Current reviews of allergy and clinical immunology (Supported by a grant from GlaxoSmithKline, Research Triangle Park, NC)

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1 Current reviews of allergy and clinical immunology (Supported by a grant from GlaxoSmithKline, Research Triangle Park, NC) Series editor: Harold S. Nelson, MD Potential adverse effects of the inhaled corticosteroids H. William Kelly, PharmD Albuquerque, NM This activity is available for CME credit. See page 33A for important information. The purpose of this review is to provide the clinician with an update on the potential adverse effects caused by the inhaled corticosteroids (ICSs). The systemic effects of ICSs are a result of that portion swallowed and absorbed through the gastrointestinal tract and not eliminated by first-pass metabolism and that portion delivered to the lung and absorbed. If administered in high enough doses, any of the ICSs will produce clinically significant systemic activity. This review will explore the risks for clinically significant adverse effects from sustained use of ICSs, as recommended by the current guidelines. The standard method for assessing systemic activity in short-term studies is measurement of hypothalamic-pituitary-adrenal axis function. The ICSs provided in the medium dose range can produce measurable effects on the hypothalamic-pituitaryadrenal axis. However, clinically significant suppression is unlikely to occur except at high doses. The effect on growth in children over 1 to 4 years occurs at low to medium doses, might be dependent on the specific ICS, and is small (1-2 cm). The data are insufficient to determine whether there is an effect on attainment of predicted adult height. The ICSs affect bone mineral density and risk of fractures in a dose-dependent fashion that appears significant at high doses. (J Allergy Clin Immunol 2003;112:469-78) Key words: Inhaled corticosteroids, adverse effects, growth, hypothalamic-pituitary-adrenal axis, bone mineral density The inhaled corticosteroids (ICSs) are the most effective long-term controller therapy for the treatment of asthma. They are currently recommended as the preferred therapy at low doses by the national and international guidelines for asthma management las monotherapy for mild persistent asthma and as the preferred therapy at medium doses or combined at low to medium doses with the long-acting inhaled β 2 -agonists for moderate asthma. 1,2 High doses of ICSs are only recommended for From the Department of Pediatrics, University of New Mexico Children s Hospital. Received for publication June 25, 2003; revised July 3, 2003; accepted for publication July 7, Reprint requests: H. William Kelly, PharmD, Professor Emeritus of Pediatrics and Pharmacy, University of New Mexico Children s Hospital, Department of Pediatrics, ACC Bldg 3rd Floor, 2211 Lomas Blvd, NE, Albuquerque, New Mexico Mosby, Inc. All rights reserved /2003 $ doi: /mai Abbreviations used AUC: Area under the concentration curve BDP: Beclomethasone dipropionate BMD: Bone mineral density CAMP: Childhood Asthma Management Program CFC: Chlorofluorocarbon DPI: Dry-powder inhaler FDA: US Food and Drug Administration FP: Fluticasone propionate FPF: Fine-particle fraction HPA: Hypothalamic-pituitary-adrenal ICS: Inhaled corticosteroid MDI: Metered-dose inhaler NAEPP: National Asthma Education and Prevention Program TAA: Triamcinolone acetonide UFC: Urinary free cortisol VHC: Valved holding chamber patients with severe persistent asthma not adequately controlled with the combination of medium-dose ICSs and long-acting inhaled β 2 -agonists. Clinicians are often reluctant to prescribe ICSs because of concerns about potential toxicities. The adverse systemic effects from ICSs have been exhaustively reviewed elsewhere, 3-8 including an eloquent review by Toogood 7 in the Journal. It is the purpose of this report to review new studies that fill in some of the gaps in our knowledge since the previous reviews were published. Hopefully, this will help the clinician address the risk of significant adverse effects from ICS use, as recommended by the current guidelines. DEVELOPMENT OF ICSs The ICSs were developed to provide the beneficial therapeutic effects of corticosteroids while minimizing the potential for the known adverse consequences of chronic use, as listed in Table I. All corticosteroid actions are mediated through the stimulation of glucocorticoid receptors in the cytoplasm of cells throughout the many tissues in the body. There can be a significant heterogeneity of response in both the topical or antiasthmatic response and the systemic activity between individuals receiving the same doses of corticosteroid, irrespective of whether adminis- 469

