Adrenal suppression with high doses of inhaled fluticasone propionate and triamcinolone acetonide in healthy volunteers Evaluation of the buccal component of systemic absorption with inhaled fluticasone propionate A randomized, double-blind study comparing the effects of beclomethasone and fluticasone on bone density over two years. Fluticasone propionate powder and lack of clinically significant effects on hypothalamic-pituitary-adrenal axis and bone mineral density over 2 years in adults with mild asthma. Bone mineral density in asthmatic women on high-dose inhaled beclomethasone dipropionate. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Adrenocortical activity with repeated administration of one-daily inhaled fluticasone propionate and budesonide in asthmatic adults The effects of inhaled glucocorticoids on bone mass and biochemical markers of bone homeostasis: a 1-year study of beclomethasone versus budesonide. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Effects of short-term inhaled budesonide and beclomethasone dipropionate on serum osteocalcin in premenopausal women. 24 hour and fractionated profiles of adrenocortical activity in asthmatic patients receiving inhaled and intranasal corticosteroids Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years One year prospective open study of the effect of high dose inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density Dose-response comparison of systemic bioactivity with inhaled budesonide and triamcinolone acetonide in asthmatic adults. Hydrofluoroalkane-134a beclomethasone dipropionate, 400 microg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 microg, for the treatment of moderate asthma. Dose-response effect for adrenal suppression with repeated twice daily inhaled fluticasone propionate and triamcinolone acetonide in adult asthmatics. Systemic bioactivity profiles of oral prednisolone and nebulized budesonide in adult asthmatics. Differential effects of inhaled budesonide and oral prednisolone on serum osteocalcin. Effects of dose and dosing schedule of inhaled budesonide on bone turnover. An inhaled corticosteroid, budesonide, reduces baseline but not allergen-induced increases in bone marrow inflammatory cell progenitors in asthmatic subjects. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. Nocturnal cortisol secretion in healthy adults before and after inhalation of budesonide. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial
Abstract Study objective : This study was conducted to compare the adrenal suppression of inhaled fluticasone propionate and triamcinolone acetonide in healthy volunteers , both given via their respective pressurised metered dose inhaler ( pMDI ) devices at high doses within the manufacturers recommended dose range . Design : We used a single ( investigator ) blind , r and omised , crossover design comparing a total daily dose of 1.625 mg fluticasone propionate delivered via a pMDI , 1.60 mg daily of triamcinolone acetonide delivered via a pMDI with integrated spacer , or placebo pMDI ; each drug was given in two divided doses at 0800 hours and 2200 hours over a 24-h period . Each drug treatment was separated by a 1-week washout . Patients : Twelve normal subjects mean age 27.5 years were studied . Measurements : Blood sample s were taken for 0800 hours plasma cortisol , i.e. 10 h following the second dose . Ten hour urine collection s ( 2200 hours until 0800 hours ) were taken for urinary cortisol and creatinine excretion . Results : For the 0800 hours plasma cortisol ( geometric mean , nmol · l−1 ) compared with placebo ( 353 ) fluticasone propionate ( 138 ) produced significant ( P<0.05 ) suppression ( 2.57-fold difference ) , whereas triamcinolone acetonide ( 263 ) did not ( 1.34-fold difference ) . Fluticasone propionate produced a 1.91-fold greater adrenal suppression than triamcinolone acetonide ( 95 % CI 1.10 to 3.33 ) . Individual subjects with abnormally low 0800 hours cortisol values < 150 nmol · l−1 ( < 5.4 μg/dl ) were n=4 for fluticasone propionate and n=0 for triamcinolone acetonide . Overnight urinary cortisol/creatinine ratio ( geometric mean , nmol/mmol ) did not show any difference between fluticasone propionate ( 1.48 ) and triamcinolone acetonide ( 1.60 ) , with both producing significant suppression versus placebo ( 4.01 ) : triamcinolone acetonide 2.50-fold difference ( 95 % CI 1.45–4.24 ) ; fluticasone propionate 2.71-fold difference ( 95 % CI 1.57–4.69 ) . Conclusion : Fluticasone propionate 1.625 mg/day ( pMDI ) produced an approximately two-fold greater adrenal suppression of 0800 hours plasma cortisol than triamcinolone acetonide 1.60 mg per day ( Oral Inhaler ) when given twice daily , and one third of subjects with fluticasone had abnormally low 0800 hours cortisol values < 150 nmol · l−1 ( < 5.4 μg · dl−1 ) . There were no differences between the drugs for urinary cortisol excretion . Further dose-ranging studies are required at steady-state in asthmatic subjects in order to see whether differences occur at lower doses on the steep part of the dose – response curve for both plasma and urinary cortisol suppression BACKGROUND Inhaled corticosteroids have dose related systemic effects determined by oral ( swallowed or oropharyngeal absorption ) and lung bioavailability . A study was undertaken to evaluate the significance of oropharyngeal absorption for fluticasone propionate . METHODS Sixteen healthy volunteers of mean age 29.3 years were studied using an open r and omised , placebo controlled , four way crossover design . Treatments were : ( a ) fluticasone metered dose inhaler ( pMDI ) 250 μg , 8 puffs ; ( b ) fluticasone pMDI 250 μg , 8 puffs + mouth rinsing/gargling ( water ) ; ( c ) fluticasone pMDI 250 μg , 8 puffs + mouth rinsing/gargling ( charcoal ) ; and ( d ) placebo pMDI , 8 puffs + mouth rinsing/gargling ( water ) . Overnight ( ONUC ) and early morning ( EMUC ) urinary cortisol/creatinine ratios and 8 am serum cortisol ( SC ) levels were measured . RESULTS Significant ( p<0.05 ) suppression of ONUC , EMUC , and SC occurred with each active treatment compared with placebo . The mean values ( 95 % CI for difference from placebo ) were : ( a ) ONUC ( nmol/mmol ) : fluticasone ( 2.8 , 95 % CI 3.6 to 7.9 ) , fluticasone + water ( 3.1 , 95 % CI 3.3 to 7.7 ) , fluticasone + charcoal ( 2.3 , 95 % CI 4.1 to 8.5 ) ; placebo ( 8.6 ) ; ( b ) EMUC ( nmol/mmol ) : fluticasone ( 5.6 , 95 % CI 8.4 to 24.5 ) , fluticasone + water ( 7.6 , 95 % CI 6.6 to 22.4 ) ; fluticasone + charcoal ( 5.6 , 95 % CI 8.7 to 24.5 ) ; placebo ( 22.1 ) . There were no significant differences between active treatments . The numbers of subjects with an overnight urinary cortisol of < 20 nmol/10 hours were 0 ( placebo ) , 11 ( fluticasone ) , 12 ( fluticasone + water ) , and 13 ( fluticasone + charcoal ) . CONCLUSIONS Oropharyngeal absorption of fluticasone does not significantly contribute to its overall systemic bioactivity as assessed by sensitive measures of adrenal suppression . In view of almost complete hepatic first pass inactivation with fluticasone , there is no rationale to employ mouth rinsing to reduce its systemic effects although it may be of value for reducing oral c and idiasis Cross-sectional studies have suggested that asthmatic patients receiving high dose inhaled corticosteroids and intermittent courses of oral corticosteroids  have reduced bone mass . This prospect i ve 2-yr study was undertaken to evaluate changes in bone density of patients receiving high doses of inhaled corticosteroids . Patients ( n = 33 ) ( males aged 18 - 50 yrs , females aged 18 - 40 yrs ) on inhaled corticosteroids 1,000 - 2,000 microg x day(-1 ) , were r and omized in a double-blind fashion to either fluticasone propionate ( FP ) 1,000 microg x day(-1 ) or beclomethasone dipropionate ( BDP ) 2,000 microg x day(-1 ) . In parallel , three open control groups of the same age range were studied : asthmatics ( n = 8) receiving low dose inhaled corticosteroids ( < or = 400 microg x day(-1 ) ) ( group A ) ; chronic , severe asthmatics ( n = 8) receiving oral corticosteroids ( > or = 10 mg x day(-1 ) ( group B ) ; and healthy untreated volunteers ( n = 7 ) ( group C ) . Bone densitometry scans ( quantitative computed tomography ( QCT ) of spine ; dual X-ray absorptiometry of spine , femoral neck , and single photon absorptiometry of forearm ) were performed at baseline and after 6 , 12 and 24 months of treatment . Biochemical bone marker measurements ( serum osteocalcin , bone alkaline phosphatase , pro-collagen type 1 carboxy terminal propeptide , deoxypyridinoline and C-telopeptide of type 1 collagen ) were collected every 3 months . Fifteen FP ( mean age 36 yrs , six male ) and 9 BDP patients ( mean age 33 yrs , five male ) ; completed the study . At 0 months , mean bone mineral density ( BMD ) was lower in patients receiving inhaled corticosteroids ( both low dose and high dose ) than in normal volunteers . In the FP-treated group , mean vertebral trabecular BMD quantitative computed tomography remained stable with no evidence of decline , whereas there was some decline in the BDP-treated group . The treatment difference between FP  and BDP was statistically significant in favour of FP for quantitative computed tomography measurements after 12 months ( p = 0.006 ) and 24 months ( p = 0.004 ) . This study suggests that over 24 months , changes in bone density are minimal in patients on high-dose inhaled corticosteroids BACKGROUND Although inhaled corticosteroids are widely used for the treatment of inflammation in asthma , prospect i ve , long-term , placebo-controlled trials characterizing their systemic safety with chronic use are lacking . OBJECTIVE This study was design ed to prospect ively evaluate the long-term safety of inhaled fluticasone propionate therapy . METHODS Fluticasone propionate powder , 500 microgram , or placebo was administered twice daily by means of the Diskhaler for 104 weeks to 64 adults with mild persistent asthma in a r and omized , double-blind , parallel-group study . Primary safety variables were measured at baseline and every 6 months thereafter . Although evaluation of efficacy was not an objective of this study , pulmonary function testing was performed at monthly intervals . RESULTS Two years of treatment with fluticasone propionate had no significant effects on the skeletal system . No clinical ly significant changes were observed in ophthalmic parameters ( glaucoma and posterior subcapsular cataracts ) . Mean change from baseline in lumbar spine ( L1 to L4 ) bone density at week 104 was not significantly different between fluticasone propionate ( -0.006 + /- 0.008 g/cm2 ) and placebo ( -0.007 + /- 0.010 g/cm2 ) . Markers of bone formation ( serum osteocalcin ) and resorption ( urinary N-telopeptide ) did not differ significantly between treatment groups . The effects of fluticasone propionate treatment on the hypothalamic-pituitary-adrenal axis were minimal , with no alterations in morning plasma cortisol concentrations and minor but statistically significant decreases in poststimulation mean peak plasma cortisol concentrations ( P = .021 ) and 8-hour plasma cortisol area under the curve values ( P = .020 ) at week 104 . Drug-related adverse events were primarily topical effects of inhaled corticosteroids . Pulmonary function improved significantly during 2 years of fluticasone propionate treatment . CONCLUSION Fluticasone propionate powder , 500 microgram twice daily for up to 2 years , was efficacious and well tolerated , with no clinical ly relevant effects on the hypothalamic-pituitary-adrenal axis , bone density , or ophthalmic parameters in adults with mild asthma Inhaled corticosteroids are the cornerstone of the modern therapy for asthma . In recent years , inhaled corticosteroids have been used in higher doses than previously . This has caused concern about possible osteoporotic side-effects . We studied bone mineral densities ( BMDs ) in 19 non-smoking women ( mean age 53 years , range 40 - 63 ) with newly diagnosed bronchial asthma and 19 voluntary healthy non-smoking women ( mean age 53 years , range 43 - 67 ) . In both groups , 13 subjects were postmenopausal . Patients started beclomethasone dipropionate from the spacer 500 micrograms twice daily as the sole corticosteroid therapy . BMDs were measured with dual-energy x-ray absorptiometry ( DEXA ) at the lumbar spine ( L2 - 4 ) and at the left proximal femur ( the neck , Ward 's triangle and the trochanteric region ) . The measurements were made at baseline and 6 and 12 months thereafter . No significant changes were observed in the measured BMDs in either study group . The results show that inhaled beclomethasone dipropionate therapy 1000 micrograms/day for one year does not affect BMD . Further studies are needed to assess the effects of inhaled corticosteroid on BMD during a longer treatment period In a controlled prospect i ve study we have measured growth and pulmonary function in children with asthma during long-term treatment with inhaled budesonide  and compared these findings with those obtained from children not treated with corticosteroids . Two hundred and sixteen children were followed at 6 monthly intervals for 1 - 2 years without inhaled budesonide and then for 3 - 6 years on inhaled budesonide .  Sixty-two children treated with theophylline , beta 2-agonists and sodium-cromoglycate but not with inhaled steroids were also followed for 3 - 7 years ( controls ) . During the period of budesonide therapy the mean daily dose decreased from 710 to 430 micrograms ( P < 0.01 ) and no signs of tachyphylaxis to the treatment were seen . Budesonide treatment was associated with a significant reduction in the number of annual hospital admissions due to acute severe asthma ( from 0.03 to 0.004 per child , P < 0.001 ) . In patients not treated with budesonide an annual decrease in % predicted FEV1 of 1 - 3 % was seen . In contrast FEV1 improved significantly with time during budesonide treatment , both compared with the run-in period and with the control group ( P < 0.01 ) . Furthermore , there was a significant ( P = 0.01 ) relationship between the duration of asthma at the start of budesonide and the annual increase in FEV1 during budesonide therapy . After 3 years of treatment with budesonide , children who started this therapy later than 5 years after the onset of asthma had significantly lower FEV1 ( 96 % ) than the children who received budesonide within the first 2 years after the onset of asthma ( 101 % ) ( P < 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Abstract Objective : The aim of this study was to evaluate the steady-state effects of once-daily inhaled fluticasone propionate ( FP ) and budesonide ( BUD ) on adrenocortical activity in asthmatic patients . Methods : Ten asthmatic patients with a mean age of 31.2 years , a mean forced expiratory volume in 1 s ( FEV1 ) of 91 % predicted and a forced mid-expiratory flow ( FEF25–75 ) of 62.3 % predicted were studied in a single-blind r and omised crossover design comparing placebo ( PL ) , FP ( 375 μg per day and 750 μg per day ) and BUD ( 400 μg per day and 800 μg per day ) all given once daily for 4 days at each dose via a pressurised metered dose inhaler ( pMDI ) at 0800 hours . After 4 days of treatment , plasma cortisol was measured at 0800 hours ( 24 h after the last dose ) and a 10-h overnight urine collection was taken , 14 h after the last dose ( 2200–0800 hours ) for analysis of cortisol and creatinine excretion . Results : Plasma cortisol levels ( nmol · l−1 , as geometric mean ) at 0800 hours demonstrated a significant difference between the highest doses of FP and BUD ( 424.1 vs 510.3 nmol · l−1 , respectively ) but not between the low doses ( 506.8 vs 514.9 nmol · l−1 ; PL 532.2 nmol · l−1 ) . For the highest dose FP ( 750 μg ) this equated to 20 % suppression of 0800 hours plasma cortisol . Likewise , for overnight urinary cortisol output ( nmol · 10 h−1 , as geometric mean ) , there was a significant difference at the high doses of FP and BUD ( 25.5 vs 38.2 nmol · 10 h−1 ) , but not at the low doses 31.3 vs 34.8 nmol · 10 h−1 ; PL 32.0 nmol · 10 h−1 . For the overnight urinary cortisol/creatinine ratio ( nmol · mmol−1 , as geometric mean ) there was a similar trend ; 4.5 vs 6.1 nmol · mmol−1 for high dose and 5.6 vs 6.3 nmol · mmol−1 for low dose ; PL 5.9 nmol · mmol−1 . Conclusion : Repeated doses of FP 750 μg once daily caused greater adrenal suppression than BUD 800 μg once daily , when comparing effects on plasma cortisol levels at 0800 hours , 24 h after the last dose , as well as effects on overnight urinary cortisol output . Neither FP 375 μg once daily nor BUD 400 μg once daily produced detectable adrenal suppression Bone mass and biochemical bone markers were prospect ively studied in 33 patients with chronic obstructive pulmonary disease treated for 1 year with inhaled beclomethasone 200 micrograms/q.i.d . ( group A , 8 men and 4 women ) , inhaled budesonide 200 micrograms/q.i.d . ( group B , 6 men and 5 women ) ,  or not requiring steroids  ( group C , 6 men and 4 women ) . Both inhaled corticosteroids decreased serum concentrations of the osteoblastic markers , osteocalcin and carboxy-terminal propeptide of type I collagen ( PICP ) . The osteoclastic marker cross-linked carboxy-terminal telopeptide of type I collagen ( ICTP ) increased significantly more in patients on beclomethasone than in those on budesonide . The decrease in bone mineral density was more pronounced in patients treated with beclomethasone ( 1.1 % in the spine 1.7 % in the hip P < 0.05 ) compared to those treated with budesonide ( 0.6 % in both spine and hip ) or in the control group . Inhaled corticosteroids affect biochemical bone markers and bone mineral density , but there is a different effect for the two corticosteroids evaluated in the present study BACKGROUND : In a previous single dosing comparison between fluticasone propionate and budesonide differences in cortisol levels measured at 08.00 hours were observed at doses in excess of 1000 micrograms . The aim of this study was to compare the adrenal suppression caused by chronic twice daily dosing with inhaled fluticasone propionate ( FP ) and budesonide ( B ) given on a microgram equivalent basis by metered dose inhaler to asthmatic patients . METHODS : Twelve stable asthmatic patients of mean age 29.7 years with forced expiratory volume in one second ( FEV1 ) 89.0 % predicted and mid forced expiratory flow ( FEF25 - 75 ) 58.9 % predicted , on 400 micrograms/day or less of inhaled corticosteroid , were studied in a double blind , placebo controlled , crossover design comparing inhaled budesonide and fluticasone propionate in doses of 250 micrograms , 500 micrograms , and 1000 micrograms twice daily . Each dose was given at 08.00 hours and 22.00 hours for four days by metered dose inhaler with mouth rinsing . Measurements were made of overnight urinary cortisol excretion and plasma cortisol levels at 08.00 hours , 10 hours after the eighth dose . RESULTS : The plasma cortisol levels ( nmol/ l ) at 08.00 hours showed that fluticasone propionate produced lower cortisol levels than budesonide at all three dose levels : F500 333.8 , B500 415.2 ( 95 % CI 28.9 to 134.0 ) ; F1000 308.3 , B1000 380.3 ( 95 % CI 10.5 to 133.5 ) ; F2000 207.3 , B2000 318.5 ( 95 % CI 5.8 to 216.7 ) ; placebo 399.9 . Fluticasone produced greater effects than budesonide on the overnight urinary cortisol/creatinine ratio ( nmol/mmol ) at all three dose levels : F500 3.12 , B500 5.55 ( 95 % CI 0.16 to 3.79 ) ; F1000 2.54 , B1000 6.12 ( 95 % CI 1.25 to 5.91 ) ; F2000 2.07 , B2000 6.09 ( 95 % CI 0.88 to 7.18 ) ; placebo 5.23 . CONCLUSIONS : With repeated dosing across a dose range of 250 - 1000 micrograms twice daily , fluticasone propionate produced significantly greater adrenal suppression than budesonide for both plasma and urinary cortisol . It was therefore possible to demonstrate differences between fluticasone and budesonide at lower doses with chronic dosing from those previously found with single dosing when given on a microgram equivalent basis in asthmatic patients . Factors contributing to the systemic adverse activity profile of fluticasone comprise enhanced receptor potency , prolonged receptor residency time , greater tissue retention , and a longer elimination half life Serum osteocalcin , a marker of bone osteoblast function , has been shown to be sensitive to even low doses of oral glucocorticoids . The effect of 1 wk of inhaled glucocorticoid therapy with budesonide ( 200 micrograms/puff ) , beclomethasone dipropionate ( 250 micrograms/puff ) , and placebo at two puffs b.i.d . and four puffs b.i.d . on 0900 serum osteocalcin were compared in a double-blind r and omized fashion . A two-way repeated- measures analysis of variance showed no main effect of drug or dosage but a significant drug-dose interaction ( p = 0.023 ) . Post hoc investigation of this interaction demonstrated that the serum osteocalcin level while taking four puffs b.i.d . ( 2,000 micrograms ) of beclomethasone dipropionate was significantly lower than that of placebo or budesonide at four puffs b.i.d . ( 1,600 micrograms ) . These results suggest that at lower doses no acute measurable effect of inhaled glucocorticoids on serum osteocalcin can be appreciated but that at higher doses inhaled beclomethasone dipropionate has a depressant effect on bone osteoblast function BACKGROUND As both rhinitis and asthma are allergic conditions , they frequently occur together . The objective of this study was to assess the diurnal adrenocortical activity in asthmatics receiving inhaled ( inh ) and intranasal ( n ) formulations of two different  corticosteroids , fluticasone propionate ( FP ) and triamcinolone acetonide ( TAA ) , both given at clinical ly recommended doses . METHODS Twelve stable moderately severe asthmatic subjects of mean age 23.9 years and mean forced expiratory volume in one second ( FEV1 ) 84 % predicted were recruited into a r and omised placebo ( PL ) controlled two-way crossover study comparing nPL + inhPL , nPL + inhFP ( 880 μg bid ) , and nFP ( 200 μg once daily ) + inhFP ( 880 μg bid ) with nPL + inhPL , nPL + inhTAA ( 800 μg bid ) and nTAA ( 220 μg once daily ) + inhTAA ( 800 μg bid ) , each given for five days with a 10 day washout period . Twenty four hour integrated and fractionated ( overnight , 08.00 hours , daytime ) serum cortisol levels and urinary cortisol/creatinine excretion were measured . RESULTS For 24 hour and fractionated serum cortisol levels and corrected urinary cortisol/creatinine excretion there were significant ( p<0.05 ) differences between all active treatments and placebo . For 24 hour integrated serum cortisol levels the ratio between inhaled TAA and FP was 2.3 fold ( 95 % CI 1.2 to 4.3 ) , and for 24 hour urinary cortisol/creatinine excretion the ratio was two-fold ( 95 % CI 1.2 to 3.4 ) . For 24 hour urinary cortisol excretion , with all active treatments , individual abnormal low values of < 40 nmol ( < 14.4 μg ) occurred in 17/24 with FP compared with 4/24 with TAA ( p<0.0005 ) . The 24 hour serum cortisol profile was flattened by FP but not with TAA . The addition of nasal corticosteroid did not produce further significant suppression of mean cortisol values , although with intranasal FP there were three more abnormal values for 24 hour urinary cortisol excretion than with inhaled FP alone . CONCLUSIONS Both inhaled FP and TAA caused significant suppression of adrenocortical activity which was twice as great with FP , the latter being associated with significantly more individual abnormal values and loss of the normal diurnal circadian rhythm . Fractionated serum cortisol levels and urinary cortisol/creatinine excretion were as sensitive as the respective integrated 24 hour measurements . Although the addition of intranasal formulations did not produce further significant suppression of mean values , there were more individual abnormal cortisol values associated with the addition of intranasal FP BACKGROUND The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease ( COPD ) remains controversial because of a lack of placebo-controlled studies . We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD . METHODS We used a r and omised , double-blind , placebo-controlled design . We enrolled from 13 European countries , New Zeal and , and South Africa , 281 outpatient current or ex-smokers , aged between 50 and 75 years . They had a forced expiratory volume in 1 s ( FEV1 ) of between 35 % and 90 % of predicted normal values , a ratio of FEV1 to forced vital capacity of 70 % or less and bronchodilator reversibility of less than 15 % , as well as a history of chronic bronchitis . Patients were r and omly assigned fluticasone propionate 500 microg ( n=142 ) or placebo ( n=139 ) twice daily via a metered-dose inhaler for 6 months . The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment , the number and severity of exacerbations , clinic lung function , diary card symptoms and peak expiratory flow and 6 min walking distance . FINDINGS 51 ( 37 % ) patients in the placebo group compared with 45 ( 32 % ) in the fluticasone propionate group had had at least one exacerbation by the end of treatment ( p=0.449 ) . Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group ( 86 % vs 60 % , p<0.001 ) . Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group ( p<0.001 , p=0.048 , respectively ) , as did clinic FEV1 ( p<0.001 ) , forced vital capacity ( p<0.001 ) , and mid-expiratory flow ( p=0.01 ) . Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo ( p=0.004 and p=0.016 , respectively ) . At the end of treatment , patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo ( p=0.032 ) . Fluticasone propionate was tolerated as well as placebo , with few adverse effects and without a clinical ly important effect on mean serum cortisol concentration . INTERPRETATION Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months .  Inhaled corticosteroids may have an important role in the long-term treatment of COPD BACKGROUND Inhaled corticosteroids are clearly beneficial for patients with asthma of moderate severity , but the risks and benefits of using them in patients with milder asthma are less clear . We have compared the change in bone mineral density over 2 years in adults with mild asthma r and omised to receive an inhaled corticosteroid or non-corticosteroid treatment . METHODS Subjects with mild asthma ( mean forced expiratory volume in one second ( FEV1 ) 86 % predicted , mean age 35 years , taking β agonists only ) were r and omised to receive inhaled budesonide , inhaled beclomethasone dipropionate , or non-corticosteroid treatment for 2 years in a prospect i ve r and omised open study in 19 centres in France , New Zeal and , Spain , and the UK . The corticosteroid dose was adjusted according to a written self-management plan . The main outcome measure — change in bone mineral density after 6 , 12 , and 24 months — was measured “ blind ” . Secondary outcomes included lung function , the relation between change in bone density and inhaled steroid dose and change in biochemical markers of bone metabolism . RESULTS Of 374 subjects r and omised , 239 ( 64 % ) completed the study and were included in the analysis . The median daily doses of inhaled budesonide ( n=87 ) and beclomethasone ( n=74 ) were 389 μg and 499 μg , respectively . Subjects treated with an inhaled corticosteroid had better asthma control than those in the reference group ( n=78 ) . Change in bone mineral density did not differ between the three groups over the 2 years , nor did it correlate with changes in markers of bone metabolism . The mean change in bone mineral density over 2 years in the budesonide , beclomethasone dipropionate , and reference groups was 0.1 % , –0.4 % , and 0.4 % for the lumbar spine and –0.9 % , –0.9 % , and –0.4 % for neck of the femur . Mean daily dose of inhaled steroid was related to reduction in bone mineral density at the lumbar spine but not at the femoral neck . CONCLUSION In subjects with mild asthma  an inhaled corticosteroid provided better asthma control than alternative non-corticosteroid treatment with no difference in change in bone mineral density over 2 years . The relation between dose of inhaled corticosteroid and change in bone density at the lumbar spine may be due to a direct effect of inhaled corticosteroids on bone . Since inhaled steroid dose is also related inversely to lung function , an effect of asthma severity on bone density was also possible BACKGROUND Inhaled corticosteroids are recognised as the most effective agents in the treatment of asthma . However , concerns have been expressed about the effects of high doses of inhaled corticosteroids on safety in relation to bone resorption and formation . This study measures the effects of two inhaled corticosteroids on bone markers and bone mineral density ( BMD ) over one year . METHODS A one year r and omised , prospect i ve , open parallel study comparing inhaled fluticasone propionate ( FP ) , 500 μg twice daily in 30 patients , and budesonide ( BUD ) , 800 μg twice daily in 29 patients , delivered by metered dose inhaler and large volume spacers was performed in adults with moderate to severe asthma . Biochemical markers of bone turnover ( osteocalcin , procollagen type 1 C-terminal propeptide ( PICP ) , immunoreactive free deoxypyridinoline ( iFDpd ) , N-terminal crosslinked telopeptides of type I collagen ( NTx ) ) , BMD at the spine and femoral neck , and serum cortisol concentrations were measured at baseline and 12 months later . RESULTS There were no significant differences between the inhaled steroids on bone markers of bone resorption and formation or bone mineral density . Bone mineral density of the spine increased slightly in both groups over the 12 month period . Serum osteocalcin levels increased from baseline in both treatment groups ( FP 16.9 % , p = 0.02 ; BUD 14.3 % , p = 0.04 ) . PICP did not differ significantly from baseline . Both markers of bone resorption ( iFDpd , NTx ) varied considerably with no significant changes after one year . There was a significant correlation in percentage change from baseline between BMD of the spine and osteocalcin at 12 months ( r = 0.4 , p = 0.017 ) . Mean serum cortisol levels remained within the normal range in both groups following treatment . CONCLUSION There was no evidence of a decrease in BMD during 12 months of treatment with high doses of either FP or BUD . The change in spine BMD correlated with the increase in osteocalcin . Studies extending over several years are needed to establish whether these findings persist BACKGROUND Budesonide ( BUD ) has recently been licensed for treatment of asthma in the United States , whereas triamcinolone acetonide ( TAA ) has been used for many years . OBJECTIVE We sought to evaluate the dose-response effect of inhaled BUD and TAA in terms of adrenal , bone , and blood markers . METHODS Twelve asthmatic subjects ( mean age , 32 years ; mean FEV1 , 91 % of predicted value ) were studied in a r and omized design comparing 3 days of treatment with placebo and low ( 200 micrograms twice daily ) , medium ( 400 micrograms twice daily ) , and high ( 800 micrograms twice daily ) doses of BUD ( Pulmicort Turbuhaler , 100 micrograms ) and TAA ( Azmacort integrated actuator/spacer , 100 micrograms ) with a 7-day period at crossover , when patients received their usual inhaled corticosteroid therapy . Measurements were made at 8 am for serum cortisol , osteocalcin , and blood eosinophils . Measurements were also made for overnight urinary cortisol/creatinine excretion . RESULTS For all measurements there were no significant differences between the 2 treatments at any dose level . Ratios between BUD and TAA ( 95 % CI ) at the highest dose levels were as follows : 8 am serum cortisol , 1.08-fold ( 0.63 to 1 . 85 ) ; urinary cortisol , 1.09-fold ( 0.63 to 1.86 ) ; eosinophils , 0 . 98-fold ( 0.69 to 1.38 ) ; and osteocalcin 1.05-fold ( 0.78 to 1.41 ) . There was no evidence of a significant overall dose-response effect for any parameter of hypothalamo-pituitary-adrenocortical axis activity , with neither drug being significantly different from placebo at any dose . For the 3 dose levels of both drugs , total abnormal low values for 8 am serum cortisol ( ie , < 5.4 micrograms/dL [ < 150 nmol/L ] ) showed 2 of 36 for BUD and 2 of 36 for TAA . There was also no significant overall dose-response effect for eosinophils or osteocalcin , although both drugs were significantly ( P < .05 ) different from placebo at the highest dose : eosinophils ( x10(9)/L ) , placebo : 0.36 , TAA : 0.24 , and BUD : 0.23 ; and osteocalcin ( nmol/L ) , placebo : 1.04 , TAA : 0.73 , and BUD : 0.77 . CONCLUSION There were no significant differences in the systemic bioactivity profiles , in terms of adrenal , blood , and bone markers , between  BUD administered by means of Turbuhaler and TAA administered by means of an integrated actuator/spacer in a dose range of 400 micrograms to 1600 micrograms/day . Both drugs exhibited a significant degree of detectable systemic bioactivity but only at the highest dose of 1600 micrograms/day for effects on eosinophil count and osteocalcin OBJECTIVE The improved lung deposition of hydrofluoroalkane-134a beclomethasone dipropionate ( HFA-BDP ) extrafine aerosol compared with chlorofluorocarbon beclomethasone dipropionate ( CFC-BDP ) suggests that lower doses of HFA-BDP may be required to provide equivalent asthma control . The present study was undertaken to test this hypothesis . DESIGN A 10- to 12-day run-in period confirmed that patients met established criteria of at least moderate asthma and the asthma was inadequately controlled by current therapy ( inhaled beta-agonist and CFC-BDP [ < or = 400 microg/d ] ) . A short course of oral prednisone , 30 mg/d for 7 to 12 days , was followed to establish the patients were steroid responsive and to provide an " in- study " baseline of " optimal " asthma control . PATIENTS A total of 347 patients were then r and omized to HFA-BDP 400 microg/d , CFC-BDP 800 microg/d , or HFA-placebo for 12 weeks . RESULTS Morning peak expiratory flow ( AM PEF ) measurements showed that HFA-BDP 400 microg/d achieved equivalent control of asthma to CFC-BDP 800 microg/d at all time intervals after oral steroid treatment . All other efficacy variables supported the AM PEF results and both active treatments were more effective than placebo . The safety profile of HFA-BDP compared favorably with that of CFC-BDP with no unexpected adverse events reported . CONCLUSIONS These findings demonstrate that HFA-BDP provides equivalent control of moderate or moderately severe asthma as CFC-BDP in the population studied , but at half the total daily dose A single blind r and omized crossover trial was performed comparing placebo ( PL ) ; low ( L ) , medium ( M ) and high ( H ) doses of fluticasone propionate ( FP ) L : 330 microg , M : 770 microg , H : 1,540 microg per day and triamcinolone acetonide ( TAA ) L : 400 microg , M : 800 microg , H : 1,600 microg per day . Each drug was given twice daily over a total of 9 d , with 3 d for each dose level . Each 9-d drug sequence was preceded by a 3-d placebo , and was separated by a 12-d washout period . Twelve mild-to-moderate , stable adult asthmatics , mean ( SEM ) age , 34.3 ( 2.9 ) yr , mean FEV1 : 82.1 ( 2.0 ) % predicted , and FEF25 - 75 % : 53.6 ( 5.5 ) % predicted , receiving up to 400 microg of inhaled corticosteroid per day , were studied . After each 3-d treatment period , blood sample s were taken for 8:00 A.M. serum cortisol . Ten-hour overnight urine collection s were taken for measurement of urinary cortisol and corrected for creatinine excretion , starting at 10:00 P.M. following the sixth dose . For 8:00 A.M. serum cortisol compared with PL there was significant ( p < 0.001 ) dose-related suppression with FP but not with TAA , which amounted to a 2.03-fold ratio for H FP versus H TAA . For corrected urinary cortisol/creatinine excretion , there was a significant ( p < 0.005 ) dose-related suppression for FP but not for TAA . This amounted to a 1.9-fold ratio for H FP versus H TAA . For doses < 1,000 microg/d , the number of individual results with an abnormal low urinary cortisol value ( < 10 nmol/10 h ) were : 10/24 for FP versus 3/24 for TAA ( p < 0.005 ) . In conclusion , for 8:00 A.M. serum cortisol and overnight corrected urinary cortisol/creatinine excretion , there was significant dose-related suppression with FP but not with TAA . For both of these parameters at the highest dose of both drugs , this amounted to a two-fold ratio in suppression STUDY OBJECTIVE Because nebulized budesonide may be used as an alternative to maintenance oral prednisolone in the treatment of severe chronic asthma , it is important to compare these two drugs to determine their relative systemic bioactivity profiles in terms of effects on adrenal , bone , and hematologic markers . DESIGN Twelve asthmatic patients ( mean age ; 34.7 years ; mean FEV1 ; 88.3 % predicted ; mean forced expiratory flow between 25 % and 75 % of FVC , 54.8 % predicted ) were studied in a double-blind , double-dummy , r and omized crossover design to compare placebo , low , medium , and high doses of nebulized budesonide given bid ( 1 , 2 , and 4 mg/d , respectively ) , and oral prednisolone given qd ( 5 , 10 , and 20 mg/d ) . All treatments and both placebos were given for 4 days at each dose level with a 7-day washout period between each treatment block with budesonide or prednisolone . All measurements were made at 8 AM after the last dose of each dose increment for plasma cortisol , serum osteocalcin , and blood eosinophil count . RESULTS Regression analysis showed significant dose-related suppression with prednisolone for 8 AM plasma cortisol ( p<0.0001 ) , osteocalcin ( p<0.05 ) , and blood eosinophil count ( p<0.0005 ) , but not with budesonide . Compared with placebo , there were significant differences only with prednisolone , at the medium- and high-dose levels for all three markers . CONCLUSIONS For all three systemic bioactivity markers ( 8 AM plasma cortisol , serum osteocalcin , and blood eosinophils ) , there was significant dose-related suppression with prednisolone but not with budesonide . Further long-term studies are required in more severe asthmatics in order to evaluate the therapeutic index Inhaled glucocorticosteroids have been developed for the treatment of asthma in an attempt to minimize the suppression of endogenous adrenal function that complicates oral or injected steroid usage , but it is unclear whether this strategy leads to reduced systemic complications in other areas , such as the skeleton . In this study we evaluated serum osteocalcin levels as a marker of skeletal metabolism in healthy volunteers treated with oral and inhaled steroids alone and in response to an oral calcitriol stimulation test . Forty subjects , aged 33 + /- 9 ( mean + /- SD ) yr were r and omized to receive either high or low dose oral prednisolone ( 40 vs. 10 mg/day ) or inhaled budesonide ( 3.2 vs. 0.8 mg/day ) . Each dose of budesonide is known to have a greater antiasthmatic potency than the dose of prednisolone with which it was compared . In addition 10 control subjects received placebos containing no active steroid drugs . During the second week of treatment , half of the subjects in each of the 4 steroid-treated groups and all subjects in the control group received oral calcitriol ( 2.0 micrograms/day ) . There was a marked dose-dependent reduction in serum cortisol levels , but this reduction was significantly less pronounced during budesonide treatment , such that low dose budesonide was without effect . During the first week of steroid therapy there were significant dose-dependent reductions in serum osteocalcin ( P = 0.003 ) , but this reduction was not significantly different between budesonide and prednisolone treatments . In response to calcitriol , serum osteocalcin increased by 35 % in the control group ( P = 0.06 ) . Osteocalcin levels increased by 56 % and 50 % in the low dose budesonide and prednisolone groups and by 106 % in the high dose budesonide group , but did not change in the high dose prednisolone group . The osteocalcin response to calcitriol was significantly higher in the budesonide groups ( P = 0.03 , by analysis of variance ) . High dose prednisolone caused increases in serum 1,25-dihydroxyvitamin D3 ( P less than 0.02 ) , urinary calcium excretion ( P = 0.07 ) , and urinary hydroxyproline ( P less than 0.01 ) . None of these changes was seen during budesonide therapy . There are as yet no data for these variables after long term use of inhaled budesonide  in asthmatic patients , but our acute studies suggest that this potent topical glucocorticoid may have considerably less impact on the skeleton than oral prednisolone , even if used at doses high enough to suppress endogenous adrenal function To assess whether the use of larger than usual doses of inhaled steroid to treat severe asthma may adversely affect bone turnover and whether such an effect may be mitigated by altering the dose schedule , we investigated the effects of budesonide ( BUD ) on serum osteocalcin and the urinary output of hydroxyproline and calcium .  Healthy adults were administered 1.2 or 2.4 mg of BUD per day ( N = 40 ) or placebo ( N = 8) in a crossover , double-blind comparison of morning versus diurnal dosing schedules for 1 month each . Both BUD doses reduced the 24-hour urinary free-cortisol output ( p less than 0.001 ) and serum osteocalcin ( p less than 0.001 ) . The larger dose reduced the morning serum cortisol levels ( p = 0.002 ) . Neither dose increased the 8 AM urinary calcium or hydroxyproline output . Osteocalcin and plasma cortisol levels were higher on morning than on diurnal dosing ( p = 0.01 ) . The 24-hour urinary free-cortisol output was the same with either schedule ( p = 0.96 ) . Additional study is required to assess the clinical importance of the inhibitory effect of BUD on bone formation , as evidence d by the reduction in osteocalcin levels . Of concern is the possibility of serious bone complications result ing from the long-term use of inhaled steroid , particularly in growing children or patients in whom other risk factors for osteoporosis are present . The clinical advantage , if any , of morning dosing remains question able We have previously shown that allergen inhalation by asthmatics is associated with increases in bone marrow eosinophil/basophil colony-forming cells ( Eo/B-CFU ) , and increases