Group: Warveen Othman, Jasmine Naim, Zuzanna Niewiadomska, Johanna Olaya

It is known that systemic steroids can slow bone growth.  Your 8 year old asthma patient’s mother is concerned that perhaps the daily inhaled steroids (given via a metered dose inhaler or MDI) could have the same effect.  What can you tell her?

Clinical Question: Mother is questioning if inhaled steroids can slow bone growth in her 8 y/o asthmatic son.

PICO Question:

Identify the PICO elements (Recalling that some questions do not have all the elements)

Do inhaled steroids slow bone growth in the pediatric population?

Population: Pediatric Asthmatics

Intervention: Inhaled Corticosteroids

Comparison: No ICS

Outcome: Slowed Bone Growth

Search Strategy:

Outline the terms used, databases  or other tools used, how many articles returned, and how  you selected the final articles to base your CAT on

Tools used: PubMed, New England Journal of Medicine

• PubMed: “inhaled corticosteroid bone growth” filters: 11/30/2021 – 12/30/2011, randomized control studies, systematic review, metaanalysis  number of articles: 8
• NEJM: “inhaled corticosteroid AND bone growth”. Filters: English, 01/2000 – 11/2021, RCT, systematic review, metaanalysis. Number of articles: 16

Articles Chosen for Inclusion (please copy and paste the abstract with link):

1.     “Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth”

1. https://onlinelibrary.wiley.com/doi/10.1002/ebch.1989
2. Abstract: Background: Asthma guidelines recommend inhaled corticosteroids (ICS) as the first choice of treatment for children with persistent asthma that is not well controlled when only a reliever inhaler is used to treat symptoms. Steroids work by reducing inflammation in the lungs and are known to control underlying symptoms of asthma. However, parents and physicians remain concerned about the potential negative effect of ICS on growth.

Review question: Does altering the dose of inhaled corticosteroids make a difference in the growth of children with asthma? WHAT EVIDENCE DID WE FIND?: We studied whether a difference could be seen in the growth of children with persistent asthma who were using different doses of the same ICS molecule and the same delivery device. We found 22 eligible trials, but only 10 of them measured growth or other measures of interest. Overall, 3394 children included in the review combined 17 group comparisons (i.e. 17 groups of children with mild to moderate asthma using a particular dose and type of steroid in 10 trials). Trials used different ICS molecules (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) either on their own or in combination with a long-acting beta2 -agonist (a drug used to open up the airways) and generally compared low doses of corticosteroids (50 to 100 μg) with low to medium (200 μg) doses of corticosteroids (converted in μg HFA-beclomethasone equivalent) over 12 to 52 weeks.

Conclusions: We report an evidence-based ICS dose-dependent reduction in growth velocity in prepubescent school-aged children with mild to moderate persistent asthma. The choice of ICS molecule (mometasone, ciclesonide or fluticasone) was not found to affect the level of growth velocity response over a year. The effect of corticosteroids on growth was not consistently reported: among 22 eligible trials, only four comparisons reported the effects of corticosteroids on growth over one year. In view of parents’ and clinicians’ concerns, lack of or incomplete reporting of growth is a matter of concern given the importance of the topic. We recommend that growth be systematically reported in all trials involving children taking ICS for three months or longer. Until further data comparing low versus high ICS dose and trials of longer duration are available, we recommend that the minimal effective ICS dose be used in all children with asthma.

2.     Inhaled corticosteroids in children with persistent asthma: effects on growth

2. https://pubmed.ncbi.nlm.nih.gov/25030198/
3. Abstract

Background: Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth.

Objectives: To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment).

Search methods: We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers’ clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014.

Selection criteria: Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma.

Data collection and analysis: Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child.

Main results: We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial.One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo.

Authors’ conclusions: Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.

Conflict of interest statement: No conflicts of interest are known.

3.     Inhaled corticosteroids used for the control of asthma in a “real-life” setting do not affect linear growth velocity in prepubertal children

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560656/

Background: Recent guidelines recommend inhaled corticosteroids as the first-line treatment for persistent asthma. However, long-term corticosteroid treatment in children has raised concerns about potential growth rate deceleration. We aimed to assess the association of growth velocity with the use of inhaled corticosteroids in prepubertal children with asthma in a “real-life” setting.