2 470 Kelly J ALLERGY CLIN IMMUNOL SEPTEMBER 2003 FIG 1. Schematic of how various perturbations of the delivery system and specific pharmacokinetics interact to determine the systemic load of various ICSs. The examples in this case are BDP and FP. Data on the gastrointestinal tract and lung deliveries are from Leach et al 19 and Dempsey et al. 29 HFA, Hydrofluoroalkane. TABLE I. Potential adverse effects from the use of ICSs Short-term effects Cough Dysphonia Thrush Suppression of basal cortisol secretion Suppression of ACTH and CRH secretion Suppression of lower leg growth Suppression of bone formation Sex hormone suppression Intermediate effects HPA axis suppression Linear growth velocity reduction BMD reduction Weight gain Cushing syndrome Mood swings, psychosis Hypokalemia Hyperglycemia Dermal thinning and skin bruising Glaucoma Long-term effects Adrenal insufficiency and crisis Growth suppression Failure to attain expected adult height Osteoporosis and fractures Cataracts CRH, Corticotrophin-releasing hormone. tration is through oral or inhalational means. 9,10 The variability in response is multifactorial, including environmental and genetic factors. 11 Genetic factors that might alter responses include polymorphisms of the oxidative enzymes responsible for clearing the drugs from the systemic circulation and polymorphisms in the glucocorticoid receptor. 12,13 Polymorphisms in the glucocorticoid receptor have been found to be associated with both increased and decreased sensitivity to exogenous corticosteroids. 14,15 However, their effect on patients with asthma have not been specifically evaluated. Because there are no significant differences between the glucocorticoid receptors from different tissues in the body, one would expect that polymorphisms of the receptor would only affect relative sensitivity to the ICSs but not alter the therapeutic index (ie, the ratio of therapeutic effect to systemic effect). However, there is some preliminary suggestion that the glucocorticoid receptor genotype might affect corticosteroid sensitivity in a tissue-specific manner. 15 Clearly,this area requires further study. Inflammation in the airways reduces the binding affinity of the glucocorticoid receptors for exogenous corticosteroids. 16 This effect is likely to result in a narrowing of the therapeutic index because the systemic glucocorticoid receptors should not be affected. However, this defect can be corrected with anti-inflammatory therapy and should only create a transient effect. Currently, neither genetic nor environmental factors would appear to have a significant effect on the therapeutic index of the ICSs. However, they both alter the dose required for optimal therapeutic effect. The method for reducing systemic activity from ICSs is to prevent the active molecule from entering the systemic circulation in quantities sufficient to produce the effect. Simply increasing the potency of a corticosteroid without addressing systemic absorption, as was done with the first ICS, dexamethasone, did not provide an increase in the therapeutic index. The 2 principal methods of reducing systemic activity include reducing bioavailability from the gastrointestinal tract (Fig 1) and prolonging residence in the lung tissue. These have been reviewed in detail elsewhere. 3,17,18 Alteration of the delivery device can result in a decrease in oral bioavailability by decreasing oral delivery and thereby reducing the amount of drug available to the gastrointestinal tract. Altering the delivery

3 J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 3 Kelly 471 FIG 2. Dose-response curves for the efficacy and toxicity of an ICS. The 2 vertical lines indicate how the therapeutic index for any ICS narrows as the dose increases. device can enhance lung delivery by producing aerosols with a higher percentage of drug in the respirable particle size, referred to as the fine-particle fraction (FPF), 9,19,20 or by reducing the ability of the large particles to deposit in the oropharynx by use of a valved holding chamber (VHC). 21 It is possible for a VHC to both decrease and increase the risk of systemic activity from an ICS depending on how well the ICS is absorbed from the gastrointestinal tract and whether the VHC can enhance the FPF of the aerosol from the metered-dose inhaler (MDI). In addition, it is well known that different VHCs will alter the FPF from the same MDI differently. 22 Because of the significant effect that the delivery device can have on systemic availability of an ICS, all ICSs will be identified with their delivery device when results of clinical trials are discussed. Alternatively, the molecule can be altered to either reduce gastrointestinal absorption or enhance first-pass gastrointestinal-liver metabolism. Prolonged retention in the lung can be achieved by increasing lipophilicity, as with fluticasone propionate (FP) and mometasone furoate, or potentially by forming soluble intracellular esters, as with budesonide and ciclosenide. 23 However, because all of the ICS that is delivered to the lung is available for systemic activity, all of the current ICSs will produce systemic activity in a dose-dependent manner. 9,23 The corticosteroids are receptor agonists, and as such, their dose-response characteristics for both anti-inflammatory activity and systemic activities are best expressed as log-linear. 