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Systematic Review of the Evidence Regarding Potential Complications of Inhaled Corticosteroid Use in Asthma*: Collaboration of American College of Chest Physicians, American Academy of Allergy, Asthma, and Immunology, and American College of Allergy, Asthma, and Immunology FREE TO VIEW

Frank T. Leone; James E. Fish; Stanley J. Szefler; Suzanne L. West; for the Expert Panel on Corticosteroid Use
Author and Funding Information

Affiliations: *From Thomas Jefferson University (Dr. Leone), Philadelphia, PA; Aventis Pharmaceuticals (Dr. Fish), Bridgewater, NJ; National Jewish Medical and Research Center (Dr. Szefler), Denver, CO; and the University of North Carolina (Dr. West), Chapel Hill, NC.,  This work was performed while Dr. Fish was on the faculty of Thomas Jefferson University.,  See Appendix for list of members of the Expert Panel on Inhaled Corticosteroid Use.

Correspondence to: Frank T. Leone, MD, MS, FCCP, Jefferson Medical College, 1015 Chestnut St, Suite M100, Philadelphia, PA 19107; e-mail: frank.leone@mail.tju.edu


Affiliations: *From Thomas Jefferson University (Dr. Leone), Philadelphia, PA; Aventis Pharmaceuticals (Dr. Fish), Bridgewater, NJ; National Jewish Medical and Research Center (Dr. Szefler), Denver, CO; and the University of North Carolina (Dr. West), Chapel Hill, NC.,  This work was performed while Dr. Fish was on the faculty of Thomas Jefferson University.,  See Appendix for list of members of the Expert Panel on Inhaled Corticosteroid Use.


Chest. 2003;124(6):2329-2340. doi:10.1378/chest.124.6.2329
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Introduction: The available clinical guidelines have been successful in improving awareness of the inflammatory nature of asthma and have promoted the use of inhaled corticosteroids (ICSs) to achieve long-term control of symptoms. Because of lingering concerns over the possible adverse consequences of ICS use, an expert panel was convened with a mandate to identify the critical questions that impact decisions regarding the use of ICSs and to evaluate the available evidence with respect to risk

Methods: A university librarian retrieved citations and abstracts from the MEDLINE and EMBASE databases using a list of National Library of Medicine search terms and key words. Reviewers were asked to systematically abstract relevant information from each of their assigned articles and to list their own clinical or scientific conclusions based on the study results. A predefined grading algorithm was used to calculate a summary quality rating score for the relevant evidence

Results: The results are presented as a series of key questions followed by a summary of the relevant evidence. An evidence grade is assigned, followed by a summary statement reflecting the panel’s consensus opinion following review.

Conclusions: The preponderance of evidence supports a conclusion that the proven clinical effectiveness of ICS treatment decidedly outweighs the proven risks.

The available asthma clinical guidelines have been successful in improving awareness of the inflammatory nature of asthma and have promoted the use of inhaled corticosteroids (ICSs) to achieve long-term control of symptoms. With alternative controller medications available, observations regarding the potential side effects of ICS therapy have generated increasing concern and may influence asthma care decisions. Because > 15 million people in the United States have asthma, even low rates of adverse events can have significant public health consequences. However, because of the tremendous potential benefits of ICS therapy, it is important that the risks be correctly valued so that clinicians can incorporate an evidence-based approach into their bedside risk-benefit considerations. To this end, this report critically evaluates the strength and direction of the available evidence regarding the complications of ICS use in patients with asthma, evidence that clinicians may choose to incorporate into their daily practice. The American College of Chest Physicians, the American Academy of Allergy, Asthma and Immunology, and the American College of Allergy, Asthma and Immunology convened an expert panel with representation from each organization. The mandate of the panel was to identify the critical questions that impact the decisions regarding the use of ICS therapy and to evaluate the evidence available to help guide the accurate assessment of risk. In this report, we list our questions regarding several important side effects of ICSs, followed by a systematic grading of the evidence available to address that question. A discussion of the key literature used to formulate a summary statement representing the composite interpretation of the evidence by the panel is presented. The discussion is not intended to represent a comprehensive report of all of the literature reviewed during the conduct of this project, but instead a synopsis to explain and support the conclusions of the panel.

Identification of Evidence

A university librarian retrieved citations and abstracts from the MEDLINE and EMBASE databases using a list of National Library of Medicine search terms and key words that had been developed in conjunction with panel members. The databases included articles entered from inception through week 4 of December 2000. The recovery of articles was limited to five clinically relevant complications, including glaucoma, cataracts, skin thinning or ease of bruising, bone density or osteoporosis, and growth retardation, and to studies performed on humans and reported at least partly in English. Search results were checked for completeness against reference lists of review articles, as well as against the personal insight of panel members. After collating the complete list of candidate articles, title and abstract screening was performed by the panel to judge the appropriateness of the study for inclusion in the final body of evidence. Studies were excluded if they did not address asthma, included only healthy volunteers, focused exclusively on therapy with systemic corticosteroids, evaluated < 15 patients in a randomized clinical trial (RCT), focused on asthma disease management, tested ICS delivery methods, or were laboratory studies. The total body of evidence was equally divided into six subsets and was distributed to the panel for review. Each article was distributed to at least two panel members for dual review.

Panel Training and Evidence Collection

Panel members were trained in the data abstraction protocol by a methodologist specializing in the development of systematic reviews. A test article was distributed and the panel output was certified for accuracy. Reviewers were asked to systematically abstract relevant information from each of their assigned articles and to record this information on the primary data collection form (Table 1 ). Reviewers also were asked to list their own clinical or scientific conclusions based on the study results. Since definitions of high-dose ICSs differed between studies, reviewers were asked to use National Asthma Education and Prevention Program guideline definitions to help qualify their own conclusions and comments. A predefined algorithm, in which points were assigned to various quality indicators, was used to calculate a summary quality rating score with a range of 0 to 40 (Table 2 ). The scoring scheme was used to standardize the methods by which reviewers abstracted and evaluated information from the individual citations, as well as being used as a tool to give the reader an objective sense of the quality of the primary studies. Reviewers entered their abstracted information into the database via the Internet, and remained blinded to the impressions of others on the panel. A third independent panel member “over-read” approximately 40% of the references in order to ensure the quality of the evidence abstraction.

Organization and Grading

The central data source was queried by complication, and the graded reviews were available for integration and interpretation. For each of the complications of interest, the panel sought to report conclusions addressing several fundamental questions wherever possible, including the following: (1) Is ICS use associated with the complication?; (2) Is there a difference between ICS formulations?; and (3) Is there an identifiable relationship between the dose of ICS and the likelihood of the complication? Because there were no generally agreed on “standards” for evidence grading at the onset of this project, a tailor-made grading approach that focused primarily on the robustness of study design and the amount of evidence was developed. The strength of the evidence supporting each of the conclusions was graded as in Table 3 .

Manuscript Preparation and Review

A subset of the panel formed the writing committee, integrating and summarizing the input of the panel. During the initial manuscript preparation, content was carefully reviewed first by the writing committee, then by the panel as a whole. A draft version of the manuscript was submitted to several independent reviewers from each supporting organization for unbiased review and comment prior to submission for external peer review. Since our data set was limited a priori to articles published through the end of 2000, members of the panel were queried at each stage of the manuscript preparation and were asked to identify any additional interim publications that potentially could impact the conclusions of the panel. At the time of submission, no such interim articles had been identified as a result of this process.