Material/Methods: This study included 844 children aged 4–9.5 years coming to the hospital for regular check-ups between October 2006 and February 2009 for asthma with/without allergic rhinitis and no other known constraints of growth. Out of the 844 children, 790 had all data needed for analysis – 245 children were not treated with ICS, 545 children received ICS (fluticasone, budesonide) with/without INCS (fluticasone, mometasone or budesonide). During the study period, 48 children with/without ICS received short SCS courses.

Results: Mean (SE) height at the first check-up was 123.1 (0.31) cm; range (100.0–147.8 cm). Mean (SE) linear growth velocity (LGV) of the included children was 0.185 (0.0035) mm/day between 2 check-ups. No significant difference was found in LGV between the group not treated with ICS (0.180 mm/day±0.0055) and the group treated with ICS (0.187±0.0044 mm/day). Also, there was no statistical difference between subgroups according to additional therapy with INCS and SCS. No significant correlation was found for LGV and daily dose of ICS (r=0.086, p>0.05).

Conclusions: In our retrospective study using electronic hospital database, ICS and combined use of corticosteroids did not show any association with LGV in prepubertal asthmatic children in a “real-life” setting.

4.    Effect of Long-Term Treatment with Inhaled Budesonide on Adult Height in Children with Asthma

a.      https://www.nejm.org/doi/full/10.1056/NEJM200010123431502

• BACKGROUND: Short-term studies have shown that inhaled corticosteroids may reduce the growth of children with asthma. However, the effect of long-term treatment on adult height is uncertain.
  • METHODS: We conducted a prospective study in children with asthma to examine the effect of long-term treatment with inhaled budesonide on adult height. We report on 211 children who have attained adult height: 142 budesonide-treated children with asthma, 18 control patients with asthma who have never received inhaled corticosteroids, and 51 healthy siblings of patients in the budesonide group, who also served as controls.
  • RESULTS: The children in the budesonide group attained adult height after a mean of 9.2 years of budesonide treatment (range, 3 to 13) at a mean daily dose of 412 μg (range, 110 to 877). The mean cumulative dose of budesonide was 1.35 g (range, 0.41 to 3.99). The mean differences between the measured and target adult heights were +0.3 cm (95 percent confidence interval, –0.6 to +1.2) for the budesonide-treated children, –0.2 cm (95 percent confidence interval, –2.4 to +2.1) for the control children with asthma, and +0.9 cm (95 percent confidence interval, –0.4 to +2.2) for the healthy siblings. The adult height depended significantly (P<0.001) on the child’s height before budesonide treatment. Although growth rates were significantly reduced during the first years of budesonide treatment, these changes in growth rate were not significantly associated with adult height.
  • CONCLUSIONS: Children with asthma who have received long-term treatment with budesonide attain normal adult height.

5. Effect of long term inhaled corticosteroid therapy on adrenal suppression, growth and bone health in children with asthma

https://bmcpediatr.biomedcentral.com/track/pdf/10.1186/s12887-019-1760-8.pdf

Background: Inhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. However adverse effects of ICS on Hypothalamo Pituitary Adrenal (HPA) axis, growth and bone metabolism are a concern. Hence the primary objective of this study was to describe the effects of long term inhaled corticosteroid therapy (ICS) on adrenal function, growth and bone health in children with asthma in comparison to an age and sex matched group of children with asthma who were not on long term ICS. Describing the association between the dose of ICS and duration of therapy on the above parameters were secondary objectives.

Method: Seventy children with asthma on ICS and 70 controls were studied. Diagnosis of asthma in selected patients was reviewed according to the criteria laid down by GINA 2018 guidelines. The estimated adult heights were interpreted relative to their Mid Parental Height (MPH) range. Serum calcium, alkaline phosphatase and vitamin D levels were analyzed in both groups and cortisol value at 30 min following a low dose short synacthen test was obtained from the study group. The average daily dose of ICS (Beclamethasone) was categorized as low, medium and high (100–200, 200–400, > 400 μg /day) respectively according to published literature.