in CD34(+ ) hemopoietic progenitors expressing the alpha-subunit of the IL-5 receptor ( IL-5Ralpha ) . This study investigated the effect of inhaled corticosteroid on baseline numbers and allergen-induced increases in these parameters . Nine subjects with mild , stable asthma inhaled budesonide ( 400 microgram/d ) for 8 d in a placebo-controlled , double-blind , r and omized crossover study . On Day 7 , subjects inhaled allergen , with bone marrow sampling before and 24 h after challenge . Budesonide inhalation significantly attenuated the allergen-induced early and late asthmatic responses , degree of increase in sputum and blood eosinophils , as well as the baseline numbers of total bone marrow CD34(+ ) cells ( p < 0.05 ) , CD34(+)IL-3Ralpha+ cells ( p < 0.01 ) and IL-5-responsive Eo/B-CFU ( p < 0.05 ) . Allergen inhalation significantly increased Eo/B-CFU grown in the presence of IL-3 , GM-CSF , or IL-5 alone ( p < 0.05 ) and in combination ( p < 0.01 ) , as well as the number of CD34(+)IL-5Ralpha+ cells ( p < 0.01 ) . However , these increases in Eo/B-CFU and CD34(+)IL-5Ralpha+ cells were not affected by budesonide treatment . These data demonstrate that short-term inhaled budesonide treatment has a systemic effect in inhibiting the turnover of a sub population of bone-marrow-derived progenitors , but that inhalation of allergen overcomes this inhibitory effect BACKGROUND Chronic obstructive pulmonary disease ( COPD ) results from a progressive decline in lung function , which is thought to be the consequence of airway inflammation . We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline . METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second ( FEV1 ) was 30 to 90 percent of the predicted value in a 10-center , placebo-controlled , r and omized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily . The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator . The secondary outcome measures included respiratory symptoms , use of health care services , and airway reactivity . In a sub study of 412 participants , we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment . RESULTS The mean duration of follow-up was 40 months . The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group ( 44.2+/-2.9 vs. 47.0+/-3.0 ml per year , P= 0.50 ) . Members of the triamcinolone group had fewer respiratory symptoms during the course of the study ( 21.1 per 100 person-years vs. 28.2 per 100 person-years , P=0.005 ) and had fewer visits to a physician because of a respiratory illness ( 1.2 per 100 person-years vs. 2.1 per 100 person-years , P=0.03 ) . Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months ( P=0.02 for both comparisons ) . After three years , the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group ( P < or = 0.007 ) . CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD , but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems . These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density We have previously demonstrated dose-dependent nocturnal cortisol suppression by inhaled beclomethasone and budesonide in asthmatic children . This has now been confirmed in a controlled study . Eighteen healthy adults inhaled either a single evening dose of 400 micrograms budesonide or placebo or 400 micrograms budesonide twice daily for 2 wk . Overnight blood samplings for cortisol and adrenocorticotropic hormone were taken at the beginning of the trial , at the end of the treatment period , and after stopping the medications . Compared with placebo , the nocturnal cortisol production was significantly reduced by 40 % after a single dose of budesonide ( p = 0.020 ) and by 37 % after 2 wk of budesonide ( p = 0.045 ) . These data indicate that there is a single-dose rather than a cumulative suppressive effect of inhaled corticosteroids using the specific dose and regimen studied in this protocol . The effect is not related to the underlying problem , namely asthma . The clinical relevance of these findings can only be eluci date d in long-term follow-up studies . We believe that our findings explain the recent identification of abnormalities in bone turnover on inhaled corticosteroids in the absence of other systemic effects . The findings emphasize the need for a cautious step-wise approach to asthma therapy Abstract Objectives : To determine the effect of long term inhaled corticosteroids on lung function , exacerbations , and health status in patients with moderate to severe chronic obstructive pulmonary disease . Design : Double blind , placebo controlled study . Setting : Eighteen UK hospitals . Participants : 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second ( FEV1 ) 50 % of predicted normal . Interventions : Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo . Main outcome measures : Efficacy measures : rate of decline in FEV1 after the bronchodilator and in health status , frequency of exacerbations , respiratory withdrawals . Safety measures : morning serum cortisol concentration , incidence of adverse events . Results : There was no significant difference in the annual rate of decline in FEV1 ( P=0.16 ) . Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo ( P<0.001 ) . Median exacerbation rate was reduced by 25 % from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate ( P=0.026 ) . Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate ( P=0.0043 ) . Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group ( 25 % v 19 % , P=0.034 ) . Conclusions : Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1 . Patients on fluticasone propionate  had fewer exacerbations and a slower decline in health status . These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease
BACKGROUND Inhaled corticosteroids form the main therapy for asthma , but there is increasing concern about the potential systematic effects of long-term inhaled corticosteroids including their effect on bone metabolism and bone loss .
OBJECTIVES To determine the effect of inhaled corticosteroids use on biochemical markers of bone turnover , bone mineral density and the development of fractures .