The MEDLINE and EMBASE searches initially yielded a total of 375 candidate articles. Following dual title and abstract reviews, 267 (71%) met the exclusion criteria, and 108 references remained to be evaluated.

Bone Density/Osteoporosis
Is There a Reduction of Bone Density in Children With Asthma Using ICS?

Bootsma et al1 reported reduced bone mineral density (BMD) as measured by dual-energy x-ray absorptiometry scanning in a cohort of prepubertal children with asthma who had been treated with moderate-to-high doses of various ICSs over a period of 3 to 8 years. However, several potential confounders, including details surrounding oral corticosteroid use, were not adequately evaluated. In a similar prospective cohort of prepubertal Australian asthma patients, Allen et al2 found that ICS therapy in these young asthma patients was associated with a significant reduction in the rate of bone mass accretion. This study was methodologically sound, however, the clinical significance of the primary outcome measure has not been determined.

A case series3 of 35 children in the Omaha metropolitan area described the BMD in children at two clinic visits, at various intervals between 13 and 60 months apart. The asthmatic male children experienced a BMD above that observed in the nonasthmatic male children. There was no difference in BMD detected between asthmatic and nonasthmatic female children. The authors concluded that their results provide support for the safety of therapy with inhaled anti-inflammatory medications in children with significant asthma. However, the study was nonblinded, employed hugely variable follow-up periods, could not control for large variability in ICS dose or formulation, and was confounded by the inclusion of patients who had concurrently received therapy with oral steroids.

A RCT conducted in 23 asthmatic children (average age, 6.7 years) with variable severity of illness attempted to assess whether therapy with fluticasone, 100 μg bid, had a different effect on BMD than therapy with beclomethasone dipropionate (BDP), 200 μg bid.4 In this trial, all children were compared to healthy age-matched and gender-matched historical control subjects. Bone density was determined at 10-week intervals for a period of 30 weeks, and then twice during the subsequent year. After 82 weeks of active treatment, neither group showed a significant deleterious effect of the ICS therapy on bone density. The authors noted that BMD was not investigated during the pubertal period of maximal bone growth, which may have reduced the potential for identifying an ICS effect on BMD if it truly existed.

In a hospital-based asthma clinic in Italy, investigators studied5 the BMD of 64 children with mild-to-moderate asthma (average age, 6.7 years). Asthma was well-controlled in all patients, and none had received therapy with oral corticosteroids for at least 6 months. The BMD among the 36 children whose asthma was controlled with low-dose BDP therapy (average dose, 319 μg/d) was no different than that of the 8 children whose asthma was controlled with high-dose BDP (average dose, 525 μg/d). Neither group showed any difference in BMD compared to the children whose asthma had been controlled by cromolyn sodium therapy alone.

In an interim analysis of an ongoing RCT,6 268 children with mild asthma (age range, 5 to 16 years; mean age, 10.1 years) were evaluated for BMD, bone mineral content, total body calcium level, and body composition by dual-energy x-ray absorptiometry scan. All 157 asthma patients in the budesonide (BUD) group (mean daily dose, 504 μg) had received therapy with ICSs for at least 3 years. The mean compliance rate with medications was assessed at 78%. The 111 children in the control group received only oral or long-acting β-agonists, theophylline, or sodium cromoglycate to effect control. The duration of illness in the control group was significantly shorter than that in the ICS group (4.5 vs 8.3 years, respectively). Both groups were the same in terms of height, weight, activity level, and distribution of Tanner stage of patients, although the children in the BUD group had a higher FEV1 overall (97% predicted vs 81% predicted, respectively). No differences in BMD or body fat composition were found.

A cross-sectional observation7 in 97 healthy children and 30 children with moderate-to-severe asthma (age range, 5 to 18 years) utilized direct comparison and linear regression modeling to quantify the effect of ICS therapy on bone density. No measured independent variable, including daily ICS dose (in micrograms per kilogram per day), lifetime cumulative ICS dose, calcium intake, percent predicted FEV1, duration of asthma, or Tanner stage was found to significantly affect BMD. The authors suggested that the lack of effect may be due to a type II error, a methodological failure to detect a statistical difference when a difference truly exists, although no discussion of power was presented in the article.

The Childhood Asthma Management Program (CAMP) Research Group published its report8 on an RCT designed to evaluate the long-term effects of BUD or nedocromil on children with mild-to-moderate asthma. In a multicenter design, 1,041 children (age range, 5 to 12 years) were randomly assigned to receive 200 μg bid inhaled BUD, 8 mg bid inhaled nedocromil, or placebo. After 4 to 6 years of treatment, no differences in the change in bone density could be demonstrated between the groups.

Evidence grade: A. Conclusion: ICS use is not associated with a reduction in bone density in children with asthma.

Is There a Reduction of Bone Density in Adults With Asthma Using ICS?

The effect of ICSs on adult bone mineralization was examined9 in a cross-sectional observation of 1,673 community-dwelling white subjects (age range, 56 to 91 years) as a subanalysis of an ongoing osteoporosis study. Thirty-four asthma patients who required ICSs and 44 subjects who used oral corticosteroids were identified. The investigators confirmed that women who used oral corticosteroids had significantly lower bone mineral densities at the mid-shaft radius, hip, and spine than never-users. Among women who had used ICSs, BMD was reduced to a level intermediate between those of oral corticosteroid users and never-users, suggesting the presence of a possible effect of ICSs. However, differences were not statistically significant. Although the overall sample size was rather large, few ICS users were identified. The authors provided no discussion of the power of the sample to detect differences in the population, therefore valid conclusions regarding the influence of ICS therapy on BMD, or lack thereof, cannot be drawn.

Herrala et al10 studied bone mineral densities in 19 newly diagnosed, nonsmoking asthmatic women (age range, 40 to 63 years) who were receiving therapy with high-dose inhaled BDP and compared their serial BMD measurements to those of similarly aged, nonsmoking, healthy female volunteers. Over the 12 months of follow-up, no significant decline in BMD was noted in either group. Interestingly, the asthmatic women showed a statistically higher BMD at all time points, including baseline, when compared to their healthy volunteer counterparts, a difference that was difficult to explain.

Packe et al11 studied 27 premenopausal women with asthma and 30 men with asthma who had attended a hospital clinic. Of the 57 asthma patients, 17 had never received ICSs, 20 required between 1,000 and 2,000 μg inhaled BDP daily and had been on stable doses for at least 1 year (range, 1 to 7 years), while 20 required daily therapy with oral prednisone for control of their asthma. The authors found a striking trend in BMD by CT densitometry, with significant reductions within the ICS group, and even more profound reductions in the systemic corticosteroid group. Of note, at least 10 patients receiving therapy with inhaled BDP had required systemic corticosteroids as treatment for an exacerbation within the year prior to the study. The results of this study are clearly intriguing. However, the potential for confounding by significant oral steroid use in the ICS group cannot be underestimated. Differential disease severity and duration between the groups (mean FEV1, 3.34 vs 1.86 L, respectively between groups) may also have affected the results.

A small clinical trial12 that was performed in China evaluated the effectiveness of antiresorptive therapy in asthmatic patients receiving high-dose ICSs. Ten healthy control subjects were recruited, and 28 asthma patients receiving an average of > 2,000 μg BDP or BUD per day were randomized to receive calcium supplementation, calcium supplementation plus etidronate, or neither. BMD was measured at 6, 12, and 18 months. Although the point of the study was to evaluate the effectiveness of antiresorptive therapy, one of the more important observations was the decline in BMD observed in the “nonintervention” asthmatic group exposed to high-dose ICSs. Subjects who did not receive calcium supplementation experienced a 1.5% decline in their BMD over > 18 months when compared to their baseline levels. Those receiving calcium supplementation experienced no such decline, with or without the addition of etidronate. Asthma patients who experienced a reduction in BMD started with the lowest bone densities overall, although they were not statistically different from the remaining three groups at baseline. Consequently, their BMDs, although reduced, remained within one SD of expected, making the clinical significance of this finding difficult to estimate.

Interesting evidence quantifying the overall effect of corticosteroid use on the risk of vertebral fractures was presented in an important cross-sectional study13 of male patients (age, ≥ 50 years of age) with COPD. The sample studied provided 90% power to detect a 16% difference in the prevalence of fractures in the ICS group compared to never-users. Despite adequate power to detect small differences, no statistically significant increase in risk could be shown.

Packe et al14 performed a cross-sectional analysis of 20 asthma patients who had been receiving 800 μg BUD daily for at least 1 year and compared the results to two populations of asthma patients, in which one group had their asthma managed with 1,000 μg BDP daily and another group had never received therapy with systemic corticosteroids or ICSs. No differences in BMD were found between the BUD and BDP groups, however, the BMDs of both groups were significantly reduced compared to the corticosteroid-naive group. Unfortunately, 33 of the 40 asthma patients in the ICS groups had been treated with intermittent systemic corticosteroids for exacerbations in the past, although no information regarding duration, frequency, or proximity to the study evaluation is available. The mean FEV1 in the ICS groups was lower than that in the corticosteroid-naive group, although activity grades were equivalent.

In a retrospective cohort study that was designed to evaluate the effects of longer term use of high-dose inhaled steroids, Boulet et al15 identified 37 asthma patients who had received ≥ 800 μg BDP daily for at least 18 months and compared their BMDs to a group of age-matched and gender-matched asthma patients who had received little or no therapy with ICSs (ie, < 500 μg/d) to control their disease. The two groups differed markedly in terms of the mean duration of ICS use (34 vs 0.6, months, respectively), the mean daily dose of ICS over the previous 2 years (1,140 vs 89 μg, respectively), and the severity of airflow obstruction (mean FEV1, 73% predicted vs 89% predicted, respectively). Both groups had normal bone densities measured at the femoral neck, the lumbar spine, and the Ward triangle. Because of the study design and the impressive clinical differences between the two groups, the lack of effect of ICS therapy on BMD is striking, even though the possibility of a type II error was not adequately addressed in the report.

Similarly, a prospective cohort study16 examined 48 consecutive asthma patients, and compared their baseline and 2-year bone density data with those of age-matched, gender-matched, and weight-matched nonexposed healthy volunteers. The average age of both groups was 55 years, with equivalent proportions of premenopausal and postmenopausal women. Despite receiving ICS therapy at a mean daily dose of 662 μg for a mean duration of 10.6 years, the asthmatic group showed no reduction in BMD at the start of the study. The rate of decline in the asthmatic group did not exceed that of the control subjects over the 2 years of available follow-up. As impressive as these data may be, the authors did not address the possibility of a type II error, again casting a shadow of significant doubt over the reported results.

In a cross-sectional observation study of 196 adult asthma patients (age range, 20 to 40 years), Wong et al17 found an inverse relationship between cumulative ICS dose and BMD of the lumbar spine and proximal femur. The study was designed to minimize confounding by age and menopausal status by restricting enrollment to patients in the 20-to-40-year-old age group. The duration of ICS therapy ranged from 0.5 to 24 years, with a median duration of 6 years. Subjects had received little or no therapy with oral, nasal, dermal, or parenteral corticosteroids prior to the study. Each doubling of the cumulative ICS dose resulted in a decrease in BMD of 0.16 SD at the lumbar spine. The authors pointed out that the clinical implication, while small, suggests that a patient who has received ICSs, 2,000 μg daily, for 7 years will likely have a BMD that is 1 SD lower than that of a similar patient who has received only 200 μg daily for 1 year, effectively doubling their risk of fracture. Changes in BMD may not be clinically important over a time period of a few years, but continuing exposures to high doses over many years may translate into clinically important effects.

Evidence grade: C. Conclusion: Adult asthma patients generally do not sustain a significant reduction in BMD in response to ICS treatment, although the effect may become clinically important in patients receiving high-dose ICSs for many years.

Cataracts
Is There an Elevated Risk of Developing Cataracts Associated With the Use of ICS?

There was clearly an increase in cataracts in an observational, community-based study18 of 2,784 asthma patients in Australia. However, in this study significant problems arose with missing data, and information regarding systemic corticosteroid use, that subjected the study to potential recall bias. Several studies are available that have suggested that there is no such increased risk. In the study by Reed and colleagues,19 there was no increased risk of cataracts associated with ICS use in a multicentered randomized trial involving 384 subjects receiving BDP therapy. However, this study monitored the subjects for only 1 year. A similar finding was reported in a cross-sectional observational study20 of children from the asthma clinic at the Royal Aberdeen Children’s Hospital. Of 333 patients who had received various doses of ICS over a 5-year period, none had developed posterior subcapsular cataracts. These data suggest a relatively negligible attributable risk for cataracts associated with ICSs. However, the population studied was very young, and the results may not be generalizable to an older population. Similarly, in a well-done case-control study21 of a young population from a Danish allergy clinic, 3 to 6 years of treatment with inhaled BUD at an average dose of 500 μg/d was not associated with an increase in subcapsular cataracts.

Garbe et al22 performed a case-control analysis of ICSs and cataract extraction claims data derived from Quebec Universal Health Insurance program enrollees. Subjects were restricted to those ≥ 70 years of age, with 3,677 cases and 21,868 control subjects identified. The authors identified an increased risk of cataract extraction in elderly ICS subjects. However, the study design precluded the identification of subclasses of cataracts. Information on ICS or systemic steroid use prior to age 65 years also was not available, introducing the potential for misclassification bias.

Finally, the CAMP Research Group8 monitored the development of posterior subcapsular cataracts in the 311 children receiving long-term treatment with inhaled BUD. At the end of the 6-year study period, only one of the children receiving BUD developed cataracts. The cataract was small, did not affect vision testing, and occurred in a subject who required 36 days of prednisone therapy as well as supplementary BDP therapy.

Evidence grade: C. Conclusion: The risk of subcapsular and nuclear cataracts associated with ICS use is negligible in young asthma patients, however, it may be elevated in older patients.

Are There Differences in Cataract Risk Associated With Different ICS Formulations?

None of the studies examined had sample sizes that were sufficiently large enough to examine individual variations in side effect frequency among different ICS formulations.

Evidence grade: F. Conclusion: There is insufficient information regarding differences in the risk of cataract formation between various ICS formulations.

