Objective To appraise the data on systemic adverse effects of inhaled corticosteroids. Methods A computerized database search from January 1, 1966, through July 31, 1998, using MEDLINE, EMBASE, and BIDS and using appropriate indexed terms. Reports dealing with the systemic effects of inhaled corticosteroids on adrenal gland, growth, bone, skin, and eye, and reports on pharmacology and pharmacokinetics were reviewed where appropriate. Studies were included that contained evaluable data on systemic effects in healthy volunteers as well as in asthmatic children and adults. A statistical meta-analysis using regression was performed for parameters of adrenal suppression in 27 studies. Results Marked adrenal suppression occurs with high doses of inhaled corticosteroid above 1.5 mg/d (0.75 mg/d for fluticasone propionate), although there is a considerable degree of interindividual susceptibility. Meta-analysis showed significantly greater potency for dose-related adrenal suppression with fluticasone compared with beclomethasone dipropionate, budesonide, or triamcinolone acetonide, whereas prednisolone and fluticasone propionate were approximately equivalent on a 10:1-mg basis. Inhaled corticosteroids in doses above 1.5 mg/d (0.75 mg/d for fluticasone propionate) may be associated with a significant reduction in bone density, although the risk for osteoporosis may be obviated by postmenopausal estrogen replacement therapy. Although medium-term growth studies showed suppressive effects with 400-µg/d beclomethasone dipropionate, there was no evidence to support any significant effects on final adult height. Long-term, high-dose inhaled corticosteroid exposure increases the risk for posterior subcapsular cataracts, and, to a much lesser degree, the risk for ocular hypertension and glaucoma. Skin bruising is most likely to occur with high-dose exposure, which correlates with the degree of adrenal suppression. Conclusions All inhaled corticosteroids exhibit dose-related systemic adverse effects, although these are less than with a comparable dose of oral corticosteroids. Meta-analysis shows that fluticasone propionate exhibits greater dose-related systemic bioactivity compared with other available inhaled corticosteroids, particularly at doses above 0.8 mg/d. The long-term systemic burden will be minimized by always trying to achieve the lowest possible maintenance dose that is associated with optimal asthmatic control and quality of life.

https://jamanetwork.com/journals/jamainternalmedicine/articlepdf/485026/ioi80741.pdf

Systemic Adverse Effects of Inhaled Corticosteroid Therapy: A Systematic Review and Meta-analysis

This article reviews the risks of osteoporosis and osteonecrosis associated with glucocorticoid use, which are present even in the absence of low bone mineral density, and discusses strategies to reduce the risk of fractures and the data to support the strategies.

/pdf/glucocorticoid-induced-bone-disease-4r6dy66fkn.pdf

Glucocorticoid-Induced Bone Disease

Patient education is a critical factor in the use and misuse of medication inhalers. Inhalers represent advanced technology that is considered so easy to use that many patients and clinicians do not receive adequate training in their use. Between 28% and 68% of patients do not use metered-dose inhalers or powder inhalers well enough to benefit from the prescribed medication, and 39-67% of nurses, doctors, and respiratory therapists are unable to adequately describe or perform critical steps for using inhalers. Of an estimated 25 billion dollars spent for inhalers annually, 5-7 billion dollars is wasted because of inhaler misuse. Reimbursement and teaching strategies to improve patient education could substantially reduce these wasted resources. Problems with inhaler use, the cost of inhalers, and myths associated with inhalers are reviewed, with recommendations for strategies and techniques to better educate patients in inhaler use.

http://rc.rcjournal.com/content/respcare/50/10/1360.full.pdf

Problems with inhaler use: a call for improved clinician and patient education.

Glucocorticoids induce rapid bone loss and increase the risk for osteoporotic fractures. The mechanisms include a phase of increased bone resorption, probably a result of the increased expression of receptor activator of nuclear factor-k-B ligand and colony stimulating factor-1, followed-up by a decrease in bone formation. This effect is central to the actions of glucocorticoids in bone and it is secondary to the loss of bone forming cells, caused by an inhibition of cell differentiation and an increase in the apoptosis of mature osteoblasts and osteocytes. Glucocorticoids also inhibit the function of mature osteoblasts and suppress the synthesis of insulin-like growth factor-I, an agent that enhances bone formation. Glucocorticoids alter the growth hormone/insulin-like growth factor axis in cartilage and, as a consequence, suppress linear growth.

