Loss of bone density with inhaled triamcinolone in Lung Health Study II

Inhaled glucocorticosteroids (ICS) are commonly prescribed for chronic obstructive pulmonary disease. No adverse effect on bone mineral density (BMD) has been proven. In a randomized double-blind, placebo-controlled trial at seven centers in North America, we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease. They used inhaled triamcinolone acetonide, 600 mcg, or placebo, twice daily. We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years, and serum osteocalcin at baseline, 3 months, 1 year, and 3 years. After 3 years, BMD at the femoral neck decreased 1.78% more with ICS than with placebo (p < 0.001). More participants in the ICS group experienced 6% or more loss of femoral neck BMD (p = 0.002). Lumbar spine BMD increased in the placebo group by 0.98% but decreased by 0.35% in the ICS group (a difference of 1.33%, p = 0.007). Changes in osteocalcin did not correlate with changes in BMD. Fractures, lost height, or osteoporosis diagnoses were not increased among ICS users compared with placebo users. In summary, the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment.     

Skin manifestations of inhaled corticosteroids in COPD patients: results from Lung Health Study II

OBJECTIVE: To define the relationship between skin bruising (as well as other cutaneous manifestations) and inhaled corticosteroid (ICS) therapy vs placebo in subjects with COPD who were participating in a clinical trial. To explore the relationship between easy skin bruising and other systemic effects of ICS therapy, including adrenal suppression and loss of bone mineral density (BMD). DESIGN: Double-blind, randomized, placebo-controlled clinical trial of triamcinolone acetonide (1200 microg daily) vs placebo in participants with mild-to-moderate COPD. SETTING: Lung Health Study II, a clinical trial to assess the effect of ICS compared to placebo in 1,116 participants in 10 centers over > 3.5 to 4.5 years. PARTICIPANTS: A total of 1,116 smokers or recent ex-smokers with mild-to-moderate COPD (age range, 40 to 69 years; mean age, 56.3 years; 37.2% female). MEASUREMENTS AND RESULTS: Every 6 months, a structured questionnaire was administered to elicit reports of any bruising and/or skin rashes, slow healing of cuts or sores, or other skin changes. Compliance with inhaler use was assessed by canister weighing. A significantly higher proportion of ICS than placebo participants who complied with using their inhaler reported easy bruising (11.2% vs 3.5%, respectively) and the slow healing of skin cuts or sores (2.4% vs 0.5%, respectively). Older men in the ICS group with good inhaler compliance appeared to be at the greatest risk of bruising. In those participants undergoing serial measurements of adrenal function and BMD, no association was noted between skin bruising and either the suppression of adrenal function or the loss of BMD as systemic complications of ICS use. CONCLUSION: These findings indicate that moderate-to-high doses of ICSs result in an increased incidence of easy bruising and impairment in skin healing in middle-aged to elderly persons with COPD. No association was noted between skin bruising and other markers of systemic toxicity from the use of ICSs.     

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

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 post-menopausal estrogen replacement therapy. Although medium-term growth studies showed suppressive effects with 400-microg/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. Metaanalysis 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.     

The effect of smoking intervention and an inhaled bronchodilator on airways reactivity in COPD: the Lung Health Study

BACKGROUND: The Lung Health Study (LHS), a 5-year, randomized, prospective clinical trial, studied the effects of smoking intervention and therapy with inhaled anticholinergic bronchodilators on FEV(1) in participants who were 35 to 60 years of age and had mild COPD. Participants were randomized into the following three groups: usual care; smoking cessation plus inhaled ipratropium bromide; and smoking cessation plus placebo inhaler. This report evaluates the effects of these interventions, demographic characteristics, smoking status, and FEV(1) changes on airway responsiveness (AR). METHODS AND RESULTS: Of 5,887 participants, 4,201 underwent methacholine challenge testing both at study entry and study completion. All groups increased AR during the 5-year period. The increase in AR was greatest in continuing smokers and was associated with a greater FEV(1) decline. An intent-to-treat analysis indicated no significant differences in AR changes among the three groups. CONCLUSIONS: Changes in AR over a 5-year period in the LHS were primarily related to changes in the FEV(1). The greater the decline in FEV(1), the greater the increase in AR. Smoking cessation had a small additional benefit in AR beyond its favorable effects on FEV(1) changes.     

