Reviews and Feature Articles
Potential adverse effects of the inhaled corticosteroids☆

https://doi.org/10.1016/S0091-6749(03)01870-0Get rights and content

Abstract

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-pituitary-adrenal 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.

Section snippets

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

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

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

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,

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

References (58)

  • AC Ferguson et al.

    Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of fluticasone propionate with budesonide

    J Pediatr

    (1999)
  • NE Lane et al.

    The science and therapy of glucocorticoid-induced bone loss

    Endocrinol Metab Clin N Am

    (1998)
  • KG Saag

    Glucocorticoid-induced osteoporosis

    Endocrinol Metab Clin N Am

    (2003)
  • PD Miller

    Bone mineral density-clinical use and application

    Endocrinol Metab Clin N Am

    (2003)
  • JH Toogood et al.

    Serum osteocalcin and procollagen as markers for the risk of osteoporotic fracture in corticosteroid-treated asthmatic adults

    J Allergy Clin Immunol

    (1999)
  • CA Wong et al.

    Inhaled corticosteroid use and bone-mineral density in patients with asthma

    Lancet

    (2000)
  • S Elmstahl et al.

    Is there an association between inhaled corticosteroids and bone density in postmenopausal women?

    J Allergy Clin Immunol

    (2003)
  • Global Initiative for Asthma. Global strategy for asthma management and prevention revised (2002). NHLBI/WHO Workshop...
  • National Institutes of Health, National Heart, Lung, and Blood Institute

    National Asthma Education and Prevention Programme. Expert Panel Report: Guidelines for the diagnosis and management of asthma update on selected topics 2002

    J Allergy Clin Immunol

    (2002)
  • S Pedersen et al.

    A comparison of the efficacy and safety of inhaled corticosteroids in asthma

    Allergy

    (1997)
  • BJ Lipworth et al.

    Dose response to inhaled corticosteroids: benefits and risks

    Semin Respir Crit Care Med

    (1998)
  • PJ Barnes et al.

    Efficacy and safety of inhaled corticosteroids: new developments

    Am J Respir Crit Care Med

    (1998)
  • BJ Lipworth

    Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis

    Arch Intern Med

    (1999)
  • S Pedersen

    State of the art: do inhaled corticosteroids inhibit growth in children?

    Am J Respir Crit Care Med

    (2001)
  • RJ Martin et al.

    Systemic effect comparisons of six inhaled corticosteroid preparations

    Am J Respir Crit Care Med

    (2002)
  • JM Drazen et al.

    Heterogeneity of therapeutic responses in asthma

    Br Med Bull

    (2000)
  • M Kozower et al.

    Decreased clearance of prednisolone, a factor in the development of corticosteroid side effects

    J Clin Endocrinol Metab

    (1974)
  • NA Huizenga et al.

    A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo

    J Clin Endocrinol Metab

    (1998)
  • Cited by (0)

    ☆

    This activity is available for CME credit. See page 33A for important information.

    View full text