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Safety of Inhaled Corticosteroids

Division of Respiratory Medicine, Nottingham University; Respiratory Medicine Unit, David Evans Research Centre, Nottingham City Hospital, Nottingham, United Kingdom

Correspondence and requests for reprints should be addressed to Anne E. Tattersfield, M.D., Division of Respiratory Medicine, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. E-mail: anne.tattersfield{at}nottingham.ac.uk

	ABSTRACT

TOP ABSTRACT EVIDENCE FOR SYSTEMIC ABSORPTION... EVIDENCE FOR SYSTEMIC BIOLOGICAL... EVIDENCE FOR ADVERSE SYSTEMIC... CAN SYSTEMIC ABSORPTION BE... CONCLUSIONS REFERENCES

 
Systemic bioavailability from the gastrointestinal tract is reduced with newer inhaled corticosteroids (ICSs) such as fluticasone, but systemic absorption still occurs via the lung. Observational studies have shown an association between ICS use and several adverse outcomes such as cataracts, glaucoma, and adrenal failure, and prospective controlled studies have confirmed a causal relationship between ICS use and bruising, reduction in bone mineral density, and reduced growth velocity. The evidence suggests that the effect of ICSs on bone mineral density is small in the short term but that patients taking moderate or high doses for long periods will be at increased risk of fractures and that this could be an appreciable public health problem. There is also evidence to suggest that the risk of long-term adverse effects is likely to differ between ICSs. The clinical message that follows is that ICSs should be used widely because they reduce the need for courses of oral corticosteroids and improve quality of life, but that they need to be managed carefully to reduce the risk of adverse effects with long-term use.

Key Words: adrenal suppression • bone mineral density • fracture • systemic absorption

Inhaled corticosteroids (ICSs) are extremely effective drugs and the cornerstone of asthma management. With approximately 4% of adults and children in the United Kingdom receiving an ICS (1–3), they are one of the most commonly prescribed treatments, and their increased use almost certainly contributed to the recent reduction in asthma deaths (4). Inhaled corticosteroids reduce the need for courses of oral prednisolone and adverse effects from oral corticosteroids, but they can have both local and systemic adverse effects. Local adverse effects in the upper respiratory tract include oral candidiasis and dysphonia, which can be a nuisance but are not serious and are not discussed further.

This article is concerned with the systemic adverse effects that occur after absorption of ICSs into the systemic circulation. We discuss the evidence for systemic absorption from ICSs, for biological effects following absorption, and for systemic adverse effects in clinical practice. The latter section focuses on the effects of ICSs on the adrenal gland and on bone, and it reviews the potential public health implications of the latter. This article also considers the different patterns of absorption associated with different ICSs and their potential relevance to the development of adverse effects.

	EVIDENCE FOR SYSTEMIC ABSORPTION OF ICS

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Inhaled corticosteroids may be absorbed from the gastrointestinal tract or from the lung. A proportion of any ICS is swallowed, although the amount is variable and dependent on the inhaler device used to administer the drug and, with some inhalers, on inhaler technique (5). Most of the drug that is swallowed will undergo first-pass metabolism and does not, therefore, enter the systemic circulation. The ICSs in current use have a high first-pass metabolism (5, 6), exceeding 99% in the case of fluticasone propionate. This compares with only 20% for prednisolone where systemic absorption is required.

All the currently available ICSs are absorbed into the systemic circulation from the lung. The extent of absorption is determined by many factors including inhaler device, particle size, and deposition site, as well as pharmacokinetic and physicochemical properties of the drug. The rapidity of absorption varies considerably and is relatively slow with fluticasone compared with budesonide, as shown in Figures 1 and 2 (7, 8). The reasons for these differences probably relate to differences in lipophilicity, because fluticasone is considerably more lipophilic than budesonide (6). The rate of dissolution of different ICSs in human bronchial fluid is directly related to their lipophilicity, being only 6 minutes for budesonide compared with over 5 hours for beclomethasone and over 8 hours for fluticasone (6). It seems likely, therefore, that the more lipophilic the drug, the more slowly it is released into and from the lung lipid layer and the longer the latency between inhalation and its appearance in plasma. Most of the absorption of both budesonide and fluticasone appears to be from the respiratory tract, as judged from the rapid absorption of budesonide and the evidence for systemic absorption of fluticasone despite its very high first-pass metabolism.