Asthma and Risk of Death from Lung Cancer: NHANES II Mortality Study

Objective. Although smoking is the most important risk factor for lung cancer, nearly 10% of lung cancer is not attributable to smoking. Insights into risk factors for lung cancer other than smoking will become increasingly important, given decreasing trends in the prevalence of smoking. Prior research suggests asthma may increase the risk of lung cancer, particularly among nonsmokers. Methods. We used Cox regression analyses of data from a nationally representative sample of 9087 adults aged 30–75 years included in the NHANES II Mortality Study (1976–1992) to estimate the relative risk (RR) of death from lung cancer associated with self-reported asthma, independent of smoking. Results. Age-adjusted prevalence of smoking was 36.0%, and the age-adjusted prevalence of asthma was 6.1% (6.2% among nonsmokers) at baseline. During approximately 17 years of follow-up, 196 adults died of lung cancer (ICD-9 160–165). Among 6144 nonsmokers, the RR of lung cancer death comparing adults with asthma to those without was 1.69 (95% CI: 0.94–3.04) although the association was not statistically significant. For nonsmokers without a history of cancer, the RR was 2.53 (95% CI: 1.42–4.52). After exclusion of adults with emphysema and chronic bronchitis, the RR of lung cancer death associated with asthma was 3.54 (95% CI: 1.93–6.42). Conclusions. Consistent with prior reports, we observed an increased risk of lung cancer mortality associated with asthma among nonsmokers without a history of cancer.     

Asthma and Risk of Death from Lung Cancer: NHANES II Mortality Study

Objective. Although smoking is the most important risk factor for lung cancer, nearly 10% of lung cancer is not attributable to smoking. Insights into risk factors for lung cancer other than smoking will become increasingly important, given decreasing trends in the prevalence of smoking. Prior research suggests asthma may increase the risk of lung cancer, particularly among nonsmokers. Methods. We used Cox regression analyses of data from a nationally representative sample of 9087 adults aged 30-75 years included in the NHANES II Mortality Study (1976-1992) to estimate the relative risk (RR) of death from lung cancer associated with self-reported asthma, independent of smoking. Results. Age-adjusted prevalence of smoking was 36.0%, and the age-adjusted prevalence of asthma was 6.1% (6.2% among nonsmokers) at baseline. During approximately 17 years of follow-up, 196 adults died of lung cancer (ICD-9 160-165). Among 6144 nonsmokers, the RR of lung cancer death comparing adults with asthma to those without was 1.69 (95% CI: 0.94-3.04) although the association was not statistically significant. For nonsmokers without a history of cancer, the RR was 2.53 (95% CI: 1.42-4.52). After exclusion of adults with emphysema and chronic bronchitis, the RR of lung cancer death associated with asthma was 3.54 (95% CI: 1.93-6.42). Conclusions. Consistent with prior reports, we observed an increased risk of lung cancer mortality associated with asthma among nonsmokers without a history of cancer.     

Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study

Objective To investigate the natural course of apparently benign adrenal incidentalomas with no overt hyperfunction at diagnosis, as their clinical significance and appropriate management are still controversial. Design Prospective long‐term follow‐up study of patients with adrenal incidentalomas with periodic hormonal and morphological evaluation. Patients and methods A total of 77 patients with incidental adrenal masses, diameter 1·0–6·0 cm (median 2·5 cm), were submitted to a hormonal assessment of adrenal function at diagnosis. This was repeated, together with an adrenal CT scan, 12 months later and then every 12–24 months, for a period of 12–154 months (mean 62·7 ± 31·9, median 60·0). Results At diagnosis, 57 patients had normal adrenal function and 20 had subclinical Cushing's syndrome. During follow‐up, adrenal function remained normal in 49 patients, subclinical Cushing's syndrome was confirmed in 12, whilst intermittent subclinical autonomous cortisol hypersecretion was found in 12 patients. Overt endocrine disease was diagnosed in 4 patients (Cushing's syndrome in 2 and phaeochromocytoma in 2). A change in mass size (≥ 0·5 cm) was observed in 26 patients (enlargement in 20 – including patients who developed overt hyperfunction – with no signs of malignancy and reduction in size in 6). Conclusions Subclinical autonomous cortisol hypersecretion is the most frequent hormonal abnormality in patients with adrenal incidentalomas, and may be intermittent in a significant percentage of cases. Few patients develop overt endocrine disease. A growth tendency is observed in some adrenal incidentalomas without evidence of malignant transformation and occasionally can be related to development of overt hyperfunction. These findings indicate the need for periodic hormonal and morphological evaluation for several years.     

Medication-attributed adverse effects in placebo groups: implications for assessment of adverse effects

Medication-attributed adverse effects are a frequent reason for poor compliance in practice and in clinical studies and are also common in patients receiving placebo. The occurrence of adverse effects in placebo groups can clarify the assessment of adverse event reporting. We analyzed data from randomized, placebo-controlled trials of statin drugs published since 1992 with sample sizes larger than 100 subjects. Reports of adverse effects and discontinuation rates in placebo groups were evaluated. We compared data on adverse effect profiles in placebo groups between trials and with expected rates from population-based studies. We also sought to determine the range of adverse effect ascertainment methods used in different studies. Methods of ascertainment of adverse events varied widely across studies. Overall, 4% to 26% of patients in the control groups of large trials of statin drugs discontinued placebo use because of perceived adverse effects. The symptom rate in placebo groups varied substantially across trials (up to a ratio of 13:1 for possibly drug-related symptoms, eg, headache, 0.2%-2.7%, or abdominal pain, 0.9%-3.9%) and were often markedly lower than those found in the general population (eg, fatigue, 1.9%-3.4%) in trials of statin drugs vs 17.7% in the general population. In conclusion, the widely varying rates of adverse effects reported by patients taking placebo and the high prevalence of such symptoms in the general population should be considered by both trialists and clinicians. In addition, variability of adverse effect ascertainment is considerable and suggests the need for better standardization in research.     

Noncardiac adverse effects and organ toxicity of moricizine during short- and long-term studies

To determine the tolerance and safety of moricizine, the incidence and nature of its noncardiac adverse effects and organ toxicity reported during short- and long-term clinical studies were examined. From a pooled data base of 1,256 adult patients and healthy subjects, the most frequent non-cardiac adverse events were gastrointestinal (nausea) and neurologic (dizziness) complaints which occurred in 10 to 15% of patients during short-term (less than 3 months) studies and increased to 20 to 25% during long-term (greater than 12 months) studies. Adverse effects led to discontinuation of moricizine therapy in 116 patients (9%). Organ toxicity consisted predominantly of drug fever, possible thrombocytopenia and elevated liver function tests and was quite low (less than 0.7%) for both short- and long-term studies. Moricizine appears to be a well-tolerated antiarrhythmic drug with low occurrence of noncardiac adverse effects without significant serious organ toxicity.     