Is Cataract Risk Dependent on the Dose of ICS?

None of the studies examined had sample sizes sufficiently large enough to examine variations in side effect frequency by cumulative ICS dose. Abuekteish et al20 suggested a low or negligible occurrence of cataracts in a young population employing relatively low doses of ICSs over a prolonged period. No data evaluating the effect of ICS therapy on an elderly population, stratified either by cumulative dose or daily dose, are currently available.

Evidence grade: F. Conclusion: The dose-effect relationship between ICS use and cataract formation is poorly understood.

Is There an Elevated Risk of Glaucoma Associated With ICS Use?

None of the studies identified dealing specifically with the association between glaucoma and ICS therapy used an experimental design. Samiy et al23 reported on a series of cases with patients who received variable doses of any number of medications. With this study design, no stratification based on ICS formulation or dose was possible, and the authors stated only that “90% of patients received beclomethasone dipropionate (BDP).” No control for potential confounders such as family history of glaucoma or past increase in intraocular pressures was attempted. Intraocular pressures measured within 12 weeks of the initiation of medication did not document an increase in ICS users. The authors concluded that the risk of glaucoma with ICS therapy is small. In a case-control study that examined the association using the claims data from > 48,000 patients, Garbe et al24 suggested that the prolonged continuous use of ICSs was the only statistically significant risk factor for ocular hypertension or glaucoma. The study did not identify the specific ICS used or the actual doses delivered to the patient. In addition, the diagnosis of glaucoma was based on codes from the International Classification of Diseases, ninth revision, and may underestimate the true prevalence of increased intraocular pressure.

Evidence grade: F. Conclusion: The risk of glaucoma associated with ICS use is likely to be small, however, further study is warranted.

Is There a Difference in Risk of Glaucoma Between ICS Formulations?

None of the studies examined had sample sizes sufficiently large enough to examine individual variations in side effect frequency among different formulations.

Evidence grade: F. Conclusion: There is insufficient information regarding differences in the risk of glaucoma between various ICS formulations.

Is the Risk of Glaucoma Related to the Dose of ICS?

Garbe et al24 concluded that the prolonged continuous use of high-dose ICSs will increase the risk of glaucoma, while there was no measurable effect of therapy with low-dose or medium-dose ICSs or with nasal steroid use.

Evidence grade: F. Conclusion: There is an apparent, although poorly studied, dose-effect relationship between ICS use and glaucoma.

Does ICS Therapy Affect the Rate of Growth in Asthmatic Children?

Several carefully performed RCTs have been performed looking at the effect of ICS use on growth rates in children at various stages of development. The CAMP trial8 was designed to evaluate the long-term growth effects of therapy with BUD or nedocromil on children with mild-to-moderate asthma. Three equivalent groups of children were treated with inhaled BUD, 200 μg bid, inhaled nedocromil, 8 mg bid, or placebo. After 4 to 6 years of treatment, the side effects of BUD were limited to a small transient reduction in growth velocity. The mean increase in height was 1.1 cm less in the BUD group than in the nedocromil or placebo groups, but this difference was observed mostly in the first year of treatment. At the end of the study, the mean height (percentile) was 51.3 in the BUD group, 55.2 in the nedocromil group, and 55.7 in the placebo group. Neither bone age nor predicted final height was different between groups.

Verberne et al25 reported their experience with 67 asthmatic children of various ages who were enrolled in an efficacy trial of BDP via dry powder inhaler (DPI). The children were at various stages of growth, and ranged in age from 6 to 16 years. After a follow-up period of 1 year, subjects who had their asthma controlled using BDP, 400 μg daily, experienced a decrease in their growth velocity compared to subjects receiving salmeterol to effect control. The relative differences in growth velocity were statistically significant (− 0.28 vs − 0.03 SD; p = 0.001). However, the absolute difference in mean height between the two groups at the end of the study period was only 1.4 cm.

Skoner et al26 have reported the results of a multicenter, randomized, open-label, active-controlled, parallel-group study that was designed to evaluate the effect of ICS therapy on growth after 52 weeks of follow-up. The subjects were 0.5 to 8 years old, all had a preexisting diagnosis of asthma, and all had been enrolled in one of three multicenter RCTs prior to the 52-week extension analysis. Changes in height SD scores differed significantly between groups receiving a BUD inhalation suspension, 500 μg daily, and their counterparts who received “conventional” asthma therapy (excluding glucocorticoids). At 52 weeks, the difference in height SD score between the ICS group and the non-ICS group was 0.19 SD (p = 0.003), while the growth velocity was reduced by 0.8 cm per year (p = 0.002).

Heuck et al27 evaluated the short-term adverse effects of a dose of 800 μg inhaled BUD on growth in a randomized, double-blind trial of 24 prepubescent asthmatic children aged 6 to 12 years. Although the study lasted only 3 months, an interesting effect was noted suggesting that frequency of administration may be an important variable affecting short-term bone growth. Subjects receiving BUD, 400 μg twice daily, experienced a greater reduction in bone growth rates compared to those receiving a BUD dose of 800 μg once daily (p = 0.04). This effect was influenced by gender, with boys experiencing a more marked reduction in growth than girls.

Verberne et al28 evaluated the effect of various doses of inhaled BDP in 177 asthmatic children (age range, 6 to 16 years) with confirmed moderate asthma. In this study, all steroid treatment groups showed a decrease in growth over the 1 year of treatment. However, the effect was most pronounced in the arm receiving the highest dose, suggesting the presence of a dose-dependent effect. The BDP used in this study was delivered in dry powder form, potentially affecting the generalizability of the results.

Another RCT studied the effect of doses of 200 and 400 μg per day of both fluticasone (administered via Diskhaler; GlaxoSmithKline; Philadelphia, PA) and BUD (administered via Turbuhaler; AstraZeneca; Wilmington, DE). The lower leg growth rate was not significantly different for low-dose fluticasone and BUD when compared to placebo. However, lower leg growth rates were significantly lower in the group receiving 400 μg BUD when compared to placebo, but not when compared to fluticasone.29 There was no statistical reduction in growth rates during fluticasone treatment using either dose.

Doull et al30 reported the results of a community-based, randomized trial that enrolled 104 children of various ages with asthma, and followed 84 children for a 7-month period. Although the overall observed reduction in growth may have been biased by the relatively high drop-out rate, the investigators followed these subjects for a poststeroid washout period of at least 4 months, during which time no evidence of “catch up” growth could be found. The relatively short poststeroid follow-up period precludes a definitive judgment.

In a study designed to look at dose-dependent effects on growth, 321 prepubescent children who had been identified as asthmatic by then current American Thoracic Society criteria, who had documented normal growth velocities and height prior to study initiation, were enrolled and randomized to receive either 50 or 100 μg fluticasone propionate (FP) via DPI or placebo twice daily. Children who were treated with FP, 50 or 100 μg twice daily for 1 year, grew at rates similar to placebo-treated control subjects, and at rates that were equal to the expected growth velocities for age, strongly suggesting that FP, at least when administered via DPI, has no discernible effect on growth in this population.31

Evidence grade: A. Conclusion: Therapy with ICSs is associated with a decrease in short-term growth rates in children, but the overall effect is small and may not be sustained with long-term therapy.

Does ICS Therapy Affect the Final Height of Children With Asthma?