View larger version (18K): [in this window] [in a new window]   Figure 1. Plasma drug concentrations in healthy subjects and patients with asthma following inhalation of fluticasone 1,000 µg or budesonide 1,200 µg by dry powder inhaler. Reprinted by permission from Ref. 7.

View larger version (22K): [in this window] [in a new window]   Figure 2. Change in plasma fluticasone concentrations in healthy sub-jects and patients with asthma after inhalation of fluticasone 1,000 µg/day for 7 days by metered-dose inhaler. Reprinted by permission from Ref. 8.

	EVIDENCE FOR SYSTEMIC BIOLOGICAL EFFECTS

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Having established that ICSs are absorbed systemically, the question that follows is whether systemic absorption is sufficient to cause biological and clinical adverse effects. Numerous studies have shown a progressive reduction in adrenal function with increasing doses of an ICS, over short periods and under carefully controlled conditions (9–11). In one study, 5 days of treatment with high doses of fluticasone and budesonide caused almost complete ablation of the 24-hour plasma cortisol profile (10), and even single doses have caused considerable suppression of the hypothalamic-pituitary-adrenal axis (11). However, many of these studies have been in healthy subjects or in patients with mild asthma who, for fluticasone at least, absorb more drug than do patients with more severe asthma. Nevertheless, these studies show that ICSs, in doses that are often given to patients, can have marked biological effects in the short term.

	EVIDENCE FOR ADVERSE SYSTEMIC EFFECTS IN CLINICAL PRACTICE

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It is important to determine whether ICSs are associated with systemic adverse effects in clinical practice and, if so, the magnitude of the effects. The evidence to support systemic effects comes from a variety of sources summarized in Table 1 (12–23). Several randomized prospective studies have shown systemic effects with ICSs when compared with placebo, including a roughly twofold increase in the number of patients who report easy bruising (12, 15) and reductions in growth velocity (13, 14) and bone mineral density (BMD) (12), as discussed below.

Controlled dose response studies have shown the potential for adrenal suppression with ICS (10, 11). The evidence for clinically important adrenal suppression, however, has come from studies linking adrenal crisis, a rare condition, with use of high doses of an ICS and demonstrating recovery when the dose of the ICS was reduced or stopped (23). The evidence for adrenal suppression and effects on BMD and fractures are discussed in more detail below.

Adrenal Suppression with ICSs
Adrenal suppression has been demonstrated frequently in people taking an ICS under controlled conditions, as discussed above. There have also been a number of case reports of adrenal crisis associated with ICSs use during recent years. In 2002, Todd and colleagues presented a series of 33 cases of adrenal crisis related to use of an ICS (23). Most (28) were in children, 23 of whom presented with acute hypoglycemia, 9 with coma, and 1 died. Thirty of the 33 patients had been taking fluticasone, usually for 1 or 2 years. Most patients were taking doses within those recommended by UK guidelines at the time (24), although the guidelines have now been amended (25). Subsequent reports from the United Kingdom (26) and Australia (27) implicate inhaled corticosteroids in a further 17 cases of adrenal crisis, 14 with fluticasone, and including a further death. These data show the potential of ICSs to cause important systemic effects over a relatively short period.

Effects of ICS on Bone
Placebo-controlled prospective studies to determine fracture risk in patients taking an ICS are unrealistic, for the reasons outlined above. Bone mineral density and markers of bone metabolism such as osteocalcin have therefore been used as proxy measures of the risk of osteoporotic fracture in cross-sectional and prospective studies. The markers of bone metabolism have poor repeatability and appear to be less sensitive in detecting change than BMD measurements, and they are not considered further. A reduction in BMD of one standard deviation is associated with a doubling of the risk of fracture in involutional osteoporosis (28), and the risk may be greater in steroid-induced osteoporosis (29). Fracture risk has also been assessed from large databases that have recorded ICS use and fractures.

Change in BMD with ICSs.
Many of the early studies looking at change in BMD were considerably underpowered. Prospective studies need to allow for the inherent variability in BMD measurements and other factors that can affect BMD. In one study, which involved independent densitometer calibration checks, the within-subject standard deviation of four repeat measurements of BMD over 2 years was 3.4% (16). A Cochrane review of the effects of ICS on bone concluded that there was no evidence of an effect on BMD (30), but it included only three studies (15, 16, 31) and excluded the positive studies with triamcinolone (12, 17). Our interpretation of the literature differs and is based on the larger, well designed studies, four of which have shown an effect of ICSs on BMD (12, 16, 17, 19).