Mechanisms of glucocorticoid action in bone

To test whether the leukotriene antagonist ONO-1078 (pranlukast) prevents asthma exacerbations during reduction of high-dose inhaled corticosteroid, we conducted a randomized, double-blind, placebo-controlled study in 79 asthma patients requiring high doses (1,500 microg/d or more) of inhaled beclomethasone dipropionate (BDI) for clinical control (duration of asthma, 11.0 +/- 3.1 yr; duration of BDI treatment, 0.5 +/- 0.3 yr; FEV1 percentage of predicted, 80.7 +/- 2.0%). After a 2-wk run-in period, the doses of BDI were halved, while the patients were assigned to receive orally ONO-1078, 450 mg twice daily, or placebo. In the placebo group FEV1 decreased by 0.33 +/- 0.20 L after 6 wk (p < 0.001). Likewise, morning and evening PEF decreased by 46 +/- 7 L/min and 18 +/- 6 L/min, respectively. By contrast these variables were sustained above baseline in the ONO-1078 group. The number of daytime and nighttime asthma symptoms and the use of beta2-agonist increased in the placebo group, whereas they remained unchanged in the ONO-1078 group. In the placebo group concentrations of serum eosinophil cationic protein and exhaled nitric oxide increased (p = 0.007 and p = 0.025, respectively), compared with no change in the ONO-1078 group. Therefore, the leukotriene antagonist ONO-1078 prevents the asthma deterioration provoked by a 6-wk reduction of the dose of inhaled BDI into half.

Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group.

Osteoporosis is a well-known, serious complication of long-term high-dose corticosteroid therapy. This study was performed to determine the effects of commonly used doses of oral and inhaled steroids on biochemical indices of bone formation. Initially we examined the long-term effects of oral steroids. Thirty-four outpatients with symptomatic asthma or chronic obstructive airways disease (COAD) receiving long-term oral prednisolone (mean 10.1 mg daily) were compared with 34 control subjects with asthma or COAD matched individually for age, sex, and menopausal status who were not taking oral steroids. Plasma osteocalcin concentrations were significantly lower (patients 6.3 +/- 0.1 ng/ml; control subjects 8.6 +/- 0.5 ng/ml, mean +/- SEM; p < 0.01) in patients on steroids with no difference in alkaline phosphatase. To examine the short-term effects of oral and inhaled corticosteroids, healthy male volunteers were given a 7-d course of either 15 mg oral prednisolone daily (n = 10) or 500 micrograms inhaled be...

Oral and inhaled corticosteroids reduce bone formation as shown by plasma osteocalcin levels.

The role of calcitonin and parathyroid hormone (PTH) in corticosteroid-induced osteoporosis is controversial. We therefore measured plasma calcitonin and PTH levels in 34 adults receiving chronic pharmacological corticosteroids for obstructive airways disease, and in controls matched for age, sex, menopause, and disease. In addition, the acute effect of a 7-day course of 15 mg prednisolone daily on fasting and calcium-stimulated calcitonin was studied in 10 normal male volunteers. There was no difference in calcitonin and PTH levels in the corticosteroid-treated patients when compared with controls. The corrected serum calcium was significantly higher in the steroid-treated patients (patients mean 2.40 (SEM 0.01) mmol/liter; controls mean 2.33 (SEM 0.01) mmol/liter; P < 0.001). The short course of corticosteroids in volunteers did not alter basal or stimulated calcitonin, PTH, or calcium levels. These results suggest that neither calcitonin deficiency nor PTH excess is a feature of corticosteroid-induced osteoporosis.

The effect of long- and short-term corticosteroids on plasma calcitonin and parathyroid hormone levels

Inhaled steroids are increasingly advocated as first line treatment for mild asthma. Some studies suggest that inhaled steroids suppress bone formation as reflected by a fall in plasma osteocalcin. Spacers have been shown to increase the proportion of inhaled aerosol that is deposited in the lungs and to reduce the amount swallowed. We measured plasma osteocalcin levels to determine the effect on bone formation of inhaled beclomethasone dipropionate (BDP) with and without a 750 ml spacer in a double-blind, randomised, placebo-controlled, cross-over study. Twenty-six healthy male volunteers took BDP 500 micrograms (two puffs of Becloforte) together with two puffs of placebo, inhaled twice daily for seven days. One inhaler was taken directly while the other was inhaled through a 750 ml spacer. After a two week washout period, the inhalers were exchanged so that BDP was taken by the alternate route for a further seven days. Fasting plasma osteocalcin levels were measured at 09.00 h before and at the end of each week. After a week of BDP taken directly (without a spacer), osteocalcin levels fell from 11.8 (SEM 0.6) ng/ml to 9.5 (SEM 0.5) ng/ml (p

https://pmj.bmj.com/content/postgradmedj/71/833/156.full.pdf

A large volume spacer significantly reduces the effect of inhaled steroids on bone formation.

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Oral and inhaled corticosteroids reduce bone formation as shown by plasma osteocalcin levels.

The effect of long- and short-term corticosteroids on plasma calcitonin and parathyroid hormone levels

A large volume spacer significantly reduces the effect of inhaled steroids on bone formation.