Some reassuring information regarding the long-term effects of ICS therapy on growth in asthmatic children was derived from a well-done cohort study of 459 adult residents of Rochester, MN.32 Those studied were children (and their age-matched and gender-matched control subjects) with onset of asthma between 1964 and 1987, who had attained an adult height at the time of the study. The ICS group had experienced a heterogeneous exposure in terms of dose, formulation, and duration of exposure. However, after appropriate analysis, the investigators found that the attained height of patients with asthma was not different from that of age-matched and sex-matched, nonasthmatic subjects. The attained height of asthmatic children who were treated with glucocorticoids was not significantly different from the adult height of children who had not been treated glucocorticoids, with the absolute group difference being only 1.2 cm. Investigators could find no significant dose-response effect.

A recent report by Agertoft and Pedersen33 confirms this finding. Observational data were collected prospectively on 211 asthmatic children who had attained adult height by the time the analysis was performed. Asthma patients who had been treated with ICSs received a mean daily dose of BUD of 412 μg for a mean duration of 9.2 years. Control subjects consisted of a small group of asthmatic children who never received ICSs, and a second group of healthy, nonasthmatic siblings of the index cases. A selection of control subjects (ie, using children whose families would not consent to changing over to BUD) may have introduced bias. However, despite the possible selection bias, it is encouraging to note that children with asthma who had received long-term treatment with BUD had attained normal adult heights by the end of the study. The primary outcome measured was the difference between the attained and predicted final heights, which were equivalent among all groups. Although the authors failed to discuss the probability of a type II error, confidence intervals surrounding the primary outcome estimates were quite small.

Evidence grade: C. Conclusion: The adult height attained by asthmatic children treated with ICSs is not different from that of nonasthmatic adults.

Do ICS Formulations Differ in Their Growth-Related Effects?

In a randomized, blinded clinical trial involving 17 Danish asthmatic adolescents (age range, 7 to 14 years), Wolthers et al34 found that, compared with therapy with FP, 200 μg twice daily, therapy with BDP, at doses of 400 and 800 μg bid, significantly suppressed lower leg growth rates. Whether FP therapy adversely affected growth rates could not be evaluated in this study because no placebo arm was employed. This was a short-term study, with perhaps limited relevance to long-term growth. Given these study limitations, if FP, 200 μg, can be accepted as being clinically equivalent in efficacy to BDP, 400 μg, this study suggests that there may be a significant difference in side effects between compounds.

Rao et al35 reported their findings following a prospective, randomized, double-blind trial comparing the effects of BDP and FP on growth in 23 steroid-naive children with moderately severe asthma (age range, 5 to 10 years). At 20 months into treatment, the children in the FP group showed no change in their height SD score (ie, z-scores), while those receiving BDP showed a significant decline in height SD score. In this study, however, the children in the BDP group started the treatment period significantly above the expected height. Their return to the expected height after 20 weeks of treatment may be a drug effect but may also represent regression to the mean.

In a study designed to evaluate the efficacy and safety of high-dose ICS therapy in children with asthma, Ferguson and colleagues36 collected height data that were necessary for calculating predicted lung function. They observed a differential growth in subjects correlating to treatment arm assignment. Seventy-six subjects randomized to receive 400 μg FP daily experienced an adjusted mean growth of 3.31 cm over the 20-week study period, while the 78 subjects assigned to receive 800 μg BUD daily grew only 1.99 cm over the same period (p = 0.002). However, this study was not designed to evaluate growth as an end point, and height measurements were not standardized across study sites.

Previously referenced studies by Agertoft and Pedersen29 and Allen et al31 suggested that FP in low doses and administered via a diskhaler could have a minimal effect on growth velocity.

Evidence grade: C. Conclusion: There is insufficient information on the difference between steroid formulations to derive definitive conclusions.

Is the Risk of Skin Thinning and Easy Bruising Elevated in Patients Receiving ICS Therapy?

Several well-done observational studies confirm the association between ICS therapy and skin thinning. Mak et al37 studied 406 asthmatic outpatients from a respiratory clinic and compared the incidence of bruising to appropriately matched subjects not receiving ICSs. Therapy with ICSs increased the risk of easy bruising, especially with increased dose and prolonged duration of use. Similarly, a report of 76 asthmatic subjects by Capewell and colleagues38 in Wales revealed a positive correlation between skin thickness/purpura and duration of use in patients receiving high-dose ICSs. Mak et al37 also suggested the presence of a relationship between gender and skin thinning. Women were deemed to be especially at risk for easy bruising. A small nonrandomized trial39 conducted in Finnish women with asthma suggested that BUD significantly decreases type I and II collagen synthesis within 6 weeks. By contrast, a case series of 27 newly diagnosed asthma patients suggested that skin thickness was not significantly decreased, even after 1 to 2 years of treatment with as much as 1,600 μg BUD daily.40 However, significant methodological flaws, including poor validation of the ICS dose, duration of use, smoking status, and other important variables plagued this report.

Of interest, one randomized controlled trial41 designed to examine this relationship was identified as a result of our search. During a 42-month treatment period, 1,277 subjects were randomized to receive either BUD or placebo. Bruises > 50 mm in diameter were counted on the volar surface of the forearms during each clinic visit. Bruising was statistically significantly increased in the group receiving moderate-to-high doses of BUD. However, all subjects were being treated for COPD (not asthma), the mean age was 53 years, and all were cigarette smokers. This raises doubt about the generalizability of these results to an asthmatic population.

Evidence grade: B. Conclusion: The risk of skin thinning and easy bruising is elevated in patients receiving ICSs. Dose, duration of use, and patient gender are important variables affecting overall risk.

Are There Differences in the Risk of Skin Thinning/Bruisability Between ICS Formulations?

None of the studies examined had sample sizes sufficiently large enough to examine individual variations in side effect frequency among different ICS formulations.

Evidence grade: F. Conclusion: There is insufficient information regarding differences in the risk of skin thinning/bruising between various ICS formulations.

Is There a Definable Relationship Between the Dose of ICSs and the Risk of Skin Thinning/ Bruising?

Most of the studies evaluating the effect of ICS therapy on skin thinning and bruising are observational, and combine variables such as ICS preparation, duration of use, and dose. Still, there appears to be a relationship between elevated doses of ICSs and the occurrence of bruising, the measurement of skin thinning, and the markers of collagen synthesis. The observed dose response to ICSs has been confirmed in several observational studies. In the study by Capewell et al,38 therapy with high-dose ICSs was associated with skin thinning, while that with low-dose ICSs was not. A similar relationship was shown in the study by Mak et al.37 ICS therapy increased the risk of easy bruising, especially in the setting of female gender, higher doses, and prolonged duration of use.37 By contrast, Autio et al39 could detect no differences in the degree of reduction of collagen synthesis between the high-dose and low-dose groups. However, there was no discussion of power to detect such differences in this study, and the results may be subject to a type II error.

Evidence grade: B. Conclusion: There is an apparent dose-effect relationship between ICS use and skin thinning/bruising.

