pulmicort and Fractures--Bone

The effect of inhaled corticosteroids (ICS) on fracture risk in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to evaluate the association between ICS and fractures in COPD.. MEDLINE, EMBASE, regulatory documents and company registries were searched up to August 2010. Randomised controlled trials (RCTs) of budesonide or fluticasone versus control treatment for COPD (≥24 weeks duration) and controlled observational studies reporting on fracture risk with ICS exposure vs no exposure in COPD were included. Peto OR meta-analysis was used for fracture risk from RCTs while ORs from observational studies were pooled using the fixed effect inverse variance method. Dose-response analysis was conducted using variance-weighted least squares regression in the observational studies. Heterogeneity was assessed using the I(2) statistic.. Sixteen RCTs (14 fluticasone, 2 budesonide) with 17,513 participants, and seven observational studies (n=69,000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p=0.04; I(2)=0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p<0.001; I(2)=37%), with each 500 μg increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p<0.001).. Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures.

Topics: Administration, Inhalation; Aged; Androstadienes; Budesonide; Dose-Response Relationship, Drug; Female; Fluticasone; Fractures, Bone; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment

Inhaled corticosteroid (ICS) therapy is central to the long-term management of asthma and is extensively used in the management of chronic obstructive pulmonary disease (COPD). While administration via inhalation limits systemic exposure compared with oral or injected corticosteroids and, therefore, the risk of systemic corticosteroid-related adverse effects, concerns over the long-term safety of ICS persist. The assessment of the long-term effects of ICS therapy requires considerable research effort over years or even decades. Surrogate markers/predictors for clinical endpoints such as adrenal crisis, reduced final height and fractures have been identified for use in relatively short-term studies. However, the predictive value of such markers remains questionable.Inhaled budesonide has been available since the early 1980s and there is a considerable evidence base investigating the safety of this agent. To assess the long-term safety of inhaled budesonide therapy in terms of the actual incidence of the clinical endpoints adrenal crisis/insufficiency, reduced final height, fractures and pregnancy complications, we undertook a review of the scientific literature. The external databases BIOSIS, Cochrane Central Register of Controlled Trials, Current Contents, EMBASE, International Pharmaceutical Abstracts and MEDLINE were searched, in addition to AstraZeneca's internal product literature database Planet, up to 29 February 2008. Only original articles of epidemiological studies, national surveys, clinical trials and case reports concerning inhaled budesonide were included.Eight surveys of adrenal crisis were found. The only survey with specified criteria for diagnosis involved 2912 paediatricians and endocrinologists and revealed 33 patients with adrenal crisis associated with ICS therapy; only one patient used budesonide (in co-treatment with fluticasone propionate). In addition, 14 case reports of adrenal crisis in budesonide-treated patients were found. In only two of these, budesonide was used at recommended doses and in the absence of interacting medication.Three retrospective studies and one prospective study assessing final height were found. None of them showed any reduced final height in patients receiving inhaled budesonide during childhood or adolescence.Seventeen epidemiological studies investigating the risk of fractures were found. When adjusting for confounding factors, they did not provide any unequivocal data for an increased fracture risk wi

Topics: Administration, Inhalation; Adrenal Gland Diseases; Adult; Asthma; Body Height; Bronchodilator Agents; Budesonide; Clinical Trials as Topic; Female; Fractures, Bone; Humans; Pregnancy; Young Adult

Deleterious effect of oral corticosteroids on bone has been well documented, whereas this remains debated for inhaled ones (ICS). Our objectives were to analyze the effects of ICS on bone mineral density, fracture risk and bone markers. We performed an exhaustive systematic research of all controlled trials potentially containing pertinent data, peer-reviewed by a dedicated WHO expert group, and comprehensive meta-analyses of the data. Inclusion criteria were ICS, and BMD/markers/fractures in asthma/chronic obstructive pulmonary diseases (COPD) and healthy patients. Analyses were performed in a conservative fashion using professional dedicated softwares and stratified by outcome, study design and ICS type. Results were expressed as standardized mean difference/effect size (ES), relative risk (RR) or odds ratio (OR), depending on study design and outcome units. Publication bias was investigated. Twenty-three trials were reviewed; 11 papers fit the inclusion criteria and were assessed for the main analysis. Quality scores for the randomized controlled trials (RCTs) were 80%, 71% for the prospective cohort studies, and 78% for the retrospective cohort and cross-sectional studies. We globally assessed ICS effects on BMD and found deleterious effects: ES=0.61 ( p=0.001) for healthy subjects, and ES=0.27 ( p<0.001) for asthma/COPD patients. For these patients, this effect was 0.21 ( p<0.01) at the lumbar spine, and 0.26 ( p<0.001) at the hip or femoral neck. A single study evaluated the impact of ICS on hip fracture and reported an increased OR of 1.6 (1.24; 2.03). Lumbar fracture rate differences did not reach the level of statistical significance: 1.87 (0.5; 6.94). Osteocalcin and PICP were decreased and ICTP, pyridinoline and deoxypyridinoline levels were not significantly affected. Budesonide (BUD) appeared to be the ICS inducing the less deleterious effects on bone, followed by beclomethasone dipropionate (BDP) and triamcinolone (TRI). Publication bias investigation provided non-significant results. In our meta-analyses, BUD at a mean daily dose (SD) of 686 microg (158 microg), BDP at 703 microg (123 microg) and TRI at 1,000 microg (282 microg) were found to affect bone mineral density and markers in patients suffering from the two major respiratory diseases. These findings could have practical implication in the long-term management of asthmatic and COPD patients.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bone and Bones; Bone Density; Budesonide; Fluticasone; Fractures, Bone; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Triamcinolone Acetonide

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Androstadienes; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Fractures, Bone; Glucocorticoids; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

We conducted a case-control study on fracture risk associated with the use of orally administered prednisolone/prednisone, budesonide, methylprednisolone, and hydrocortisone to assess if the various preparations were associated with different fracture patterns. Cases were all subjects with any fracture sustained during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. Adjustments were made for concurrent diseases, use of other drugs, and a number of other factors. Oral prednisolone/prednisone was associated with a dose-dependent increase in fracture risk starting from a dose of around 6.7 mg/day. Oral budesonide was not associated with an increase in overall fracture risk, but the doses in general were low (<3 mg/day). Oral hydrocortisone was not associated with overall risk of fractures. Oral methylprednisolone was only used intermittently and was not associated with an increase in overall fracture risk at the low doses used. After termination of oral prednisolone/prednisone, it took more than 1 year for fracture risk to return to the levels of the background population. Oral prednisolone is associated with a dose-dependent increase in overall fracture risk. Budesonide at low doses did not seem to be associated with fracture risk. Hydrocortisone was not associated with an increase in the risk of fractures. It may take a year from last use of prednisolone/prednisone before fracture risk returns to that of the general population.

Topics: Administration, