McDerra EJ, Pollard MA, Curzon ME. The dental status of asthmatic Britishchlorofluorocarbon-free beclomethasone dipropionate extrafine aerosol. Annschool children. Pediatr Dent 1998; 20 (4): 281-7Allergy Asthma Immunol 2001; 86 (5): 557-6528. O’Sullivan EA, Curzon MEJ. Drug treatments for asthma may cause erosive tooth
49. Affrime MB, Kosoglou T, Thonoor CM, et al. Mometasone furoate has minimaldamage [letter]. BMJ 1998; 317 (7161): 820effects on the hypothalamic-pituitary- adrenal axis when delivered at high29. Oelkers W. Adrenal insufficiency. N Engl J Med 1996; 335 (16): 1206-12doses. Chest 2000; 118 (6): 1538-46
30. Law CM, Marchant JL, Honour JW, et al. Nocturnal adrenal suppression in50. Allen DB, Bronsky EA, LaForce CF, et al. Growth in asthmatic children treatedasthmatic children taking inhaled beclomethasone dipropionate. Lancet 1986; I
with fluticasone propionate. Fluticasone Propionate Asthma Study Group. J(8487): 942-4Pediatr 1998; 132 (3 Pt 1): 472-7
31. Patel L, Wales JK, Kibirige MS, et al. Symptomatic adrenal insufficiency during51. Wong J, Black P. Acute adrenal insufficiency associated with high dose inhaledinhaled corticosteroid treatment. Arch Dis Child 2001; 85 (4): 330-4
steroids [letter]. BMJ 1992; 304 (6839): 141532. Drake AJ, Howells RJ, Shield JP, et al. Symptomatic adrenal insufficiency52. Zwaan CM, Odink RJ, Delemarre-van de Waal HA, et al. Acute adrenal insuffi-presenting with hypoglycaemia in children with asthma receiving high dose
ciency after discontinuation of inhaled corticosteroid therapy. Lancet 1992; 340inhaled fluticasone propionate. BMJ 2002; 324 (7345): 1081-2(8830): 1289-9033. Todd GR, Acerini CL, Buck JJ, et al. Acute adrenal crisis in asthmatics treated
53. Taylor AV, Laoprasert N, Zimmerman D, et al. Adrenal suppression secondary towith high-dose fluticasone propionate. Eur Respir J 2002; 19 (6): 1207-9inhaled fluticasone propionate. Ann Allergy Asthma Immunol 1999; 83 (1):34. Holt PR, Lowndes DW, Smithies E, et al. The effect of an inhaled steroid on the68-70hypothalamic-pituitary-adrenal axis: which tests should be used? Clin Exp
54. Todd GR, Acerini CL, Ross-Russell R, et al. Survey of adrenal crisis associatedAllergy 1990; 20 (2): 145-9with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002; 8735. Shah A, Stanhope R, Matthew D. Hazards of pharmacological tests of growth(6): 457-61hormone secretion in childhood. BMJ 1992; 304 (6820): 173-4
55. Macdessi JS, Randell TL, Donaghue KC, et al. Adrenal crises in children treated36. Galloway PJ, McNeill E, Paterson WF, et al. Safety of the insulin tolerance test.with high-dose inhaled corticosteroids for asthma. Med J Aust 2003; 178 (5):Arch Dis Child 2002; 87 (4): 354-6214-6
37. Gonzalez-Gonzalez JG, De la Garza-Hernandez NE, Mancillas-Adame LG, et al.56. The General Practioner in Asthma Group, the British Association of Accident andA high-sensitivity test in the assessment of adrenocortical insufficiency: 10
Emergency Medicine, the British Paediatric Respiratory Society, and the Royalmicrog vs 250 microg cosyntropin dose assessment of adrenocortical insuffi-College of Paediatrics and Child Health. Asthma in adults and school children.ciency. J Endocrinol 1998; 159 (2): 275-80Thorax 1997; 52 Suppl. 1: S2-5
38. Suliman AM, Smith TP, Labib M, et al. The low-dose ACTH test does not provide57. The General Practioner in Asthma Group, the British Association of Accident anda useful assessment of the hypothalamic-pituitary-adrenal axis in secondary
Emergency Medicine, the British Paediatric Respiratory Society, and the Royaladrenal insufficiency. Clin Endocrinol (Oxf) 2002; 56 (4): 533-9College of Paediatrics and Child Health. Asthma in adults and school children.
39. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a system-Thorax 1997; 52 Suppl. 1: S20
atic review and meta-analysis. Arch Intern Med 1999; 159 (9): 941-5558. Tanner JM, Davies PS. Clinical longitudinal standards for height and height
40. Clavano A, Ambler GR, Cowell CT, et al. The effect of inhaled steroids on bonevelocity for North American children. J Pediatr 1985; 107 (3): 317-29
density and adrenal gland function in children [abstract]. In: Proceedings of the59. Allen DB. Inhaled corticosteroid therapy for asthma in preschool children: growthEndocrine Society of Australia 40th Annual Scientific Meeting. Melbourne
issues. Pediatrics 2002; 109 (2 Suppl.): 373-80(VIC): The Endocrine Society of Australia, 1997: 14760. Abu EO, Horner A, Kusec V, et al. The localization of the functional glucocorti-41. Fitzgerald D, Van Asperen P, Mellis C, et al. Fluticasone propionate 750
coid receptor alpha in human bone. J Clin Endocrinol Metab 2000; 85 (2):micrograms/day versus beclomethasone dipropionate 1500 micrograms/day:883-9comparison of efficacy and adrenal function in paediatric asthma. Thorax 1998;
61. Russell G. Asthma and growth. Arch Dis Child 1993; 69 (6): 695-853 (8): 656-6162. Martin AJ, Landau LI, Phelan PD. The effect on growth of childhood asthma. Acta42. Kannisto S, Korppi M, Remes K, et al. Adrenal suppression, evaluated by a low
Paediatr Scand 1981; 70 (5): 683-8dose adrenocorticotropin test, and growth in asthmatic children treated with63. Balfour-Lynn L. Growth and childhood asthma. Arch Dis Child 1986; 61 (11):inhaled steroids. J Clin Endocrinol Metab 2000; 85 (2): 652-7
1049-5543. Lipworth BJ, Clark DJ, McFarlane LC. Adrenocortical activity with repeated twicedaily dosing of fluticasone propionate and budesonide given via a large volume 64. Shaw NJ, Fraser NC, Weller PH. Asthma treatment and growth. Arch Dis Childspacer to asthmatic school children. Thorax 1997; 52 (8): 686-9 1997; 77 (4): 284-6
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
504 Randell et al.
65. de Benedictis FM, Teper A, Green RJ, et al. Effects of 2 inhaled corticosteroids on 84. Gilsanz V, Kovanlikaya A, Costin G, et al. Differential effect of gender on thegrowth: results of a randomized controlled trial. Arch Pediatr Adolesc Med sizes of the bones in the axial and appendicular skeletons [published erratum2001; 155 (11): 1248-54 appears in J Clin Endocrinol Metab 1997 Jul; 82 (7): 2274]. J Clin Endocrinol
66. Allen DB. Limitations of short-term studies in predicting long-term adverse effects Metab 1997; 82 (5): 1603-7of inhaled corticosteroids. Allergy 1999; 54 Suppl. 49: 29-34
85. Schoenau E, Neu CM, Rauch F, et al. The development of bone strength at the67. Wolthers OD, Hansen M, Juul A, et al. Knemometry, urine cortisol excretion, and proximal radius during childhood and adolescence. J Clin Endocrinol Metab
measures of the insulin-like growth factor axis and collagen turnover in children2001; 86 (2): 613-8
treated with inhaled glucocorticosteroids. Pediatr Res 1997; 41 (1): 44-5086. Lu PW, Cowell CT, LLoyd-Jones SA, et al. Volumetric bone mineral density in
68. Agertoft L, Pedersen S. Short-term knemometry and urine cortisol excretion innormal subjects, aged 5-27 years. J Clin Endocrinol Metab 1996; 81 (4):children treated with fluticasone propionate and budesonide: a dose response1586-90study. Eur Respir J 1997; 10 (7): 1507-12
87. Kroger H, Kotaniemi A, Vainio P, et al. Bone densitometry of the spine and femur69. Visser MJ, van Aalderen WM, Elliott BM, et al. Short-term growth in asthmaticchildren using fluticasone propionate. Chest 1998; 113 (3): 584-6 in children by dual-energy x-ray absorptiometry [published erratum appears in
Bone Miner 1992 Jun; 17 (3): 429]. Bone Miner 1992; 17 (1): 75-8570. Anhoj J, Bisgaard AM, Bisgaard H. Systemic activity of inhaled steroids in 1- to3-year-old children with asthma. Pediatrics 2002; 109 (3): E40 88. Sievanen H, Kannus P, Nieminen V, et al. Estimation of various mechanical