The established efficacy of ICS therapy generally has placed this class of medications at the center of current asthma treatment recommendations. However, despite the general acceptance of ICSs over the past several decades, substantial concerns about their undesirable effects linger, particularly in “special” populations such as children, women, and the elderly. As alternative controller medications become increasingly available, these nagging concerns have taken on new significance. Our systematic review revealed ample, robust evidence refuting the perceived associations between ICS use and clinically relevant height or BMD complications in children. Adults may experience significant reductions in BMD, but the effect attributable directly to ICS therapy appears to be related to prolonged, high-dose treatment. There is an apparent dose-dependent effect on skin thickness and ease of bruising, but the relationships between ocular complications and ICS use are poorly understood. The preponderance of evidence supports a conclusion that the proven clinical effectiveness of ICS treatment decidedly outweighs the proven risks.

A considerable body of work exists that specifically evaluates the side effects of ICSs. This project was important because the evidence either supporting or refuting associations between complications and ICS use is sometimes sketchy and incomplete. Our hope was to create a systematic approach for evaluating the strength of study design, estimating the potential for bias or confounding and integrating the weighted conclusions into a well-reasoned consensus. Furthermore, it was our hope that the logic employed to develop the consensus statements would be readily visible to the reader, who could then utilize the conclusions of the panel to help guide daily practice decisions. Another strength of this method is the ability for individual readers to evaluate the primary data sources for themselves. Data summaries, derived from the studies used in the preparation of this manuscript, are available to interested readers on the World Wide Web at www.chestnet.org/cgi/content/full/124/6/2329/DC1.

The project employed standard methods for the identification and evaluation of relevant studies included in the data set. Several limitations may be important to note. First, because of the breadth of the project, it was necessary to evaluate many studies with many different study designs, outcome measures, and analysis methods. This diversity precluded the development of meaningful data tables and summary-effect size estimates. It was not our purpose to focus on meta-analyses of subsets of studies, but rather to answer broad and clinically relevant questions by integrating the evidence in a meaningful way. Second, because the method required a subjective analysis of the available evidence, interpretations and conclusions are potentially subject to preexisting reviewer bias. Attempts to minimize this effect included convening a panel made up of experts with varied backgrounds and diverse perspectives, standardizing the quality rating score, and utilizing a process of dual review and quality assurance prior to inclusion in the data summaries. Finally, the ongoing validity of our conclusions is limited by the degree to which they incorporate the most current information. Studies published through the end of calendar year 2000 were included in this analysis. Panel members were asked to identify any important work, published during the preparation of this manuscript, that had the potential to alter our conclusions fundamentally. No such work has been identified to date, but it is clear that we are becoming more sophisticated at answering questions about the complications of ICS use as time moves on. The readers should not consider the book to be closed; only the mere foundation has been laid for future evidence-based clinical decisions regarding potential complications of ICS therapy in asthma patients.

Expert Panel Members

James E. Fish, MD, FCCP (Co-Chair), Thomas Jefferson University, Philadelphia, PA; Stanley J. Szefler, MD (Co-Chair), National Jewish Medical and Research Center, Denver, CO; Marianne Frieri, MD, Nassau Medical Center, East Meadow, NY; David Lang, MD, Thomas Jefferson University, Philadelphia, PA; Stephen C. Lazarus, MD, University of California at San Francisco, San Francisco, CA; Dennis Ledford, MD, University of South Florida, College of Medicine, Tampa, FL; Frank T. Leone, MD, MS, FCCP, Thomas Jefferson University, Philadelphia, PA; Harold Nelson, MD, National Jewish Medical and Research Center, Denver, CO; Diane Schuller, MD, Penn State University, Hershey, PA; Christine A. Sorkness, PharmD, The University of Wisconsin, Madison, WI; and Suzanne L. West, PhD (Methodologist), University of North Carolina at Chapel Hill, Chapel Hill, NC.

Abbreviations: BDP = beclomethasone dipropionate; BMD = bone mineral density; BUD = budesonide; CAMP = Childhood Asthma Management Program; DPI = dry powder inhaler; FP = fluticasone propionate; ICS = inhaled corticosteroid; RCT = randomized clinical trial

This work was supported by The American College of Chest Physicians, The American Academy of Allergy, Asthma and Immunology, and The American College of Allergy, Asthma and Immunology.

Online data summaries are available at http://www.chestjournal.org/cgi/content/full/124/6/2329/DC1.

Table Graphic Jump Location
Table 1. Primary Study Data Collected by Reviewers
Table Graphic Jump Location
Table 2. Variables Assessed for Reviewer Quality Rating Scale
Table Graphic Jump Location
Table 3. Evidence Grades

We are indebted to Drs. Ann Koopman and Rodney Murray of the Scott Memorial Library at Thomas Jefferson University. Without Dr. Koopman’s flexibility, talent, and diligence during the evidence collection phase, and without Dr. Murray’s patience during the Internet data-collection phase, this project surely would not have been possible. The panel thanks the American College of Chest Physicians staff, Sydney Parker, PhD, Arlene Karavich, and former staff member Beth Welch, for their assistance in producing this report.

Bootsma, GP, Dekhuijzen, PN, Festen, J, et al (1996) Fluticasone propionate does not influence bone metabolism in contrast to beclomethasone dipropionate.Am J Respir Crit Care Med153,924-930. [PubMed]
 
Allen, HD, Thong, IG, Clifton-Blight, P, et al Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma.Pediatr Pulmonol2000;29,188-193. [CrossRef] [PubMed]
 
Hopp, RJ, Degan, JA, Biven, RE, et al Longitudinal assessment of bone mineral density in children with chronic asthma.Ann Allergy Asthma Immunol1995;75,143-148. [PubMed]
 
Gregson, RK, Rao, R, Murrills, AJ, et al Effect of inhaled corticosteroids on bone mineral density in childhood asthma: comparison of fluticasone propionate with beclomethasone dipropionate.Osteoporos Int1998;8,418-422. [CrossRef] [PubMed]
 
Martinati, LC, Betoldo, F, Gasperi, E, et al Effect on cortical and trabecular bone mass of different anti-inflammatory treatments in preadolescent children with chronic asthma.Am J Respir Crit Care Med1996;153,232-236. [PubMed]
 
Agertoft, L, Pedersen, S Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide.Am J Respir Crit Care Med1998;157,178-183. [PubMed]
 
Kinberg, KA, Hopp, RJ, Biven, RE, et al Bone mineral density in normal and asthmatic children.J Allergy Clin Immunol1994;94,490-497. [CrossRef] [PubMed]
 
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.N Engl J Med2000;343,1054-1063. [CrossRef] [PubMed]
 
Marystone, JF, Barrett-Connor, EL, Morton, DJ Inhaled and oral corticosteroids: their effects on bone mineral density in older adults.Am J Public Health1995;85,1693-1695. [CrossRef] [PubMed]
 
Herrala, J, Puolijoki, H, Impivaara, O, et al Bone mineral density in asthmatic women on high-dose inhaled beclomethasone dipropionate.Bone1994;15,621-623. [CrossRef] [PubMed]
 
Packe, GE, Douglas, JG, McDonald, AF, et al Bone density in asthmatic patients taking high dose inhaled beclomethasone dipropionate and intermittent system corticosteroids.Thorax1992;47,414-417. [CrossRef] [PubMed]
 
Wang, WQ, Ip, MS, Tsang, KW, et al Antiresorptive therapy in asthmatic patients receiving high-dose inhaled steroids: a prospective study for 18 months.J Allergy Clin Immunol1998;101,445-450. [CrossRef] [PubMed]
 