Two of these large prospective studies allowed patients to take whatever dose of ICSs was necessary to control their asthma (16, 17). Change in BMD was determined over the subsequent 2 or 3 years, respectively, and was related to the dose of ICSs taken. In the study by Israel and coworkers (17), 109 premenopausal women already taking an ICS took triamcinolone for 3 years, whereas in the study by Tattersfield and associates (16), 161 patients who were previously steroid-naive took inhaled budesonide or beclomethasone dipropionate for 2 years. Both studies showed a relationship between the dose of ICSs taken during the study and the reduction in BMD at 1 site, after allowing for other factors that affect BMD.

A study by the National Heart and Lung Institute compared triamcinolone 600 µg twice daily with placebo in patients with mild chronic obstructive pulmonary disease (COPD), and 412 subjects underwent BMD measurements (12). Subjects randomized to triamcinolone showed a greater reduction in BMD over 3 years than did those allocated to placebo. No such difference was seen in the EUROSCOP study of budesonide in patients with COPD (15), which may be because of differences between budesonide and triamcinolone, because of the doses given, or because the number of patients studied was smaller (194 subjects).

In a large cross-sectional study of 196 well characterized patients, aged 20 to 40 years, we found a relationship between BMD measurements and total lifetime cumulative dose of ICSs, after allowing for potential confounding factors (19). We studied young patients because BMD is stable at this age and not subject to confounding by menopausal status, and patients were included only if they had had minimal or no use of corticosteroids by other routes in the past. The size of the effect of ICSs on BMD was small over 1 year but increased with cumulative dosing. The regression equation suggests that a patient taking 1,000 µg/day ICSs for 14 years (or 2,000 µg for 7 years) could expect a reduction in BMD of one standard deviation over that time, as a result of the ICS. This figure is similar to calculations based on the findings in the two prospective cohort studies of patients with asthma, detailed previously (16, 17). It was not possible to look at individual ICSs in this study, but 80% were taking beclomethasone at the time of recruitment. A recent cross-sectional study in postmenopausal women did not show any effect of ICSs on BMD (32). The number of patients taking an ICS (106) was smaller than in our study (19), and it is probably too small considering the large and variable effects of menopause on BMD.

Few studies have had sufficient power to compare different ICSs. In a 6-month crossover study, 306 patients changed their inhaled corticosteroid to beclometasone or fluticasone at half the dose. There was an increase in BMD at the spine and femur with fluticasone and a reduction at the femur with beclomethasone, the difference being statistically significant (33).

Risk of fracture with ICSs.
We have looked at the risk of fracture associated with use of ICSs in a case–control analysis of 16,341 cases of hip fracture and 29,889 control subjects from the United Kingdom General Practice Research Database (21). Using conditional logistic regression and allowing for potential confounders such as comorbid illness, we found that the risk of hip fracture was associated with use of ICSs, with an odds ratio of 1.19 after adjusting for oral steroid use. There was a dose–response relation between ICS use and risk of hip fracture, the odds ratio rising to 1.87 in patients taking more than 1,600 µg ICSs daily. The study did not have sufficient power to look at different inhaled corticosteroids but the majority (84%) of prescriptions were for beclometasone. The findings in a cohort analysis of hip fracture in the General Practice Research Database were broadly similar (34). A recent Canadian case–control study found a dose–response relation between inhaled corticosteroid use and fracture, although the increased risk appeared to be mainly explained by concurrent exposure to oral corticosteroids and inhaled bronchodilators (35). Finally, in a nested case–control study within a cohort of patients with COPD, Lee and colleagues found an increase in fracture risk amongst patients currently using an ICS at a dose of 700 µg a day or more (36).

These studies have looked at fractures in elderly patients whose prior exposure to ICSs may be fairly limited. Future cohorts may have taken an ICS for a much longer period, particularly patients with asthma, and the size of the effect may increase as a consequence.

Public health implications.
ICSs are used very widely now and are often started in childhood. The likelihood for many patients is that they will be continued for many decades, if not throughout life. Estimates suggest that over half a million people in the United Kingdom were taking more than 800 µg/day of an ICS in 1995/1996 (1). Osteoporosis is common in older people and causes enormous morbidity and mortality, with an estimated 51,863 hip fractures in the United Kingdom each year (37) and over a quarter of a million in the United States (38). There are also major financial consequences, the cost of osteoporosis being estimated at £940 million per year in the United Kingdom (37). Thus, even a small increase in the risk of hip fracture has considerable public health consequences.

