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Systemic effects of intranasal steroids: An endocrinologist’s perspective

  • David B Allen
    Correspondence
    Reprint requests: David B. Allen, MD, H4/448 CSC-Pediatrics, 600 Highland Ave, Madison, WI 53792
    Affiliations
    Department of Pediatrics, Division of Endocrinology, University of Wisconsin Children’s Hospital
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      Abstract

      Intranasal steroids (INSs) are established as first-line treatment for allergic rhinitis. Extensive use of INSs with few reported adverse events supports the safety of these medications. Nevertheless, the prescription of more potent INSs for consistent and more prolonged use to younger and older patients, often in combination with inhaled corticosteroids, justifies the careful examination of their potential adverse systemic effects. Systemic bioavailability of INSs, by way of nasal and intestinal absorption, can be substantial; but current INSs vary significantly in their degree of first-pass hepatic inactivation and clearance from the body of the swallowed drug. For safety studies of INSs, distinguishing detectable physiologic perturbations from important adverse events is aided by an understanding of normal endocrine physiology and the methods used to test these systems. A review of available information indicates that (1) sensitive tests can measure the effects of INSs on biologic feedback systems, but they do not accurately predict clinically relevant adverse effects; (2) the primary factors that influence the relationship between therapeutic and adverse systemic effects of INSs are dosing frequency and efficiency of hepatic inactivation of swallowed drug; (3) INS treatment in recommended doses does not cause clinically significant hypothalamic-pituitary-adrenal axis suppression; (4) growth suppression can occur with twice-daily administration of certain INSs but does not appear to occur with once-daily dosing or with agents with more complete first-pass hepatic inactivation; (5) harmful effects of INSs on bone metabolism have not yet been adequately studied but would not be expected with the use of an INS dose and dosing frequency that do not suppress basal hypothalamic-pituitary-adrenal axis function or growth; and (6) these conclusions apply to INS treatment alone and in recommended doses-the risk of adverse effects in individual patients who are treated with INSs is increased by excessive dosing or concomitant inhaled corticosteroid or other topical corticosteroid therapy. (J Allergy Clin Immunol 2000;106:S179-90.)

      Keywords

      Nomenclature

      ACTH:
      Adrenocorticotropic hormone
      BMD:
      Bone mineral density
      HPA:
      Hypothalamic-pituitary-adrenal
      ICS:
      Inhaled corticosteroid
      IN-BDP:
      Intranasal beclomethasone dipropionate
      IN-BUD:
      Intranasal budesonide
      IN-FLU:
      Intranasal flunisolide
      IN-FP:
      Intranasal fluticasone propionate
      IN-MF:
      Intranasal mometasone furoate
      IN-TA:
      Intranasal triamcinolone acetonide
      INS:
      Intranasal steroid

      Background perspective

      Intranasal steroids (INSs) have become established as first-line treatment for allergic rhinitis, with well-documented efficacy compared with placebo and antihistamines.
      • Wilson AM
      • Sims EJ
      • McFarlane LC
      • Lipworth BJ
      Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.
      • International Rhinitis Management Working Group
      International consensus report on the diagnosis and management of rhinitis.
      • Foresi A
      • Pelucchi A
      • Gherson G
      • Mastropasqua B
      • Chiapparino A
      • Testi R
      Once daily intranasal fluticasone propionate (200 micrograms) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis.
      • Bronsky EA
      • Dockhorn RJ
      • Meltzer EO
      • et al.
      Fluticasone propionate aqueous nasal spray compared with terfenadine tablets in the treatment of seasonal allergic rhinitis.
      Several available intranasal agents (beclomethasone dipropionate [IN-BDP],
      • Chervinsky P
      Clinical review of once-daily beclomethasone dipropionate for seasonal allergic rhinitis.
      budesonide [IN-BUD],
      • Wolthers OD
      • Jørgensen BA
      • Pedersen S
      A double-blind, placebo-controlled study of the effect of intranasal budesonide in the treatment of children with seasonal rhinitis.
      triamcinolone acetonide [IN-TA],
      • Bernstein DI
      • Creticos PS
      • Busse WW
      • et al.
      Comparison of triamcin-olone acetonide nasal inhaler with astemizole in the treatment of ragweed-induced allergic rhinitis.
      fluticasone propionate [IN-FP],
      • Bronsky EA
      • Dockhorn RJ
      • Meltzer EO
      • et al.
      Fluticasone propionate aqueous nasal spray compared with terfenadine tablets in the treatment of seasonal allergic rhinitis.
      flunisolide [IN-FLU],
      • Turkeltaub PC
      • Norman PS
      • Johnson JD
      • Crepea S
      Treatment of seasonal and perennial rhinitis with intranasal flunisolide.
      and mometasone furoate [IN-MF]
      • Graft D
      • Aaronson D
      • Chervinsky P
      • et al.
      A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone furoate aqueous nasal spray.
      ) have been shown to be effective in treating both seasonal and perennial rhinitis. Extensive use of INSs over many years with few reported adverse events supports the assertion that a profile of clinical safety for these medications is already well established.
      However, there remain reasons for closely examining potential adverse systemic effects of INSs. First, awareness of the effectiveness of newer and more potent INSs has led to their being prescribed for more consistent and more prolonged use and to younger and older patients in whom mild degrees of cortisol excess could have important effects on growth or bone metabolism. Second, in patients treated with INSs who are also receiving inhaled corticosteroid (ICS) or other topical corticosteroid treatment, an additive systemic steroid burden may become significant. Third, it would be reasonable to expect that the administration of some corticosteroids to the abundant vascularity of the nasal mucosa could be associated with a high level of systemic bioavailability. If, as believed, the nose does not provide first-pass inactivation, the absorbed drug would retain its native high potency in the systemic circulation. Fourth, although modern aqueous pump sprays provide delivery directly to the nasal mucosa, a large percentage of the dose is still transported into the gastrointestinal tract by mucociliary clearance. To avoid systemic effects of this portion of the administered dose, swallowed drug must be inactivated by first-pass hepatic metabolism, and currently used agents vary significantly in the extent they are inactivated by this pathway.
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      • Harding SM
      The human pharmacology of fluticasone propionate.
      • Corren J
      Intranasal corticosteroids for allergic rhinitis: How do different agents compare?.
      • Clissold SP
      • Heel RC
      Budesonide: a preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis.
      • Pakes GE
      • Brogden RN
      • Heel RC
      • Speight TM
      • Avery GS
      Flunisolide: a review of its pharmacological properties and therapeutic efficacy in rhinitis.
      Finally, when INSs are combined with ICSs used in the treatment of asthma, airway corticosteroid therapy represents the primary care provider’s most common interaction with therapeutic steroids. For physicians who treat the large group of patients who are affected by asthma and rhinitis, a clear understanding of how reports of systemic effects of INSs relate to possible important adverse effects is essential to the safe and appropriate use of these drugs.
      Discussions of drug safety must strive to distinguish measurable systemic effects from clinically relevant systemic adverse effects. When clinically relevant side effects are identified, they must be weighed against the benefit of the drug and the morbidity of untreated disease for individual patients. Well-known side effects of systemic corticosteroid therapy arise when plasma corticosteroid concentrations either exceed normal physiologic needs or disrupt diurnal hormonal rhythms. Highly sensitive tests (eg, measuring area-under-the-curve plasma cortisol concentrations) often reveal measurable effects indicative of the effect of drug presence on normal biologic feedback systems. The clinical significance of such findings is unknown. The detection of potential systemic adverse effects can be achieved in controlled studies that examine either short-term (eg, knemometry) or surrogate markers (eg, osteocalcin) of the effect in question (eg, linear growth). However, the predictive value of such studies for long-term drug effects is extremely poor. Establishing the clinical relevance of systemic INS effects requires that trials be performed using clinically relevant doses for clinically relevant time periods in patients with disease severity and age similar to those for which the drugs would normally be prescribed.
      INSs can be absorbed into systemic circulation through airway and gastrointestinal routes (Fig 1). Like inhaled corticosteroids, most of the dose of an INS is swallowed.
      • Edsbäcker S
      • Andersson KE
      • Ryrfeldt Å
      Nasal bioavailability and systemic effects of the glucocorticoid budesonide in man.
      Although currently prescribed INSs demonstrate favorable degrees of first-pass hepatic inactivation compared with steroids prescribed for oral use, important differences exist among INSs. For example, the percent of drug systemically available after oral administration has been estimated to be less than 1% for FP,
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      • Harding SM
      The human pharmacology of fluticasone propionate.
      less than 1% for MF,
      • Corren J
      Intranasal corticosteroids for allergic rhinitis: How do different agents compare?.
      10.6% for TA,
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      11% for BUD,
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      • Clissold SP
      • Heel RC
      Budesonide: a preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis.
      21% for FLU,
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      • Pakes GE
      • Brogden RN
      • Heel RC
      • Speight TM
      • Avery GS
      Flunisolide: a review of its pharmacological properties and therapeutic efficacy in rhinitis.
      and 41% for BDP.
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      Absorption of drug across (ie, not merely into) the nasal mucosa into the circulation also varies significantly and is increased for agents with enhanced water solubility (eg, IN-BUD
      • Edsbäcker S
      • Andersson KE
      • Ryrfeldt Å
      Nasal bioavailability and systemic effects of the glucocorticoid budesonide in man.
      ) compared with more lipophilic compounds (eg, IN-MF
      • Lumry WR
      A review of the preclinical and clinical data of newer intranasal steroids used in the treatment of allergic rhinitis.
      and IN-FP
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • Daley-Yates PT
      • McAllister T
      Systemic bioavailability of fluticasone propionate administered as nasal drops (FP-Drops) and aqueous nasal spray formulations (FPANS) [abstract].
      ). Consequently, estimated absolute bioavailability of a dose after intranasal administration varies from 49% (IN-FLU)
      • Pakes GE
      • Brogden RN
      • Heel RC
      • Speight TM
      • Avery GS
      Flunisolide: a review of its pharmacological properties and therapeutic efficacy in rhinitis.
      to 44% (IN-BDP)
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      to 34% (IN-BUD)
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      to less than 1% (IN-FP
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • Daley-Yates PT
      • McAllister T
      Systemic bioavailability of fluticasone propionate administered as nasal drops (FP-Drops) and aqueous nasal spray formulations (FPANS) [abstract].
      and IN-MF
      • Lumry WR
      A review of the preclinical and clinical data of newer intranasal steroids used in the treatment of allergic rhinitis.
      ; Table I). Although differences exist between drugs in absorption across the nasal mucosa, clinically relevant differences in systemic bioavailability appear to primarily reflect the differences in oral bioavailability caused by different degrees of first-pass hepatic metabolism. Other important drug attributes (potency and lipophilicity) primarily affect therapeutic microgram-for-microgram comparisons but are less useful than oral bioavailability (ie, amount of drug that appears in circulation without first providing the therapeutic effect on the target organ) in predicting differences in the ratio between the therapeutic and systemic effects between drugs.
      Figure thumbnail gr1
      Fig. 1. The fate of intranasal steroids. The amount of intranasal corticosteroid that reaches the systemic circulation is the sum of nasal and oral bioavailable fractions. The majority of the drug is swallowed, and systemic bioavailability will be determined by the absorption from the gastrointestinal tract and the degree of first-pass hepatic inactivation. The absorption of the fraction that is deposited on the nasal mucosa varies from drug to drug and is influenced by solubility characteristics and other factors. NA, not available. Estimated percentages of systemic bioavailability are from the following sources: IN-FLU, IN-BDP, IN-BUD, IN-MF, and IN-FP.
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • Daley-Yates PT
      • McAllister T
      Systemic bioavailability of fluticasone propionate administered as nasal drops (FP-Drops) and aqueous nasal spray formulations (FPANS) [abstract].
      Table IEstimates of the relative bioavailabilities of FP, MF, TA, BUD, BDP, and FLU when administered intranasally or orally
      CorticosteroidBioavailability (%)
      Intranasal administrationOral administration
      Fluticasone propionate<1
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • Daley-Yates PT
      • McAllister T
      Systemic bioavailability of fluticasone propionate administered as nasal drops (FP-Drops) and aqueous nasal spray formulations (FPANS) [abstract].
      <1
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      • Harding SM
      The human pharmacology of fluticasone propionate.
      Mometasone furoate<1
      • Lumry WR
      A review of the preclinical and clinical data of newer intranasal steroids used in the treatment of allergic rhinitis.
      <1
      • Corren J
      Intranasal corticosteroids for allergic rhinitis: How do different agents compare?.
      Triamcinolone acetonideNA10.6
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      Budesonide34
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      11
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      • Clissold SP
      • Heel RC
      Budesonide: a preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis.
      Beclomethasone dipropionate44
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      41
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      Flunisolide49
      • Pakes GE
      • Brogden RN
      • Heel RC
      • Speight TM
      • Avery GS
      Flunisolide: a review of its pharmacological properties and therapeutic efficacy in rhinitis.
      21
      • National Asthma Education and Prevention Program
      Expert panel report 2: guidelines for the diagnosis and management of asthma.
      • Pakes GE
      • Brogden RN
      • Heel RC
      • Speight TM
      • Avery GS
      Flunisolide: a review of its pharmacological properties and therapeutic efficacy in rhinitis.
      The total systemic bioavailability of INSs reflects contributions of absorbed, unaltered swallowed drug in addition to drug absorbed across the nasal mucosa.
      NA , Not available.
      Potency is assessed in vitro in several ways. The McKenzie assay is useful for measuring topical vasoconstriction effects of glucocorticoids, but it may not accurately assess relative anti-inflammatory properties. More recently, direct measurements of inhibition of T-cell cytokine production in healthy volunteers (eg, IL-4, IL-5, IFN-γ) have demonstrated that inhaled MF and inhaled FP were equally effective and substantially more active than other compounds that were tested.
      • Umland SP
      • Nahrebne DK
      • Razac S
      • et al.
      The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-γ production by cultured primary CD4+ T cells.
      An analysis of glucocorticoid receptor binding affinity, which correlates well with receptor-mediated transactivation of gene expression and is often considered the best comparative measure of potency, reveals the rank order of INSs to be, from highest to lowest, IN-MF, IN-FP, IN-BUD, IN-TA, and dexamethasone.
      • Smith CL
      • Kreutner W
      In vitro glucocorticoid receptor binding and transcriptional activation by topically active glucocorticoids.
      Lipophilicity refers to the lipid-partitioning properties of compounds. Highly lipophilic agents will show an increased and faster uptake by the mucosa, a greater retention in the absorbing tissue, and an enhanced ability to reach the cytosolic glucocorticoid receptor. The rank order of some currently prescribed INSs according to lipophilicity is, from highest to lowest, IN-MF, IN-FP, IN-BDP, IN-BUD, IN-TA, and IN-FLU.
      • Corren J
      Intranasal corticosteroids for allergic rhinitis: How do different agents compare?.
      • Johnson M
      Development of fluticasone propionate and comparison with other inhaled corticosteroids.
      This review presents an endocrinologist’s view of the literature regarding the safety of INSs. Accordingly, comparisons of drug efficacy are not discussed, nor are therapeutic strategies addressed. Instead, the focus is on the interpretation of published studies as they relate to the normal physiology of the endocrine systems, the methods of testing the function of these systems, and the known adverse effects of prolonged glucocorticoid excess. Understanding these complexities is critical to making the distinction between detectable indicators of systemic drug presence and a likely unwanted systemic effect. It is hoped that the reader will gain a better understanding of not only previously published results but also physiologic principles that will aid in the proper design and interpretation of future studies.

      INSs and HPA axis function

      The presence of any exogenous glucocorticoid in the bloodstream will reduce the need for endogenous cortisol production. Consequently, measurements of basal hypothalamic-pituitary-adrenal (HPA) activity, such as area-under-the-curve cortisol concentrations and urinary free cortisol excretion, provide the most sensitive indication of systemic bioavailability of INSs, and these laboratory measures of HPA axis function are frequently used to compare the systemic effects of INSs. However, it is important to keep in mind that the mere presence of an exogenous glucocorticoid in circulation does not necessarily indicate a risk of adverse consequences (Fig 2).
      • Allen DB
      Limitations of short-term studies in predicting long-term adverse effects of inhaled corticosteroids.
      Such effects are only anticipated if the exogenous glucocorticoid either exceeds normal cortisol production or provides a pattern of glucocorticoid exposure that, by differing significantly from normal diurnal fluctuations in cortisol levels, adversely affects other physiologic systems.
      Figure thumbnail gr2
      Fig. 2. Short-, intermediate-, and long-term tests of the effects of corticosteroids administered to the airways on the HPA axis. Sensitivity for the detection of the systemic presence of INSs or ICSs is greatest with integrated studies of basal HPA axis function (eg, area-under-the-curve cortisol measurements); positive predictive value for risk of adrenal insufficiency is increased by the performance of dynamic tests of adrenal-gland responsiveness (eg, ACTH stimulation [relative predictive values of low-dose vs high-dose ACTH tests have not yet been determined]). AUC , area under the curve; UFC , urinary free cortisol. (Adapted from Allen DB. Limitations of short-term studies in predicting long-term adverse effects of inhaled cortico-steroids. Allergy 1999;54:29-34; © 1999 Munksgaard International Publishers Ltd, Copenhagen, Denmark. With permission.)
      Tests of HPA axis function that assess basal cortisol production indicate that the absorption of INSs can occur in sufficient amounts to replace, to varying degrees, the need for endogenous cortisol production. For example, IN-BUD and IN-BDP administered to healthy volunteers once in the evening or twice daily at doses of 200, 400, or 800 μg/d suppressed urinary free cortisol excretion to varying degrees.
      • Wihl JA
      • Andersson KE
      • Johansson SA
      Systemic effects of two nasally administered glucocorticosteroids.
      However, although these results can be considered biologic markers of systemic glucocorticoid activity, they do not indicate clinical adrenal dysfunction.
      Stimulation tests of the HPA axis are less sensitive in detecting the presence of systemically bioavailable INSs but are more predictive of a possible clinically significant effect. Given the small apparent effects of INSs on basal HPA axis function, abnormal responses to adrenal axis stimulation tests would not be expected. Studies that used dynamic tests of adrenal function (eg, standard-dose adrenocorticotropic hormone [ACTH] stimulation test) have shown no significant effects of INSs alone in adults with rhinitis (IN-BDP 336 μg/d,
      • Brannan MD
      • Herron JM
      • Reidenberg P
      • Affrime MB
      Lack of hypotha-lamic-pituitary-adrenal axis suppression with once-daily or twice-daily beclomethasone dipropionate aqueous nasal spray administered to patients with allergic rhinitis.
      IN-FP 200 μg once daily or 400 μg twice daily,
      • Vargas R
      • Dockhorn RJ
      • Findlay SR
      • Korenblat PE
      • Field EA
      • Kral KM
      Effect of fluticasone propionate aqueous nasal spray versus oral prednisone on the hypothalamic-pituitary-adrenal axis.
      and IN-TA 220 or 440 μg/d
      • Howland III, WC
      • Dockhorn R
      • Gillman S
      • et al.
      A comparison of effects of triamcinolone acetonide aqueous nasal spray, oral prednisone, and placebo on adrenocortical function in male patients with allergic rhinitis.
      ). In children, IN-TA administration at 220 and 440 μg/d for 6 weeks did not result in the suppression of response to standard-dose ACTH.
      • Nayak AS
      • Ellis MH
      • Gross GN
      • et al.
      The effects of triamcinolone acetonide aqueous nasal spray on adrenocortical function in children with allergic rhinitis.
      Recent longer-term (1-year) studies of prepubertal children who were treated with either IN-BDP 168 μg twice daily
      • Skoner DP
      • Rachelefsky GS
      • Meltzer EO
      • et al.
      Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate.
      or IN-MF 100 μg once daily
      • Schenkel EJ
      • Skoner DP
      • Bronsky EA
      • et al.
      Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray.
      also showed no effects on ACTH responsiveness. Although these studies are reassuring, it is now known that low-dose (eg, 0.5 μg) ACTH stimulation testing may more accurately detect adrenal gland suppression than the standard-dose (250 μg) test.
      • Broide J
      • Soferman R
      • Kivity S
      • et al.
      Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled cortico-steroids.
      When low-dose ACTH stimulation was used in healthy volunteers to assess HPA axis function after very short-term treatment with IN-FP 200 μg/d, IN-TA 220 μg/d, or IN-BDP 336 μg/d, no significant suppression was observed.
      • Wilson AM
      • McFarlane LC
      • Lipworth BJ
      Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal-axis activity.
      Confirmation of normal responses to low-dose ACTH stimulation after more prolonged treatment with INSs should be a future objective.
      In addition to being affected by the choice of tests used, results of HPA axis studies are profoundly influenced by the frequency of drug administration. Cortisol levels normally decrease steadily and fairly rapidly after the early morning peak, and daytime/evening production of cortisol is significantly reduced compared with nocturnal/early morning production. Consequently, morning administration of INSs would be expected to have relatively little effect on (already declining) daytime cortisol concentrations. In addition, because both endogenous cortisol and systemically absorbed INS levels would be low in the evening after morning administration, there would be minimal disruption of the normal diurnal HPA axis rhythm. Studies that examined once-daily (ie, morning) administration of INSs (IN-BDP at 336 μg/d,
      • Wilson AM
      • McFarlane LC
      • Lipworth BJ
      Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal-axis activity.
      IN-TA at 220 μg/d,
      • Wilson AM
      • Sims EJ
      • McFarlane LC
      • Lipworth BJ
      Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.
      • Wilson AM
      • McFarlane LC
      • Lipworth BJ
      Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal-axis activity.
      IN-MF at 200 μg/d,
      • Wilson AM
      • Sims EJ
      • McFarlane LC
      • Lipworth BJ
      Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.
      IN-BUD at 200 μg/d,
      • Wilson AM
      • Sims EJ
      • McFarlane LC
      • Lipworth BJ
      Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.
      and IN-FP at 200 μg/d [when urine collections were corrected for creatinine]
      • Wilson AM
      • McFarlane LC
      • Lipworth BJ
      Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal-axis activity.
      • Bachert C
      Safety of intranasal steroids [letter].
      • Storms WW
      Systemic effects of intranasal corticosteroids [letter].
      ) show no significant effect on the basal HPA axis function.
      Increased lipophilicity could theoretically prolong the systemic drug effect sufficiently to undermine the advantage of once-daily dosing. Plasma drug levels might also underestimate drug absorption caused by the retention of drug in tissue. However, a study in healthy volunteers indicates that plasma levels of FP after intranasal administration
      • McDowall JE
      • Mackie AE
      • Ventresca GP
      • Bye A
      Pharmacokinetics and bioavailability of intranasal fluticasone in humans.
      are much lower than those after oral inhalation,
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      indicating the utility of post-dose plasma FP concentrations in predicting systemic bioavailability of equal doses of FP that are administered by different routes. Furthermore, once-daily administration of the lipophilic agents IN-FP 200 μg/d (when corrected for creatinine excretion)
      • Wilson AM
      • McFarlane LC
      • Lipworth BJ
      Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal-axis activity.
      • Bachert C
      Safety of intranasal steroids [letter].
      • Storms WW
      Systemic effects of intranasal corticosteroids [letter].
      and IN-MF 200 μg/d
      • Wilson AM
      • Sims EJ
      • McFarlane LC
      • Lipworth BJ
      Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.
      resulted in no significant effects on the HPA axis, nor did IN-FP or IN-MF when administered every 8 hours at a total of 12 times the normal intranasal daily dose.
      • Daley-Yates PT
      • Kunka RL
      • Shen YY
      • Andrews SM
      • Callejas S
      • Ng C
      The relative systemic exposure to fluticasone propionate (FP) and mometasone furoate (IN-MF) administered as aqueous nasal sprays in healthy subjects [abstract].
      Interpreting studies of INS effects on the HPA axis is also made more difficult for readers by microgram-for-microgram comparisons, which ignore known differences in drug potency. As described earlier, marked differences in receptor affinity between, for example, IN-FP or IN-MF and IN-TA should obviate a direct comparison of similar microgram doses, as it would a milligram-for-milligram comparison between oral hydrocortisone and prednisone. More informative would be comparisons of clinically equivalent doses of compounds. In addition, subtle decisions regarding data description can affect the conclusions drawn. For example, 1 report that concluded that overnight urinary cortisol was significantly suppressed by IN-FP 200 μg/d
      • Wilson AM
      • McFarlane LC
      • Lipworth BJ
      Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal-axis activity.
      was contradicted when collections were corrected for creatinine excretion.
      • Bachert C
      Safety of intranasal steroids [letter].
      • Storms WW
      Systemic effects of intranasal corticosteroids [letter].
      Taken together, the data suggest that the administration of INS alone in recommended and moderate doses has minimal effect on the HPA axis. Substantial differences in the attributes of individual INSs, such as oral bioavailability, may affect studies of basal HPA axis function, particularly after nocturnal administration, but have not been shown to have clinical relevance with regard to adrenal gland responsiveness. Once-daily administration of recommended doses of INSs appears to have negligible effects on the HPA axis and, from a safety standpoint, should be preferred if effective (particularly if a higher INS dosage is required). Additive exogenous steroid effects on the HPA axis, however, can occur when INS treatment accompanies concurrent ICS or other topical corticosteroid therapy.

      INSs and childhood growth

      The study of childhood growth is complex because of changes in primary factors that regulate growth, normal variation in the tempo of growth and pubertal development, and frequent (sometimes abrupt) changes in growth rate. As with measures of the HPA axis, techniques for the evaluation of the growth effects of INSs vary in their sensitivity for the detection of short-term and perhaps transient disruptions in the growth process versus their predictive value for a clinically significant effect on statural growth (Fig 3).
      • Allen DB
      Limitations of short-term studies in predicting long-term adverse effects of inhaled corticosteroids.
      Figure thumbnail gr3
      Fig. 3. Short-, intermediate-, and long-term tests of the effects of corticosteroids administered to the airways on growth. Highly sensitive knemometry is a poor predictor of long-term growth, which is more accurately assessed by intermediate-term or long-term whole body stadiometry. (Adapted from Allen DB. Limitations of short-term studies in predicting long-term adverse effects of inhaled corticosteroids. Allergy 1999;54:29-34; © 1999 Munksgaard International Publishers Ltd, Copenhagen, Denmark. With permission.)
      Corticosteroids are potent inhibitors of linear growth, exerting suppressive effects at virtually every level of a child’s growth axis (Fig 4).
      • Allen DB
      • Julius JR
      • Breen TJ
      • Attie KM
      Treatment of glucocorticoid-induced growth suppression with growth hormone.
      The blunting of pulsatile growth hormone release, downregulation of growth hormone receptor expression, inhibition of insulin-like growth factor-1 bioactivity, and suppression of collagen synthesis and adrenal androgen production are all known mechanisms by which corticosteroids can inhibit growth. Small amounts of exogenous corticosteroid in excess of normal physiologic requirements are capable of suppressing childhood growth.
      • Allen DB
      Growth suppression by glucocorticoid therapy.
      Consequently, growth suppression is both a sensitive and relatively specific indicator of excessive corticosteroid effect, which distinguishes it from highly sensitive measures of basal HPA axis function that have limited predictive value for clinically meaningful effects.
      Figure thumbnail gr4
      Fig. 4. Mechanisms of growth suppression by corticosteroids (derived from both in vivo and in vitro studies). GHRH, growth hormone releasing hormone; GH, growth hormone; IGF-1, insulin-like growth factor-1. (From Allen DB, Julius JR, Breen TJ, Attie KM. Treatment of glucocorticoid-induced growth suppression with growth hormone. J Clin Endocrinol Metab 1998;83(8):2824-9; © The Endocrine Society. With permission.)
      The difficulty of conducting controlled studies of the effects of INSs or ICSs on long-term growth prompted interest in short-term studies (ie, <6 months) of growth using knemometry (precise measurement of lower-leg growth). The advantages of knemometry include the ability to use (1) very short observation periods; (2) controlled, randomized, double-blind conditions; and (3) cross-over trials.
      • Wolthers OD
      Long-, intermediate-, and short-term growth studies in asthmatic children treated with inhaled glucocorticosteroids.
      The major disadvantage of knemometry is that short-term lower-leg growth rates cannot be extrapolated to intermediate or long-term growth. Childhood growth normally occurs in spurts, interspersed with periods during which essentially no growth occurs.
      • Hermanussen M
      • Geiger-Benoit K
      • Burmeister J
      • Sippell WG
      Periodical changes of short term growth velocity (`mini growth spurts') in human growth.
      The precision of knemometry allows detection of this irregular pattern, which, when combined with its focus on lower-leg growth only, actually becomes a liability in the prediction of overall linear bodily growth. Even when these measurements are performed over 4 months, 6-month growth velocity is only predicted within 28.8% (mean ± 2 SDs), and correlations between growth of the lower leg and total height over 6 months are indifferent.
      • Wales JKH
      • Milner RDG
      Knemometry in assessment of linear growth.
      Measurements performed over shorter time intervals produce even poorer predictions.
      The high sensitivity of knemometry may be useful in comparing differences in systemic activity between drugs and in identifying generally safe doses of INSs or ICSs. Still, prospective studies that combine the early application of knemometry with careful stadiometry measurements and close monitoring of INSs or ICSs that are administered at consistent doses over a period of 12 months or longer (to account for seasonal variations in growth rate) are needed to further evaluate the predictive value of knemometry measurements in this setting. Until then, carefully designed and conducted stadiometry studies that evaluate 12 or more months of growth provide the most clinically useful information about the effects of INSs and ICSs on growth.
      In addition to drug properties that influence the degree of systemic effects observed at a given dosage, patient characteristics also affect susceptibility to growth suppression. These include age and growth pattern of the child, underlying disease severity, and timing of drug administration. Childhood growth can be conceptually divided into age-related phases: (1) a rapid but rapidly decelerating period during infancy that is controlled primarily by nutrition and nutrition-dependent growth factors; (2) childhood growth, during which growth rate, under primary regulation by growth hormone, gradually declines; and (3) pubertal growth, during which growth rate accelerates under combined growth hormone and sex hormone stimulation then declines as epiphyseal closure occurs.
      • Wolthers OD
      Long-, intermediate-, and short-term growth studies in asthmatic children treated with inhaled glucocorticosteroids.
      • Karlberg J
      • Jalil F
      • Lam B
      • Low L
      • Yeung CY
      Linear growth retardation in relation to the three phases of growth.
      In some children, susceptibility to growth suppression by a variety of influences is increased during transitions from 1 phase to another. This is particularly true in the 2 to 3 years before puberty, when growth rates are low and the resiliency of the growth hormone axis is transiently and physiologically low. Significantly, most studies of growth effects of INSs or ICSs have focused on children of this age, and results cannot confidently be extrapolated to infants or adolescents.
      Chronic disease during childhood is known to adversely affect the tempo of growth, an effect observed in asthmatic children predominantly late in childhood and early in adolescence.
      • Merkus PJFM
      • van Essen-Zandvliet EEM
      • Duiverman EJ
      • van Houwelingen HC
      • Kerrebijn KF
      • Quanjer PH
      Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma.
      Pubertal development and attainment of (normal) adult height is delayed. In contrast to asthma, allergic rhinitis alone does not appear to have an important effect on growth. Timing of drug administration, on the other hand, may be important. Growth hormone secretion in prepubertal children is pulsatile and primarily nocturnal, with the initiation of pulses corresponding to the normal late-evening nadir in plasma cortisol concentrations. Absorption of exogenous corticosteroid at that time might be expected to have a more pronounced suppressive effect on growth hormone release than morning dosage (Fig 5). Interestingly, short-term studies of IN-BUD suggest that 200 μg twice daily causes significant suppression in short-term lower-leg growth,
      • Wolthers OD
      • Pedersen S
      Short-term growth in children with allergic rhinitis treated with oral antihistamine, depot and intranasal glucocorticosteroids.
      whereas 400 μg administered once daily in the morning does not.
      • Wolthers OD
      • Pedersen S
      Knemometric assessment of systemic activity of once daily intranasal dry-powder budesonide in children.
      Figure thumbnail gr5
      Fig. 5. Interaction of childhood growth and HPA axes. The commencement of nocturnal pulsatile growth hormone secretion normally coincides with the nadir in plasma cortisol concentrations. Consequently, the administration and absorption of airway corticosteroids at bedtime could theoretically have a disproportionate suppressing influence on growth, compared with early morning dosing. GH , growth hormone.
      Recent observations that certain ICSs can measurably slow growth rates in prepubertal children with asthma
      • Doull IJ
      • Freezer NJ
      • Holgate ST
      Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate.
      • Verberne AAPH
      • Frost C
      • Roorda RJ
      • van der Laag H
      • Kerrebijn KF
      • The Dutch Paediatric Asthma Study Group
      One year treatment with salmeterol compared with beclomethasone in children with asthma.
      prompted concerns about a possible similar effect from chronic INS administration. Early short-term studies that used knemometry suggested potential effects of INSs on growth.
      • Wolthers OD
      • Pedersen S
      Short-term growth in children with allergic rhinitis treated with oral antihistamine, depot and intranasal glucocorticosteroids.
      • Wolthers OD
      • Pedersen S
      Controlled study of linear growth in asthmatic children during treatment with inhaled glucocorticosteroids.
      In 1 study, lower-leg growth was reduced from a pretreatment rate of 0.59 mm/wk to 0.05 mm/wk during treatment with IN-BUD 200 μg twice daily administered as an aqueous nasal spray. On the other hand, a subsequent knemometry study showed that IN-BUD 200 μg/d or 400 μg/d administered once daily with a dry powder inhaler had no significant effect on growth.
      • Wolthers OD
      • Pedersen S
      Knemometric assessment of systemic activity of once daily intranasal dry-powder budesonide in children.
      These findings could reflect differences in bioavailability of the different drug formulations (ie, aqueous, dry powder, or aerosol) or differences in the effect of once-daily versus twice-daily dosing.
      • Wolthers OD
      • Pedersen S
      Short-term growth in children with allergic rhinitis treated with oral antihistamine, depot and intranasal glucocorticosteroids.
      • Wolthers OD
      • Pedersen S
      Knemometric assessment of systemic activity of once daily intranasal dry-powder budesonide in children.
      A recent knemometry study showed no significant differences in lower-leg growth rates among children receiving once-daily treatment with IN-MF 100 μg or 200 μg, IN-BUD 400 μg, or placebo for 2-week periods (Fig 6).
      • Agertoft L
      • Pedersen S
      Short-term lower leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide.
      Although reassuring, this study also illustrates the limitations of knemometry and the wide variations in growth rates observed over very short periods of study; that is, growth rates in the IN-MF 100 μg group were significantly greater than those in both the placebo and IN-BUD 400 μg groups, which suggests the alternate (and nonphysiologic) conclusion that IN-MF increased short-term growth rates. Proponents of knemometry acknowledge its limitations in predicting long-term growth reduction and assert that this method is more useful for defining doses of airway corticosteroids that are unlikely to be associated with any adverse effects on long-term growth.
      • Agertoft L
      • Pedersen S
      Short-term lower leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide.
      Figure thumbnail gr6
      Fig. 6. Mean lower-leg growth rates during once-daily treatment with IN-MF 100 μg/d (0.58 mm/wk) or 200 μg/d (0.48 mm/wk), IN-BUD 400 μg/d (0.37 mm/wk), or placebo (0.35 mm/wk). Marked interindividual differences in growth velocity were observed during all 4 treatments. (Adapted from Agertoft L, Pedersen S. Short-term lower leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide. J Allergy Clin Immunol 1999;104:948-52. With permission.)
      Longer-term studies that used stadiometry have revealed detectable differences in the effects of various INSs and/or dosing regimens on growth.
      • Skoner DP
      • Rachelefsky GS
      • Meltzer EO
      • et al.
      Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate.
      • Schenkel EJ
      • Skoner DP
      • Bronsky EA
      • et al.
      Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray.
      A 12-month, double-blind, placebo-controlled study of prepubertal children with perennial allergic rhinitis demonstrated that IN-BDP 168 μg twice daily caused a small (0.9 cm) but statistically significant reduction in annual height gain (Fig 7).
      • Skoner DP
      • Rachelefsky GS
      • Meltzer EO
      • et al.
      Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate.
      Subtle problems with study design (eg, older average age of the children treated with IN-BDP) may have exaggerated the observed growth effect, but correcting the results for differences in expected growth rates did not eliminate a significant drug effect.
      Figure thumbnail gr7
      Fig. 7. Mean change in standing height from baseline over 1 year of treatment with IN-BDP 168 μg twice daily or placebo. (Adapted from Skoner DP, Rachelefsky GS, Meltzer EO, et al. Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate. Pediatrics [electronic pages] 2000;105:E23. Reproduced by permission of Pediatrics, © 2000.)
      Primarily, but not solely, based on this IN-BDP stadiometry study, the US Food and Drug Administration Pulmonary and Allergy Drug Advisory Panel recommended in 1998 that the following precaution be included in all INS label information (excerpts): ″Cortico-steroids, including intranasal corticosteroids, have been shown to cause a reduction in growth velocity in children and adolescents . The long-term effects of the observed reduction of growth velocity in children and adolescents using intranasal corticosteroids, including the impact on final adult height, are unknown . The growth of children and adolescents receiving intranasal cortico-steroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained, and the availability of treatment alternatives. To minimize the systemic effects of intranasal corticosteroids,  all patients should be titrated to the lowest effective dose.”

      Orally inhaled/intranasal corticosteroids and growth in children (Proceedings from the Food and Drug Administration Center for Drug Evaluation and Research, Joint Pulmonary and Allergy Drug Advisory Committee/Endocrinologic and Metabolic Drug Advisory Committee; July 31, 1998; Bethesda, Md).

      This recommendation was based on the finding that there was overrepresentation of growth velocity percentile ranks in the lower ranges in children treated with IN-BDP. Fluctuations in children’s annual growth velocity percentile rank are relatively more pronounced than changes in height standard deviation scores. Consequently, this approach could sensitively detect transient growth effects that did not/would not persist over time. However, the qualitative similarity of IN-BDP growth data to that of some inhaled cortico-steroids that more clearly indicated 1-year growth suppression, coupled with the identification of some children who were treated with IN-BDP whose growth appeared particularly sensitive to suppression by INSs, was invoked to support the labeling recommendation.
      In contrast to 1-year treatment with IN-BDP 168 μg twice daily, 1-year treatment with IN-MF 100 μg once daily showed no evidence of the retardation of growth (Fig 8).
      • Schenkel EJ
      • Skoner DP
      • Bronsky EA
      • et al.
      Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray.
      Although the results of prospective 1-year trials of IN-FP alone are not yet available, 1 study that examined the addition of INSs to ICS treatment for asthma (inhaled BDP 200 μg twice-daily or inhaled FP 100 μg twice daily) showed no effect on 1-year growth when IN-FP was added to either inhaled FP or inhaled BDP therapy, whereas the addition of IN-BDP resulted in growth suppression of children who were treated with inhaled FP and those treated with inhaled BDP.
      • Fiocchi A
      • Hughes S
      • Medley HV
      Effects of inhaled and intranasal cortico-steroids on growth velocity in children: a comparison of fluticasone propionate with beclomethasone dipropionate [abstract].
      Further, data extrapolated from a study of the long-term growth effects of inhaled FP (which is associated with a higher bioavailability [26.4%
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      ] than intranasal administration [<1%
      • Richards DH
      • Daley-Yates PT
      Choice of inhaled and intranasal steroids when used in combination for asthma and rhinitis in children [abstract].
      • Daley-Yates PT
      • McAllister T
      Systemic bioavailability of fluticasone propionate administered as nasal drops (FP-Drops) and aqueous nasal spray formulations (FPANS) [abstract].
      ]) would predict no significant effect of a similar dose of IN-FP. In this prospective and tightly controlled 12-month study of prepubertal children with asthma, the administration of inhaled FP at 50 μg or 100 μg twice daily had no significant effect on growth (Fig 9).
      • Allen DB
      • Bronsky EA
      • LaForce CF
      • et al.
      Growth in asthmatic children treated with fluticasone propionate.
      Figure thumbnail gr8
      Fig. 8. Mean change in standing height from baseline over 1 year of treatment with IN-MF 100 μg once daily or placebo. (Adapted from Schenkel EJ, Skoner DP, Bronsky EA, et al. Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics [electronic pages] 2000;105:E22. Reproduced by permission of Pediatrics, © 2000.)
      Figure thumbnail gr9
      Fig. 9. Mean change in standing height from baseline over 1 year of treatment with inhaled FP 50 μg or 100 μg twice daily or placebo. (Adapted from Allen DB, Bronsky EA, LaForce CF, et al. Growth in asthmatic children treated with fluticasone propionate. J Pediatr 1998;132:472-7. With permission.)
      These studies allow the following conclusions regarding the effects of INSs given in therapeutic doses on childhood growth: (1) a detectable slowing of 1-year growth in prepubertal children can occur with continuous, twice-daily treatment with IN-BDP; (2) the long-term effects of IN-BDP on growth or adult height remain unknown; (3) once-daily administration of recommended doses of an INS with more efficient first-pass hepatic inactivation (eg, IN-FP or IN-MF) should not suppress growth; (4) twice-daily administration of an INS may be required to cause detectable growth suppression; (5) because total systemic corticosteroid burden reflects absorption of exogenous corticosteroid administered by any route, the risk for growth suppression is increased when INS and ICS therapies are combined; and (6) titration to the lowest effective dose, a once-daily dosing regimen, and the choice of an INS with efficient inactivation of swallowed drug will minimize the already low risk of growth suppression by INS therapy alone.

      Bone metabolism and risk for osteoporosis

      Corticosteroid excess affects normal bone metabolism in multiple ways (Fig 10). Calcium homeostasis is disrupted by the direct alteration of osteoblastic and osteoclastic activity that leads to increased bone dissolution.
      • Wilson AM
      • Sims EJ
      • McFarlane LC
      • Lipworth BJ
      Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.
      Increases in urinary calcium losses coupled with the inhibition of vitamin D–mediated intestinal calcium absorption result in total body calcium deficiency and secondary hyperparathyroidism.
      • Lukert BP
      • Raisz LG
      Glucocorticoid-induced osteoporosis: pathogenesis and management.
      Particularly in females, reductions in sex hormone production further reduce bone mass. Thus, an important long-term side effect of corticosteroid excess is osteoporosis and the associated increased risk of fractures.
      Figure thumbnail gr10
      Fig. 10. Interaction of corticosteroids with bone metabolism, which contributes to the increased risk for osteoporosis.
      Although the adverse effects of corticosteroids on bone metabolism are well known, the determination of possible effects of INSs or ICSs on this system is challenging. Multiple potentially confounding factors must be considered, such as nutrition history, heredity, control of underlying disease, physical activity, and previous exposure to oral corticosteroids. In children, the stage of development is also critical because the rate of bone mineral accretion increases rapidly in adolescence and because delayed puberty itself is associated with significantly lower peak bone mass/density.
      • Finkelstein JS
      • Klibanski A
      • Neer RM
      A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty.
      Short-term effects of exogenous steroids on bone can be evaluated by the measurement of the biochemical markers of bone formation (eg, osteocalcin) and degradation (eg, urinary telopeptides). However, the predictive value of changes in markers of bone turnover for clinically important adverse effects is unproved. Dual x-ray absorptiometry is the most valid technique for the assessment of bone mineral density (BMD). However, even the finding of reduced BMD has only a statistical association with future fracture risk and is of marginal clinical use for the assessment of risk in individual patients; that is, a decrease of 1 population SD in BMD is associated with a doubling of the risk of fracture from data in older women.
      • Wasnich R
      Bone mass measurement: prediction of risk.
      Although studies that investigated the association between ICS treatment and BMD in adults have given inconsistent results, recent data provide evidence for a negative relation between total cumulative ICS dose (approximately 80% of patients using inhaled BDP) and BMD in patients with asthma.
      • Wong CA
      • Walsh LJ
      • Smith CJP
      • et al.
      Inhaled corticosteroid use and bone-mineral density in patients with asthma.
      As indicated earlier, the importance of this observation to the effects of INSs on bone metabolism most likely relate to the additive effects of ICS and INS treatment in individual patients, rather than to expected effects of INSs alone on BMD. Presently, there are limited data that examine the long-term effects of INSs on BMD. No studies that used dual x-ray absorptiometry measurements of children or adults who were treated with INSs could be found. Short-term administration of IN-BUD 200 μg/d, IN-TA 220 μg/d, or IN-MF 200 μg/d resulted in no suppression of plasma osteocalcin levels.
      • Wilson AM
      • Sims EJ
      • McFarlane LC
      • Lipworth BJ
      Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.
      Nevertheless, studies of HPA axis function and growth during INS therapy allow predictions to be made for bone metabolism, because these systems offer more sensitive indicators of the systemic corticosteroid effect. That is, INS treatment regimens that do not suppress basal measures of HPA axis function and have no detectable effects on childhood growth would be expected to have no significant effect on osteoporosis risk. As mentioned earlier, when INSs are used in combination with corticosteroids administered by other routes, small increases in systemic corticosteroid effect resulting from INS use could theoretically occur, and the choice of an INS with minimal oral bioavailability would be advised.

      Safety of INSs: Conclusions

      Although topical airway corticosteroid therapies for asthma and allergic rhinitis have markedly improved the control of these diseases and have significantly lessened the risk of corticosteroid side effects, the use of these therapies continues to be accompanied by the fear of potential adverse systemic effects. Unfortunately, these fears result in some patients being deprived of appropriate and effective treatment or even exposed to a greater risk of periodic oral corticosteroid treatment. Nevertheless, continued development of more potent INS compounds, which will be increasingly used for longer periods of time in patients with mild disease and in younger patients, demands careful examination of potential systemic effects.
      Although INSs have not been nearly as thoroughly investigated as ICSs, information is now rapidly accumulating to support the safety of INSs that are used in recommended doses. Some important overall conclusions appear to be well supported by the studies taken together and to make sense from an endocrinologic point of view. First, although usually detectable in the systemic circulation after administration, INSs that are used in small doses or intermittently present no significant risk for systemic side effects. When INSs are used at higher dosages and continuously for long periods of time, important differences in drug characteristics, particularly the efficiency of inactivation of swallowed drug (which does not exert a therapeutic effect before gaining access to the systemic circulation), affect the ratio of therapeutic-to-systemic effect of individual INSs. Once-daily morning INS administration, which prevents a nonphysiologic corticosteroid effect during the normal late-evening nadir in endogenous cortisol levels and increase in growth hormone secretion, reduces any potential suppression of the HPA or growth axis.
      From a practical viewpoint, the long-term clinical history of INS therapy is informative. Clinically significant suppression of the HPA axis because of INS therapy alone appears to be exceedingly rare. Detectable suppression of childhood growth was observed when an INS with relatively poor first-pass inactivation was administered twice daily continuously throughout the year. Once-daily administration of INSs has not been associated with either clinically relevant effects on HPA axis function or childhood growth. Harmful effects of INSs on bone metabolism, although not yet adequately studied, would not be expected with the use of an INS, dose, and dosing frequency that do not suppress basal HPA axis function or childhood growth. An important caveat to these conclusions is that they refer to the use of INSs alone , not in combination with ICSs or other topical corticosteroids.
      Although the study design of trials that investigate INS safety has improved over the last decade, comparisons of equal microgram doses of drugs with markedly different potencies, lack of consensus regarding ″clinically equivalent dosages,” and the use of short-term, highly sensitive measurements to imply significant long-term risk continue to confuse rather than to clarify the issues. Future competition among manufacturers of INSs for an incremental ″edge” for their product may encourage continued blurring of the distinctions between detectable physiologic fluctuations and meaningful biologic effects. An understanding of the basic endocrinologic principles described earlier will help reviewers to evaluate study design and data quality and readers/prescribers to interpret and implement new information toward the best care for their patients.

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