McEvoy, CE, Ensrud, KE, Bender, F, et al Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.Am J Respir Crit Care Med1998;157,704-709. [PubMed]
 
Packe, GE, Robb, O, Robins, SP, et al Bone density in asthmatic patients taking inhaled corticosteroids; comparison of budesonide and beclomethasone dipropionate.J R Coll Physicians Lond1996;30,128-132. [PubMed]
 
Boulet, LP, Giguere, MC, Milot, J, et al Effects of long-term use of high-dose inhaled steroids on bone density and calcium metabolism.J Allergy Clin Immunol1994;94,796-803. [CrossRef] [PubMed]
 
Luengo, M, del Rio, L, Pons, F, et al Bone mineral density in asthmatic patients treated with inhaled corticosteroids; a case-control study.Eur Respir J1997;10,2110-2113. [CrossRef] [PubMed]
 
Wong, C, Walsh, L, Smith, C, et al Inhaled corticosteroid use and bone-mineral density in patients with asthma.Lancet2000;3355,1399-1403
 
Cumming, RG, Mitchell, P, Leeder, SR Use of inhaled corticosteroids and the risk of cataracts.N Engl J Med1997;337,8-14. [CrossRef] [PubMed]
 
Reed, CE, Offord, KP, Nelson, HS, et al Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma.J Allergy Clin Immunol1998;101,14-23. [CrossRef] [PubMed]
 
Abuekteish, F, Kirkpatrick, JN, Russell, G Posterior subcapsular cataract and inhaled corticosteroid therapy.Thorax1995;50,674-676. [CrossRef] [PubMed]
 
Agertoft, L, Larsen, FE, Pedersen, S Posterior subcapsular cataracts, bruises, and hoarseness in children with asthma receiving long-term treatment with inhaled budesonide.Eur Respir J1998;12,130-135. [CrossRef] [PubMed]
 
Garbe, E, Suissa, S, LeLorier, J Association of inhaled corticosteroid use with cataract extraction in elderly patients.JAMA1998;280,539-543. [CrossRef] [PubMed]
 
Samiy, N, Walton, DS, Dreyer, EB Inhaled steriods: effect on intraocular pressure in patients without glaucoma.Can J Ophthalmol1996;31,120-123. [PubMed]
 
Garbe, E, LeLorier, J, Boivin, J, et al Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma.JAMA1997;277,722-727. [CrossRef] [PubMed]
 
Verberne, AAPH, Frost, C, Roorda, RJ, et al One year treatment with salmeterol compared with beclomethasone in children with asthma.Am J Respir Crit Care Med1997;156,688-695. [PubMed]
 
Skoner, D, Szefler, S, Welch, M, et al Longitudinal growth in infants and young children treated with budesonide inhalation suspension for persistent asthma.J Allergy Clin Immunol2000;105,259-268. [CrossRef] [PubMed]
 
Heuck, C, Wolthers, OD, Kollerup, G, et al Adverse effects of inhaled budesonide (800 mcg) on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration.J Pediatr1998;133,608-612. [CrossRef] [PubMed]
 
Verberne, AAPH, Frost, C, Duiverman, EJ, et al Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma.Am J Respir Crit Care Med1998;158,213-219. [PubMed]
 
Agertoft, L, Pedersen, S Short-term knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study.Eur Respir J1997;10,1507-1512. [CrossRef] [PubMed]
 
Doull, IJ, Freezer, NJ, Holgate, ST Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate.Am J Respir Crit Care Med1995;151,1715-1719. [PubMed]
 
Allen, DB, Bronsky, EA, LaForce, CF, et al Growth in asthmatic children treated with fluticasone propionate: Fluticasone Propionate Asthma Study Group.J Pediatr1995;126,297-303. [CrossRef] [PubMed]
 
Silverstein, MD, Yunginger, JW, Reed, CE, et al Attained adult height after childhood asthma: effect of glucocorticoid therapy.J Allergy Clin Immunol1997;99,466-474. [CrossRef] [PubMed]
 
Agertoft, L, Pedersen, S Effect of long-term treatment with inhaled budesonide on adult height in children with asthma.N Engl J Med2000;343,1064-1069. [CrossRef] [PubMed]
 
Wolthers, OD, Hansen, M, Juul, A, et al Knemometry, urine cortisol excretion, and measure of insulin-like growth factor axis and collagen turnover in children treated with inhaled glucocorticosteroids.Pediatr Res1997;41,44-50. [PubMed]
 
Rao, R, Gregson, R, Jones, A, et al Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclomethasone.Eur Respir J1999;13,87-94. [CrossRef] [PubMed]
 
Ferguson, A, Spier, S, Manjra, A, et al Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of fluticasone propionate and budesonide.J Pediatr1999;134,422-427. [CrossRef] [PubMed]
 
Mak, VH, Melchor, R, Spiro, SG Easy bruising as a side-effect of inhaled corticosteroids.Eur Respir J1992;5,1068-1074. [PubMed]
 
Capewell, S, Reynolds, S, Shuttleworth, D, et al Purpura and dermal thinning associated with high dose inhaled corticosteroids.BMJ1990;300,1548-1551. [CrossRef] [PubMed]
 
Autio, P, Karjalainen, J, Risteli, L, et al Effects of an inhaled steroid (budesonide) on skin collagen synthesis of asthma patientsin vivo.Am J Respir Crit Care Med1996;153,1172-1175. [PubMed]
 
Haapasaari, K, Rossi, O, Risteli, J, et al Effects of long-term inhaled corticosteroids on skin collagen synthesis and thickness in asthmatic patients.Eur Respir J1998;11,139-143. [CrossRef] [PubMed]
 
Pauwels, RA, Lofdahl, C, Laiatinen, LA, et al Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking: European Respiratory Society Study on Chronic Obstructive Pulmonary Disease.N Engl J Med1999;340,1948-1953. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Primary Study Data Collected by Reviewers
Table Graphic Jump Location
Table 2. Variables Assessed for Reviewer Quality Rating Scale
Table Graphic Jump Location
Table 3. Evidence Grades

References

Bootsma, GP, Dekhuijzen, PN, Festen, J, et al (1996) Fluticasone propionate does not influence bone metabolism in contrast to beclomethasone dipropionate.Am J Respir Crit Care Med153,924-930. [PubMed]
 
Allen, HD, Thong, IG, Clifton-Blight, P, et al Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma.Pediatr Pulmonol2000;29,188-193. [CrossRef] [PubMed]
 
Hopp, RJ, Degan, JA, Biven, RE, et al Longitudinal assessment of bone mineral density in children with chronic asthma.Ann Allergy Asthma Immunol1995;75,143-148. [PubMed]
 
Gregson, RK, Rao, R, Murrills, AJ, et al Effect of inhaled corticosteroids on bone mineral density in childhood asthma: comparison of fluticasone propionate with beclomethasone dipropionate.Osteoporos Int1998;8,418-422. [CrossRef] [PubMed]
 
Martinati, LC, Betoldo, F, Gasperi, E, et al Effect on cortical and trabecular bone mass of different anti-inflammatory treatments in preadolescent children with chronic asthma.Am J Respir Crit Care Med1996;153,232-236. [PubMed]
 