71. Agertoft L, Pedersen S. Short-term lower leg growth rate in children with rhinitis characteristics of human bones using dual energy X-ray absorptiometry: meth-treated with intranasal mometasone furoate and budesonide. J Allergy Clin odology and precision. Bone 1996; 18 (1 Suppl.): 17-27SImmunol 1999; 104 (5): 948-52
89. Carter DR, Bouxsein ML, Marcus R. New approaches for interpreting projected72. Simons FE. A comparison of beclomethasone, salmeterol, and placebo in children bone densitometry data. J Bone Miner Res 1992; 7 (2): 137-45
with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate90. Sorva R, Turpeinen M, Juntunen-Backman K, et al. Effects of inhaled budesonideStudy Group. N Engl J Med 1997; 337 (23): 1659-65
on serum markers of bone metabolism in children with asthma. J Allergy Clin73. Sharek PJ, Bergman DA. The effect of inhaled steroids on the linear growth of
Immunol 1992; 90 (5): 808-15children with asthma: a meta-analysis. Pediatrics 2000; 106 (1): E8
91. Wong CA, Walsh LJ, Smith CJ, et al. Inhaled corticosteroid use and bone-mineral74. Sharek PJ, Bergman DA, Ducharme F. Beclomethasone for asthma in children:density in patients with asthma. Lancet 2000; 355 (9213): 1399-403effects on linear growth (Cochrane Review). Available in The Cochrane Libra-
ry [database on disk and CD ROM]. Updated quarterly. The Cochrane Collabo- 92. Israel E, Banerjee TR, Fitzmaurice GM, et al. Effects of inhaled glucocorticoids onration; issue 4. Oxford: Update Software, 2002
bone density in premenopausal women. N Engl J Med 2001; 345 (13): 941-775. The Childhood Asthma Management Program Research Group. Long-term effects
93. Baraldi E, Bollini MC, De Marchi A, et al. Effect of beclomethasone dipropionateof budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343
on bone mineral content assessed by x-ray densitometry in asthmatic children: a(15): 1054-63longitudinal evaluation. Eur Respir J 1994; 7 (4): 710-4
76. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on94. Harris M, Hauser S, Nguyen TV, et al. Bone mineral density in prepubertaladult height in children with asthma. N Engl J Med 2000; 343 (15): 1064-9
asthmatics receiving corticosteroid treatment. J Paediatr Child Health 2001; 3777. Todd G, Dunlop K, McNaboe J, et al. Growth and adrenal suppression in asthmatic(1): 67-71children treated with high-dose fluticasone propionate. Lancet 1996; 348
(9019): 27-9 95. Gregson RK, Rao R, Murrills AJ, et al. Effect of inhaled corticosteroids on bone
mineral density in childhood asthma: comparison of fluticasone propionate with78. Schenkel EJ, Skoner DP, Bronsky EA, et al. Absence of growth retardation inchildren with perennial allergic rhinitis after one year of treatment with momet- beclomethasone dipropionate. Osteoporos Int 1998; 8 (5): 418-22asone furoate aqueous nasal spray. Pediatrics 2000; 105 (2): E22
96. van Staa TP, Leufkens HG, Cooper C. Use of inhaled corticosteroids and risk of79. Jonasson G, Carlsen KH, Mowinckel P. Asthma drug adherence in a long term fractures. J Bone Miner Res 2001; 16 (3): 581-8
clinical trial. Arch Dis Child 2000; 83 (4): 330-397. Ma DQ, Jones G. Clinical risk factors but not bone density are associated with
80. Wolthers OD, Allen DB. Inhaled corticosteroids, growth, and compliance. N Engl Jprevalent fractures in prepubertal children. J Paediatr Child Health 2002; 38 (5):
Med 2002; 347 (15): 1210-1497-500
81. Leonard MB, Zemel BS. Current concepts in pediatric bone disease. Pediatr ClinNorth Am 2002; 49 (1): 143-73
82. Reilly SM, Hambleton G, Adams JE, et al. Bone density in asthmatic children Correspondence and offprints: Dr Peter P. Van Asperen, Department oftreated with inhaled corticosteroids. Arch Dis Child 2001; 84 (2): 183-4
Respiratory Medicine, The Children’s Hospital at Westmead, Locked Bag83. Lu PW, Briody JN, Ogle GD, et al. Bone mineral density of total body, spine, and
4001, Westmead, Sydney, NSW 2145, Australia.femoral neck in children and young adults: a cross-sectional and longitudinalstudy. J Bone Miner Res 1994; 9 (9): 1451-8 E-mail: peterv@chw.edu.au
© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)
top related