9,24-27 Thus, it might take a 4-fold increase in dose to produce a 50% increase in effect, explaining the relatively flat nature of the dose-response curves for ICSs. Fig 2 represents the topical and systemic doseresponse curves for an ICS. In developing new ICSs, it is advantageous to somehow widen the gap between each of the curves by various mechanisms, as presented above. However, as seen in Fig 2, as the dose of any ICS is increased, the therapeutic index decreases. To gain US Food and Drug Administration (FDA) approval for a product, it is important for the manufacturer to demonstrate that the drug is both safe and effective. In the large Phase 3 clinical trials, the drugs are administered in doses that are unlikely to show any significant risk of systemic effects from the product. These doses are unlikely to span the entire dose-response curves for efficacy and toxicity and thus provide incomplete pictures of the relative efficacy and safety of the various ICSs. Studies that measure only one of the dose-response curves, whether efficacy or systemic activity, are merely comparisons of the relative potency of the ICSs in that particular measurement and cannot provide an assessment of their relative therapeutic indexes. The relative potencies of the ICSs have been extensively reviewed elsewhere and are beyond the scope of this review. 2-5,18,27 Table II provides the reader with comparable clinically efficacious doses from the most recent update of the National Institutes of Health Guidelines. 2 These doses are based on comparative clinical trials that incorporate both differences in molecular potency and differences in lung delivery between various aerosol devices. The relative molecular potency of the ICSs is as follows: FP = mometasone furoate > budesonide = beclomethasone dipropionate (BDP) > flunisolide = triamcinolone acetonide (TAA). 2,27 The differences between potencies when unequal are in the range of 2 to 4 times, whereas they are considered equal if less than 2 times (which appears to be the minimally detectable difference). 3,5,18,26,27 The high dose range is defined as the dose above that associated

4 472 Kelly J ALLERGY CLIN IMMUNOL SEPTEMBER 2003 TABLE II. Comparable clinically efficacious doses of the ICSs Low daily dose (µg) Medium daily dose (µg) High daily dose (µg) Preparation Adult Child Adult Child Adult Child BDP CFC MDI >840 >672 BDP HFA MDI >480 >320 BUD DPI >1200 >800 BUD NEB SUSP FLU CFC MDI >2000 >1250 FP CFC MDI >660 >440 FP DPI >600 >400 TAA CFC MDI >2000 >1200 HFA, Hydrofluoroalkane; BUD, budesonide; NEB SUSP, nebulizer suspension; FLU, flunisolide. TABLE III. Sensitivity and clinical significance of measures of systemic effects of ICSs Sensitivity/Significance HPA-axis function Linear growth Bone metabolism 24-h AUC cortisol Knemometry Serum osteocalcin 24-h UFC PICP Overnight UFC Urine hydroxyproline Urinary cortisol ICTP metabolites CRH stimulation 1-year growth velocity Bone mineral density Low-dose cosyntropin by stadiometry Insulin-induced hypoglycemia AM cortisol >5-year growth velocity Standard cosyntropin by stadiometry Osteopenia Osteoporosis Cushingoid habitus Final adult height Adrenal crisis Fractures HFA, Hydrofluoroalkane; BUD, budesonide; NEB SUSP, nebulizer suspension; FLU, flunisolide. with a high risk of clinically significant systemic activity. 2 The high dosage is at or near the maximal FDA-approved labeling that is generally recommended for patients whom the clinician wishes to taper off oral corticosteroids. In that setting the increased risk of systemic activity would be considered acceptable compared with the risk from oral corticosteroids. MEASURES OF SAFETY OF THE ICSs Until recently, the FDA used the standard tests of adrenal corticosteroid excretion (ie, morning plasma cortisol concentration) and hypothalamic-pituitary-adrenal (HPA) axis responsiveness (ie, high-dose cosyntropin stimulation) as the primary measures of safety for the ICSs in Phase 2 and 3 clinical trials. However, in 1998, the FDA convened a combined advisory panel of the Pulmonary and Allergy/Endocrinologic and Metabolic Advisory Committees to review data on the effect of both ICSs and intranasal corticosteroids on growth in children. 28 The principal findings were that growth suppression was a class effect that occurred with low-to-medium doses that did not produce impairment of the HPA axis. Thus, 1-year growth studies in children are required for all newly introduced ICSs. In addition to growth, interest in other long-term consequences of systemic corticosteroids, such as increased osteoporotic fractures and cataract formation, has increased in recent years. 2 Because it is not clear whether the standard measures of HPA axis effect are sensitive enough surrogates for predicting these long-term cumulative responses to systemic corticosteroid exposure, the potential risks of these adverse outcomes will also be reviewed. Table III summarizes the sensitivity and clinical significance of the various measures of systemic activity of the ICSs. The more sensitive the measure, the more questionable is its clinical significance. The more sensitive measures are primarily used for clinical pharmacology studies to establish relative therapeutic indexes between ICSs or between delivery devices of the same ICS. In addition, they have often been used as surrogate measures of systemic availability or lung delivery for the ICSs with minimal oral bioavailability. 29 One could reasonably question the validity of such studies because the sensitive measures do not necessarily predict clinically significant outcomes (only systemic activity) and reflect