Agertoft, L, Pedersen, S Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide.Am J Respir Crit Care Med1998;157,178-183. [PubMed]
 
Kinberg, KA, Hopp, RJ, Biven, RE, et al Bone mineral density in normal and asthmatic children.J Allergy Clin Immunol1994;94,490-497. [CrossRef] [PubMed]
 
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.N Engl J Med2000;343,1054-1063. [CrossRef] [PubMed]
 
Marystone, JF, Barrett-Connor, EL, Morton, DJ Inhaled and oral corticosteroids: their effects on bone mineral density in older adults.Am J Public Health1995;85,1693-1695. [CrossRef] [PubMed]
 
Herrala, J, Puolijoki, H, Impivaara, O, et al Bone mineral density in asthmatic women on high-dose inhaled beclomethasone dipropionate.Bone1994;15,621-623. [CrossRef] [PubMed]
 
Packe, GE, Douglas, JG, McDonald, AF, et al Bone density in asthmatic patients taking high dose inhaled beclomethasone dipropionate and intermittent system corticosteroids.Thorax1992;47,414-417. [CrossRef] [PubMed]
 
Wang, WQ, Ip, MS, Tsang, KW, et al Antiresorptive therapy in asthmatic patients receiving high-dose inhaled steroids: a prospective study for 18 months.J Allergy Clin Immunol1998;101,445-450. [CrossRef] [PubMed]
 
McEvoy, CE, Ensrud, KE, Bender, F, et al Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.Am J Respir Crit Care Med1998;157,704-709. [PubMed]
 
Packe, GE, Robb, O, Robins, SP, et al Bone density in asthmatic patients taking inhaled corticosteroids; comparison of budesonide and beclomethasone dipropionate.J R Coll Physicians Lond1996;30,128-132. [PubMed]
 
Boulet, LP, Giguere, MC, Milot, J, et al Effects of long-term use of high-dose inhaled steroids on bone density and calcium metabolism.J Allergy Clin Immunol1994;94,796-803. [CrossRef] [PubMed]
 
Luengo, M, del Rio, L, Pons, F, et al Bone mineral density in asthmatic patients treated with inhaled corticosteroids; a case-control study.Eur Respir J1997;10,2110-2113. [CrossRef] [PubMed]
 
Wong, C, Walsh, L, Smith, C, et al Inhaled corticosteroid use and bone-mineral density in patients with asthma.Lancet2000;3355,1399-1403
 
Cumming, RG, Mitchell, P, Leeder, SR Use of inhaled corticosteroids and the risk of cataracts.N Engl J Med1997;337,8-14. [CrossRef] [PubMed]
 
Reed, CE, Offord, KP, Nelson, HS, et al Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma.J Allergy Clin Immunol1998;101,14-23. [CrossRef] [PubMed]
 
Abuekteish, F, Kirkpatrick, JN, Russell, G Posterior subcapsular cataract and inhaled corticosteroid therapy.Thorax1995;50,674-676. [CrossRef] [PubMed]
 
Agertoft, L, Larsen, FE, Pedersen, S Posterior subcapsular cataracts, bruises, and hoarseness in children with asthma receiving long-term treatment with inhaled budesonide.Eur Respir J1998;12,130-135. [CrossRef] [PubMed]
 
Garbe, E, Suissa, S, LeLorier, J Association of inhaled corticosteroid use with cataract extraction in elderly patients.JAMA1998;280,539-543. [CrossRef] [PubMed]
 
Samiy, N, Walton, DS, Dreyer, EB Inhaled steriods: effect on intraocular pressure in patients without glaucoma.Can J Ophthalmol1996;31,120-123. [PubMed]
 
Garbe, E, LeLorier, J, Boivin, J, et al Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma.JAMA1997;277,722-727. [CrossRef] [PubMed]
 
Verberne, AAPH, Frost, C, Roorda, RJ, et al One year treatment with salmeterol compared with beclomethasone in children with asthma.Am J Respir Crit Care Med1997;156,688-695. [PubMed]
 
Skoner, D, Szefler, S, Welch, M, et al Longitudinal growth in infants and young children treated with budesonide inhalation suspension for persistent asthma.J Allergy Clin Immunol2000;105,259-268. [CrossRef] [PubMed]
 
Heuck, C, Wolthers, OD, Kollerup, G, et al Adverse effects of inhaled budesonide (800 mcg) on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration.J Pediatr1998;133,608-612. [CrossRef] [PubMed]
 
Verberne, AAPH, Frost, C, Duiverman, EJ, et al Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma.Am J Respir Crit Care Med1998;158,213-219. [PubMed]
 
Agertoft, L, Pedersen, S Short-term knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study.Eur Respir J1997;10,1507-1512. [CrossRef] [PubMed]
 
Doull, IJ, Freezer, NJ, Holgate, ST Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate.Am J Respir Crit Care Med1995;151,1715-1719. [PubMed]
 
Allen, DB, Bronsky, EA, LaForce, CF, et al Growth in asthmatic children treated with fluticasone propionate: Fluticasone Propionate Asthma Study Group.J Pediatr1995;126,297-303. [CrossRef] [PubMed]
 
Silverstein, MD, Yunginger, JW, Reed, CE, et al Attained adult height after childhood asthma: effect of glucocorticoid therapy.J Allergy Clin Immunol1997;99,466-474. [CrossRef] [PubMed]
 
Agertoft, L, Pedersen, S Effect of long-term treatment with inhaled budesonide on adult height in children with asthma.N Engl J Med2000;343,1064-1069. [CrossRef] [PubMed]
 
Wolthers, OD, Hansen, M, Juul, A, et al Knemometry, urine cortisol excretion, and measure of insulin-like growth factor axis and collagen turnover in children treated with inhaled glucocorticosteroids.Pediatr Res1997;41,44-50. [PubMed]
 
Rao, R, Gregson, R, Jones, A, et al Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclomethasone.Eur Respir J1999;13,87-94. [CrossRef] [PubMed]
 
Ferguson, A, Spier, S, Manjra, A, et al Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of fluticasone propionate and budesonide.J Pediatr1999;134,422-427. [CrossRef] [PubMed]
 
Mak, VH, Melchor, R, Spiro, SG Easy bruising as a side-effect of inhaled corticosteroids.Eur Respir J1992;5,1068-1074. [PubMed]
 
Capewell, S, Reynolds, S, Shuttleworth, D, et al Purpura and dermal thinning associated with high dose inhaled corticosteroids.BMJ1990;300,1548-1551. [CrossRef] [PubMed]
 
Autio, P, Karjalainen, J, Risteli, L, et al Effects of an inhaled steroid (budesonide) on skin collagen synthesis of asthma patientsin vivo.Am J Respir Crit Care Med1996;153,1172-1175. [PubMed]
 
Haapasaari, K, Rossi, O, Risteli, J, et al Effects of long-term inhaled corticosteroids on skin collagen synthesis and thickness in asthmatic patients.Eur Respir J1998;11,139-143. [CrossRef] [PubMed]
 
Pauwels, RA, Lofdahl, C, Laiatinen, LA, et al Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking: European Respiratory Society Study on Chronic Obstructive Pulmonary Disease.N Engl J Med1999;340,1948-1953. [CrossRef] [PubMed]
 
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