Hydralazine in the long-term treatment of chronic heart failure: Lack of difference from placebo

Although hydralazine improves cardiac performance in patients with chronic left ventricular failure, its long-term clinical efficacy has not been established in controlled trials. We carried out a double-blind randomized trial of hydralazine (200 mg daily in 16 patients) versus placebo (16 patients) in patients with class III and IV symptoms while they were taking digitalis and diuretics. Maximal treadmill exercise time was determined prior to and at 4, 10, 18, and 26 weeks of hydralazine or placebo treatment; average follow-up was 20 weeks. We found no change in body weight, clinical class, resting heart rate and blood pressure, or heart size (by chest x-ray examination and echocardiogram) during treatment in either group. The total number of complicating clinical events was insignificantly fewer in the hydralazine treated group (8 vs 13). Control exercise duration in the hydralazine group averaged 259 ± 21 seconds (SEM), and increased to 347 ± 35 seconds at 4 weeks (p < 0.01) and 421 ± 38 seconds at 26 weeks (p < 0.001). Exercise duration also increased significantly in the placebo group, from 271 ± 30 seconds at control to 340 ± 44 seconds at 4 weeks (p < 0.02) and 339 ± 46 seconds at 26 weeks (p < 0.02). No differences between groups were significant. Left ventricular ejection fraction remained depressed and unchanged in both groups. Thus long-term vasodilator treatment with hydralazine alone is not significantly more effective than placebo in chronic heart failure.     

哮喘儿童持续吸入低剂量糖皮质激素的全身性副作用

目的 探讨我国哮喘儿童吸入糖皮质激素的全身性副作用.方法 将30例14岁以下轻度哮喘儿童随机分为安慰剂组(A组)、二丙酸倍氯松(BDP)200 μg组(B组)、BDP 400 μg组(C组),每组10例,分别持续吸入安慰剂及BDP 200、400 μg/d 1年,观察患儿气道高反应性(BHR)、身高增长、骨密度(BMD)、钙磷代谢及下丘脑-垂体-肾上腺轴(HPAA)功能的影响.结果 B组及C组患儿吸入BDP后PD20-FEV1即一秒钟用力呼气容积下降20% 时累积吸入的组胺剂量[Log(PD20- FEV1)]分别为(2.70±0.13) μg及(3.15±0.18) μg,与治疗前[B组(2.04±0.47) μg,C组(1.94±0.46) μg]比较,差异有显著性(P均<0.01),而B组与C组间比较,差异有显著性(P<0.01).A、B及C组患儿吸入BDP后血骨钙素分别为(29±12) μg/L、(22±6) μg/L、(31±11) μg/L,血钙为(2.49±0.11) mmol/L、(2.39±0.28) mmol/L、(2.20±0.35) mmol/L, 血磷为(1.8±0.6) mmol/L、(1.7±0.7) mmol/L、(1.5±0.4) mmol/L,血碱性磷酸酶为(410±113) U/L、(337±99) U/L、(351±122) U/L(P>0.05),桡骨BMD为(0.40±0.10) g/cm2、(0.42±0.05 ) g/cm2、(0.44±0.02) g/cm2,尺骨BMD为(0.32±0.07) g/cm2、(0.36±0.08) g/cm2、(0.35±0.04) g/cm2,腰椎4～5BMD为(0.62±0.09) g/cm2、(0.59±0.08) g/cm2、(0.64±0.06) g/cm2,血皮质醇基础值为(350±86)nmol/L、(407±199) nmol/L、(365±71)nmol/L, 三组间比较差异无显著性(P均>0.05).但C组治疗后血皮质醇对促肾上腺皮质激素(ACTH)刺激的反应值为(482±97) nmol/L, 与治疗前(621±199 )nmol/L比较,差异有显著性(P<0.01),而A组和B组治疗后分别为 (566±203) nmol/L,(452±97)nmol/L,与治疗前[A组(534±204)nmol/L,B组(481±82)nmol/L]比较,差异无显著性(P均>0.05).A组患儿吸入BDP后身高标准差计分(SDS)为(1.2±0.9)分,B组为(1.3±0.9)分,C组为(1.0±0.7)分,三组比较差异均无显著性(P均>0.05).结论 14岁以下轻度儿童哮喘吸入200 μg/d的BDP即能有效降低BHR,且无明显全身性副作用.而当剂量达400 μg/d时,血皮质醇对ACTH刺激的反应性明显降低,有必要作进一步的研究.