5 J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 3 Kelly 473 a narrower therapeutic index. However, the use of the more sensitive surrogates is probably reasonable for assessing the relative risk of systemic activity between ICSs and their various delivery systems but not for establishing absolute therapeutic indexes for a given ICS. MEASURES OF THE HPA AXIS The 8 AM morning serum cortisol concentration and standard 250-µg cosyntropin stimulation test have been the standard methods for assessing basal cortisol secretion and HPA axis responsiveness, respectively. 30,31 These tests have been criticized for lack of sensitivity to detect low levels of HPA axis suppression, particularly that produced by ICSs. 32,33 The standard 250-µg cosyntropin test has been criticized because it uses a supraphysiologic dose of cosyntropin that would miss mild adrenal gland suppression, as well as isolated central adrenal insufficiency (corticotrophin-releasing hormone production suppression in the hypothalamus or ACTH reduction in the pituitary gland) Thus, investigators have advocated the use of the low-dose short cosyntropin test that uses 0.5 µg/m 2 or 1 µg of cosyntropin, which represents a more physiologic dose. 30,32 The low-dose cosyntropin test correlates well with the insulin-induced hypoglycemia test, which is still widely considered the definitive study of HPA axis integrity. 30,31,34 By comparison, the low-dose cosyntropin test results in fewer falsenegative results (studies that show no suppression when it exists) compared with the standard dose test. 34 However, the test is still relatively new, so that some authors recommend that if its results are only mildly abnormal, it should be followed by an insulin-induced hypoglycemia or metyrapone test, both of which are technically difficult, require hospitalization, and are more hazardous and expensive. 30,31 Corticotropin-releasing hormone stimulation is currently available but is very expensive, and there is limited clinical experience with this procedure. 30,31 The standard test of basal cortisol secretion is the morning serum cortisol concentration. Unfortunately, it is poorly predictive of adrenal suppression, particularly acute suppression after exogenous corticosteroid administration. 31,32 As a result, numerous investigators have used more sensitive measures, such as 24-hour area under the concentration curve (AUC) for plasma cortisol measurement or 24-hour or overnight urinary free cortisol (UFC) excretion (Table III). 5,6,9,21,26,29 Any systemic exposure of exogenous corticosteroid will result in a diminution of basal cortisol excretion. The advantage of these more sensitive tests is that they often detect suppression in a dosedependent manner, thus allowing dose-response curves to be constructed. 6,9,26 However, like serum morning cortisol concentration measurement, they are not predictive of clinical adrenal suppression. Indeed, the 24-hour UFC test was devised as a test of hypercortisolism and not suppression. Approximately 1% of secreted cortisol is excreted unchanged in the urine at the usual concentrations; however, as the cortisol concentrations go from 200 to 400 µg/l, there is a 5-fold increase in the unbound fraction or free cortisol concentration. 35 Overlap of its reference intervals are too great to predict clinical suppression. It is primarily used in children because it is noninvasive, and correction for creatinine excretion can overcome incomplete (overnight) collections. 3,7 HPA axis suppression by ICSs Any dose of corticosteroid sufficient to inhibit corticotrophin-releasing hormone and ACTH production and not allow recovery between doses will produce adrenal insufficiency centrally, and if suppressed for a sufficient time period, this will result in peripheral adrenal gland atrophy. 31,35 Thus, for the systemic corticosteroids, suppression is dependent on dose, timing of the dose, biologic half-life of the drug, and duration of therapy. The general rule of thumb is that any usual daily anti-inflammatory dose (5-60 mg of prednisone equivalent) of less than 1 week s duration is unlikely to produce significant suppression, and recovery should occur within a couple of days. 31 For longer-term administration, doses greater than 15 mg of prednisone equivalent daily invariably produce suppression, whereas daily doses of between 5 and 15 mg produce variable suppression. 35 For the relatively short-acting corticosteroids hydrocortisone and prednisone, administering them as a single dose in the morning or as a split dose in the morning and early evening (3-5 PM) produces less suppression than late evening doses because they are less likely to suppress the early morning ACTH surge. 31 However, recent studies have suggested that adrenal insufficiency from systemic corticosteroids is not predictable on the basis of dose, duration, or cumulative dose. 32 Using the low-dose cosyntropin test, Hensen et al 32 reported that 45% of 75 patients receiving a minimum dose of 25 mg of prednisone equivalent (range, mg) for 5 to 30 days had suppressed adrenal responses. There were no distinguishing features between those with and without suppression. Those with suppression had normal responses after 7 to 14 days of stopping treatment, except for 2 patients whose responses remained suppressed for 6 months. This study is consistent with others showing that the duration and cumulative dose of corticosteroid are not strong predictors of adrenal insufficiency. 31 Adrenal insufficiency leading to acute adrenal crisis is an exceedingly rare event after ICS therapy. 4,5,7 However, the results of a recent survey of physicians from the United Kingdom seeking reports of adrenal crisis should be ample warning to practitioners that the use of ICSs in excess of the current guideline recommendations can produce disastrous results. 36 They reported 33 (28 children aged years) cases of adrenal crisis and one death. Thirty-one (94%) of the patients were receiving FP in doses of 500 to 2000 µg daily. Although the authors failed to provide sufficient data to assess the dosing, the minimal daily dose per body surface area of 660 µg would suggest a small child received the lowest dose. Regardless, the mean values of 980 µg daily for children and 1380 µg daily for adults are 2-fold greater than the high dose recommended by the guidelines and approxi-

6 474 Kelly J ALLERGY CLIN IMMUNOL SEPTEMBER 2003 FIG 3. Comparison of the various doses required to produce a 10% reduction in 24-hour AUC for plasma cortisol for budesonide (BUD) administered by means of a DPI and FP administered by means of both a DPI and an MDI with an Optichamber. The labeled dose is that labeled by the manufacturer, the emitted dose is that dose that leaves the device measured in vitro, and the inhaled dose is the amount of drug in the FPF (particles <4.7 µm). The inhaled dose for FP is similar for both delivery systems and about one half that of budesonide, which is consistent with the differences in potency. Data are from Martin et al. 9 mately equivalent to 2000 µg of budesonide daily and 2800 µg of BDP daily in children. One cannot find justification for such high doses of ICSs in the literature, and these were likely a result of the assumption that all of the ICSs were equipotent on a microgram basis. These authors and others have hypothesized that the greater HPA axis suppression seen with equal microgram amounts of FP compared with budesonide and BDP are due to its greater lipophilicity, resulting in greater accumulation in the tissues. 6,36 However, no direct evidence supporting that hypothesis exists, and the results of such studies are consistent with the known differences in potency between the ICSs. 9,23,26,27 A landmark study by the National Institutes of Health sponsored Asthma Clinical Research Network evaluated the systemic activity of 6 ICS preparations available in the United States by using a cumulative doseresponse technique, doubling the dose every week for 4 doses. 9 The purpose of the study was to ultimately design a method for assessing the therapeutic index of various ICSs by first establishing the dose-response characteristics of each of the preparations for systemic activity. This would then be followed by a dose-response study for efficacy at predetermined levels of systemic activity to establish each preparation s therapeutic index. 10 Each preparation was dosed in a way that was consistent with the first 2 doses in the low dose range of the National Asthma Education and Prevention Program (NAEPP) recommendation and the next 2 doses in the medium and high dose ranges. Thus, they were administered in approximately equipotent dosages (although that was not absolutely determined by measures of efficacy). The researchers measured 24-hour AUC for plasma cortisol, 12- and 24- hour UFC excretion, and serum osteocalcin levels as measures of systemic activity. Only the 24-hour AUC for plasma cortisol gave consistently significant dose-response measurements so that the various preparations could be compared. In addition to the systemic activity, they measured the emitted dose and the FPF to determine the fineparticle dose from each of the delivery devices. They used an Optichamber with the BDP, FP, and flunisolide chlorofluorocarbon (CFC) propelled MDIs, which might have blunted the systemic response from BDP and flunisolide. Interestingly, they reported that the FP CFC-propelled MDI plus Optichamber and the TAA CFC-propelled MDI (with its built-in spacer device) were the most suppressive, whereas FP administered by means of a dry-powder inhaler (DPI) was the least suppressive. The comparison of dose response with the fine-particle and emitted doses with that of the labeled doses lends some insight into some of the variability noted across clinical trials. The FP DPI could only be used to establish a 10% reduction in 24-hour AUC, and the 95% CI was wide and contained zero, so that the authors rightly questioned its significance. However, although the mean labeled dose and emitted doses were much greater for the FP DPI than for the FP CFC-propelled MDI plus Optichamber, the fine-particle dose or that likely inhaled

7 J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 3 Kelly 475 was very similar for both delivery systems (Fig 3). On the basis of the labeled dose and emitted dose, the FP DPI appears to possess a significantly greater therapeutic index than either the FP MDI or the budesonide DPI, and the budesonide DPI would appear to have a greater safety margin than the FP MDI. However, on inspection of the fine-particle dose, the degree of suppression is consistent with the differences in potency between the FP and budesonide molecules. For the fine-particle dose, the ratio of FP MDI to budesonide DPI remained the same from 10% to 40% suppression. Because this occurred over a 4-week time period of escalating doses, no increased accumulation of FP producing greater suppression was evident. Thus, differences in systemic activity between the ICSs are predictable on the basis of differences in molecular potency, oral bioavailability, and delivery devices. Long-term use and HPA axis suppression It is clear that low to medium doses of the ICSs provide sufficient exogenous corticosteroid to mildly perturb the basal cortisol secretion in adults and children. It has been largely unknown whether this mild perturbation over months to years would produce a cumulative effect resulting in clinically significant HPA axis suppression. This question was recently reviewed by the Blue Cross and Blue Shield Technology Evaluation Center to provide an evidence-based report to the NAEPP for support of the 2002 Update of the Guidelines for the Diagnosis and Management of Asthma. 2,37 No cumulative effect was found for 3 prospective, randomized clinical trials of at least 12 months duration for 100 µg of FP daily administered through a DPI, 500 µg of budesonide nebulizer suspension daily, and 336 µg of BDP daily. In addition, a single-armed trial of 200 µg of budesonide daily administered through a DPI for 12 months found no cumulative effect. These results are consistent with the preliminary findings of a subset of children in the Childhood Asthma Management Program (CAMP) who underwent standard cosyntropin studies at baseline and after 1 and 3 years of therapy with 400 µg of budesonide daily administered through a DPI or nedocromil or placebo. 38,39 Thus,no long-term cumulative effect on the HPA axis has been detected in children receiving low to medium doses of ICSs. ICSs AND GROWTH IN CHILDREN This topic has been extensively reviewed, as well as subjected to a meta-analysis and a systematic review by the Blue Cross and Blue Shield Technology Evaluation Center for the NAEPP. 8,37,40 Short-term sensitive studies of lower leg growth by means of knemometry have no relationship to long-term linear growth in children but can be used to assess systemic activity from ICSs. 8 Intermediate-term studies ( 1 year) of growth velocity by using stadiometry demonstrate an average of a 1-cm (range, cm) decrease in growth in prepubertal children receiving low to medium doses (400 µg) of BDP through a CFC-propelled MDI, BDP through a DPI, and budesonide through a DPI. 8,40 More recently, a 3-year study of 200 µg of budesonide once daily administered through a DPI reported a 1.34-cm reduction in growth compared with placebo in almost 2000 children younger than 11 years. 41 Similar to basal cortisol secretion, the reduction in growth velocity appears to be dependent on the ICS and the delivery method. A 1-year comparison of 100 and 200 µg of FP daily administered through a DPI reported no significant reduction in growth after 1 year compared with placebo in 325 prepubescent children. 42 A shorter-duration study comparing higher doses of 400 µg of FP administered through a DPI with 800 µg of budesonide daily administered through a DPI in 333 children with moderate-to-severe asthma seemed to confirm the therapeutic index for FP. 43 After 20 weeks, the children receiving FP had a greater improvement in peak expiratory flow and grew 6.2 mm more than those receiving budesonide. Unfortunately, there was no non-ics control group to determine whether the higher-dose FP also reduced growth velocity. It requires emphasis that all of the year-long trials of FP on growth in children used the DPI formulation. The use of the FP MDI with a spacer (a method frequently used in children) has been inadequately evaluated, and on the basis of studies of HPA axis suppression, one would expect that the therapeutic index advantage might be lost. Whether the 1-cm loss in growth results in failure of the children to attain their maximum potential adult height remains an unanswered question. However, data that are available have been reassuring. The longest controlled prospective trial to date has been the CAMP trial, which treated patients for 4 to 6 years. 38 This study reported that the reduction in growth velocity from 400 µg of budesonide administered through a DPI daily occurred in the first year of therapy, and thereafter, growth velocity was similar in all treatment groups. Thus, a cumulative 1-cm-per-year reduction in growth did not occur. However, by the end of the trial, catch-up growth also did not occur, even 4 months after discontinuation of therapy. These results are consistent with other shorterterm trials with BDP, demonstrating that much of the reduction in growth velocity occurs within the first 3 months of therapy and verifying the lack of catch-up growth despite 4 months without therapy. 8 In contrast to these findings is the recent 3-year trial with a low-dose budesonide administered through a DPI in which a greater reduction occurred in the first year (0.58 cm), but continued additive reductions occurred in years 2 (0.43 cm) and 3 (0.33 cm). 41 Whether this apparent cumulative effect is due to the use of a lower dose of budesonide is unclear. Further answers await the planned 2-year open-label follow-up to this study. The Blue Cross and Blue Shield Technology Evaluation Center reviewed 3 cohort studies evaluating the attainment of adult target height in patients who received ICSs (primarily BDP and budesonide) throughout childhood. 2,37 One of the 3 studies found a reduction in adult height between ICS users and nonusers (2.54 cm, P <

8 476 Kelly J ALLERGY CLIN IMMUNOL SEPTEMBER ) that was consistent with a lack of cumulative effect. The other 2 studies found no effect of ICS use on attainment of target adult height. The CAMP trial attempted to address this issue by using a predictive equation that used growth velocity and bone age at the end of the study. 38 They reported no difference in the predicted final height between groups. However, because there was no evidence for catch-up growth by the end of the trial, the definitive answer awaits the ongoing long-term followup of these patients. In conclusion, one can expect to see a decrease in growth velocity that would be expected to produce a 0.5- to 1.5-cm difference in height after 1 year in children receiving the ICSs BDP and budesonide in low to medium doses that is unlikely to be predicted on the basis of suppression of the HPA axis. Other ICSs with similar therapeutic indexes, such as flunisolide MDI, TAA MDI, and BDP-hydrofluoroalkane MDI, are likely to produce similar effects. 8,9,28 The current evidence suggests that this is not a cumulative effect; however, there is still insufficient evidence to know whether continuous administration through childhood affects attainment of final adult height. ICSs AND THE RISK OF OSTEOPOROSIS AND FRACTURES Since the last review, there have been a significant number of studies, both randomized clinical trials and epidemiologic studies, on the potential increased risk for osteoporosis and fractures caused by ICSs. Corticosteroids have multiple effects on bone metabolism, including decreased osteoblast activity, increased bone resorption, decreased calcium absorption, decreased renal calcium reabsorption, and decreased sex hormone production. 44 However,decreased osteoblastic function,evident by a decrease in serum osteocalcin concentration, appears to be the primary event responsible for corticosteroid-induced osteoporosis. 45 There does not appear to be a threshold dose below which no bone loss occurs because a single dose of 2.5 mg of prednisone will prevent the nocturnal increase in osteocalcin. 44 Risk factors for corticosteroid-induced osteoporosis have not been well defined. There is continued debate whether a cumulative dose or a daily dose is more predictive of bone loss and fractures. 44,45 It has been estimated that 30% to 50% of patients taking chronic oral corticosteroids will experience fractures. 44 In the now classic study by Adinoff and Hollister, 46 11% of patients with asthma taking oral corticosteroids for 1 year experienced fractures. The corticosteroids preferentially affect trabecular bone (lumbar spine and proximal femur) first and then the cortical bone of the long bones. 44 In most but not all reports, lumbar spine is affected to the greatest degree. 44,45 Longitudinal studies suggest the greatest loss occurs within the first 6 months of therapy. The preferred diagnostic tool for assessing corticosteroid-induced osteoporosis is assessing bone mineral density (BMD) by means of dual-energy x-ray absorptiometry, with the lumbar spine and hip as preferable sites. 45 The World Health Organization has established criteria for the diagnosis of osteoporosis. The World Health Organization uses a young normal population base standard deviation score or T score system. A T score of 2.5 or lower is defined as osteoporosis because of the increase in lifetime fracture risk found at this cutoff point. 47 A T score of between 1 and 2.5 is considered osteopenic, and the relative risk of fracture is less, but it is more of a gradient in risk as opposed to a threshold. 