Results: Heights of all children were within the MPH range. There was no statistically significant difference in the bone profiles and vitamin D levels between the two groups (Ca: p = 0.554, vitamin D: p = 0.187) but vitamin D levels were insufficient (< 50 nmol/l) in 34% of cases and 41% of controls. Suppressed cortisol levels were seen in 24%. Doses of ICS were low, medium and high in 56, 32 and 12% of children respectively. The association between adrenal suppression with longer duration of therapy (p < 0.01) and with increasing dose of ICS (p < 0.001) were statistically significant.

Conclusion: ICS had no impact on the growth and bone profiles but its dose and duration were significantly associated with adrenal suppression.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Pruteanu, et. al. December 9, 2014	Meta Analysis of Randomized Control Trials	10 trials 3,394 children	Does altering the dose of ICS make a difference in the growth of children with asthma?	There was a small, but statistically significant group difference in growth velocity that favors low doses of ICS to low/medium doses of HFA-beclomethasone.	Lack of systematic growth reporting. Incomplete reporting of growth velocity.
Zhang, L et al. July 17,2014	Meta-analysis of randomized control studies	25 trials with 8,471 children with mild -moderate persistent asthma	Assess the impact of ICS on linear bone growth in kids with persistent asthma.	A reduction of .48cm/year were seen in the first year of treatment that were dose independent. Bone growth reduction was less pronounced in subsequent years.	Children in the studies were only followed for 1-3 years. Newer molecules of ICS (mometasone, ciclesonide) were not included in study.
Erceg, D et. al. Sept 1, 2012	Retrospective observational study	790 pts aged 4–9.5 years (545 treated w/ ICS, 245 were not treated w/ ICS)	ICS effect on growth velocity of prepubertal children.	ICS did not show to result in growth retardation in prepubertal children.	Conclusion is only based on conventional doses. Lack of tx randomization. Lack of data certainty/accuracy.
Angertoft, et al. October 12, 2000	Prospective long-term observational study	n=211 children 142 treated with budesonide 69 controls	the effect of long-term treatment with inhaled budesonide on adult height	Children who have been treated with inhaled budesonide attain normal adult height.	-Only looks at budesonide effects. -There were few children remaining in the control group by the end of the study. So had to compare height to siblings. -Most subjects who remained in the study had mild asthma.
Kwda, Anuradha et. al 2019	Cross sectional descriptive study	n=140   Study Group (70): Children aged 3 to 9 years with asthma on long term inhaled corticosteroids for at least 6 months Control Group (70): Children aged 3 to 9 years not receiving ICS	Effect of Low, medium and High dose of ICS on Adrenal suppression, Bone Health/ Growth via Calcium, ALT and Vitamin D levels.	Adrenal Suppression: Findings: adrenal suppression when administered in high doses (> 400 μg/day) and for longer durations. (> 18 to 24 months)   Bone Growth Findings: . A significant effect on the growth of the children who were on ICS was not demonstrated from the findings of this study	-small Sample Size -Cross sectional Study estimated growth using parental heights rather doing prospective study   -due to being cross sectional, unable to provide effects on velocity of growth

Conclusion(s):

 Inhaled corticosteroid treatment may slow bone growth velocity of children at the beginning of treatment especially in the first year but are less pronounced in the subsequent years of treatment. Notably, one retrospective study showed most children end up attaining normal adult height. Also studies showed that the ICS molecule itself was more strongly associated with the growth suppressing in the first year rather than the device or low/medium dosing in persistent asthma.

Clinical Bottom Line:

Considering we only found one study showing evidence of normal adult height in patients treated with inhaled corticosteroid, we do think more research needs to be done to address the long term effects of ICS treatment in children. We would still recommend the ICS for the child. We would be honest with the mom about our findings and explain that in this situation the complications of asthma outweigh the 1-2cm of height reduction the child may experience.