Is there a threshold effect?
Whether there is a threshold dose at which adverse effects with ICSs appear is uncertain. Studies looking at the effects of high doses are more likely to be statistically significant, but this could be due to greater statistical power. As far as can be determined our data on fractures (21) and BMD (19) would fit best with a linear dose–response relation. The effect on bone is likely to be determined by cumulative lifetime dose of ICSs for which current dose is seen as a proxy measure.

Effect in different groups.
The pharmacologic effects of corticosteroids (e.g., reduction in bone density) are likely to occur at any age. Several of the adverse effects occur more frequently in the elderly (e.g., fracture, cataract, and glaucoma) and the effect of ICSs is consequently more apparent in this age group. Genetic polymorphisms relating to the glucocorticoid receptor and/or end organ response (e.g., bone) are likely to help determine the risk of adverse effects but there are no data on this, or on differences between patient groups, as yet.

	CAN SYSTEMIC ABSORPTION BE REDUCED?

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Assuming that all the beneficial effects of ICSs relate to their local effects in the lung, an ideal ICS would be one that was deposited at the required site of action and metabolized there, or as soon as it entered the systemic circulation, so that it had no systemic activity. This may become possible but is not an option at present. Another approach, however, is to identify the factors that determine lung absorption to see whether they can be used to maximize the benefit/risk balance for current ICS use.

The reduced absorption of inhaled fluticasone by subjects with asthma compared with healthy subjects would be expected to cause reduced systemic adverse effects in patients with asthma who had severe rather than mild airflow obstruction. In keeping with this, Weiner and colleagues (39) showed a close inverse relation between FEV₁ and serum cortisol levels in patients with asthma following a single dose of inhaled fluticasone. Harrison and associates (40) also showed that inhaled fluticasone 1,500 µg/day for 1 week caused a greater reduction in 24-hour urinary cortisol metabolites in healthy subjects than in patients with asthma (mean FEV₁ 60% predicted), as shown in Figure 3. This was not the case with budesonide in this study, however, since the effect of 1,600 µg/day budesonide for 1 week was similar in healthy subjects and in subjects with asthma (40). These data suggest that there are important differences in the pattern of absorption between different ICSs and that the adverse effects of some ICSs will be greater in subjects with well preserved lung function.

View larger version (16K): [in this window] [in a new window]   Figure 3. Total cortisol metabolite (TCM) levels in subjects with asthma and in healthy subjects after inhalation of fluticasone propionate (FP) 1,500 µg, budesonide 1,600 µg, or placebo (healthy subjects only) for 7 days. Reprinted from Ref. 40. The difference between subjects with asthma and control subjects was significant for fluticasone (p = 0.02) but not for budesonide (p = 0.5).

	CONCLUSIONS

TOP ABSTRACT EVIDENCE FOR SYSTEMIC ABSORPTION... EVIDENCE FOR SYSTEMIC BIOLOGICAL... EVIDENCE FOR ADVERSE SYSTEMIC... CAN SYSTEMIC ABSORPTION BE... CONCLUSIONS REFERENCES

 
It is clear from pharmacokinetic studies that ICSs are absorbed into the systemic circulation, and it is also clear that they can have clinical adverse effects when given in high doses. The need now is to quantify more precisely the extent to which they have adverse effects on clinically important endpoints such as osteoporosis, adrenal function, cataract, and glaucoma. Understanding and quantifying the dose-related adverse effects of ICSs is important to minimize these effects. Exploring the reasons for the differences between different ICSs should aid in the design of better treatment strategies and improve prescribing for different patient populations.

Adverse effects from ICSs have to be placed in context with their beneficial effects and the fact that, when used judiciously, the drugs prevent the need for courses of prednisolone. The clinical message must be that the dose and perhaps the particular ICS should be tailored to the patient's needs. For some ICSs, the dose may need to be reduced as lung function improves. High doses should be given only to patients who require high doses, and such patients need to be aware that they should not stop treatment suddenly, that they may need to cover intercurrent illnesses and infections with oral prednisolone, and they may need advice or treatment to help prevent osteoporosis.

	ACKNOWLEDGMENTS

 
A.E.T. received consultancy fees from Schering-Plough in 2002 for £1,396 and received lecture fees in 2002 from Schering-Plough for $2,500 and £750 and from AstraZeneca for £500; T.W.H. has been supported by AstraZeneca to attend a respiratory conference and received speaker fees and advisory board fees from AstraZeneca and GlaxoSmithKline; R.B.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form February 18, 2004; accepted in final form April 6, 2004)

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