47 It has been recommended that any patient who receives at least 7.5 mg of prednisone daily for at least 1 to 6 months should have his or her BMD monitored. 45 However, although BMD determined by means of dual-energy x-ray absorptiometry is capable of predicting population risk for future fracture, it is not specific enough to identify individuals who will have a fracture. 48 Indeed, a comparison of oral steroid dependent patients with asthma and patients with involutional osteoporosis found that vertebral fractures occurred in patients with asthma at higher BMDs than in patients with involutional osteoporosis. 49 This suggests that steroid use might be an independent risk factor. A recent cross-sectional cohort study of 117 patients receiving oral corticosteroids for respiratory diseases also found that the cumulative prednisone dose was an independent risk factor for development of fractures. 50 They postulated that corticosteroids might alter bone architecture, as well as decrease BMD. No apparent safe oral dose of corticosteroids for bone loss exists, and ICSs have been reported to reduce serum osteocalcin and procollagen concentrations, which are markers of bone formation. 45 Thus there have been increased investigations on ICSs and the risk for osteoporosis and fractures. Numerous studies have shown that ICSs can decrease serum osteocalcin concentrations. 5-8 However, investigators have failed to show that reduction of osteocalcin or procollagen is predictive of the development of osteoporosis. 51 Interestingly, lower BMDs at both the spine and hip were significantly associated with lower basal serum cortisol levels, which suggests that serum cortisol measurement might be a useful screen to determine whether a BMD test is necessary. Prospective clinical trials incorporating BMD measures have had mixed results. Many have been of short duration ( 1 year). A recent meta-analysis of 6 studies of lumbar spine BMD of at least 3 years duration that included a non- ICS control group concluded that the ICS group had a nonsignificant 4.1% reduction in BMD. 52 One of the included studies did report a significant dose-related decrease in BMD at the total hip and trochanter in premenopausal women, with no apparent effect at the lumbar spine or femoral neck. 53 The yearly change in BMD appeared to become negative at greater than 10 puffs of TAA per day, which is the beginning of the medium dose range. Why they found no effect on the lumbar spine, which has greater amounts of trabecular bone, is unclear. Although they attempted to control for activity level by questionnaire and activity score, it is unclear whether confounding by indication occurred (ie, patients with

9 J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 3 Kelly 477 more severe disease received higher doses and were less physically active). It is difficult to relate these findings to clinical use of ICSs because the investigators used TAA, which has a relatively narrow therapeutic index even when used with its built-in tube spacer inhaler device. 9 To more accurately measure compliance, the investigators used a Chronolog monitoring device that does not contain a spacer, so that oral bioavailability could be further increased. In children the CAMP trial found no effect of 400 µg of budesonide administered through a DPI daily for 4 to 6 years on BMD. 38 Cross-sectional studies have reported dose- or duration-dependent decreases in BMD in adults with asthma receiving ICSs. 54,55 In both of these studies, negative relationships were found for the lumbar spine and cumulative ICS dose, but only one study found a similar relationship with the femoral neck and trochanter. 55 In a more recent and much larger cohort study with a mean duration of ICS exposure of 8.2 years, no ICS effect was found on BMD. 56 Lastly,a population case-control study reported a dose-related increased risk of hip fractures associated with ICS use, even when controlling for the annual number of courses of oral corticosteroids. 57 The overall odds ratio was 1.19, with a 95% CI of 1.10 to Ninety-eight percent of patients were receiving BDP or budesonide. When excluding patients with prescriptions for oral corticosteroids, the lower end of the 95% CI did not exceed 1 until the daily dose exceeded 400 µg. This was a small increased risk in a population with a mean age of 79 years, and again, confounding by indication cannot be completely ruled out. In conclusion, there is increasing evidence that there might be an increased risk of osteoporosis and fractures in patients taking ICSs, although primarily at high doses that affect the HPA axis. The increased risk appears small, but patients with other risk factors for osteoporosis receiving high doses of ICSs should have their BMD tested and should be started on appropriate therapy for their osteoporosis if detected. REFERENCES 1. Global Initiative for Asthma. Global strategy for asthma management and prevention revised (2002). NHLBI/WHO Workshop Report. 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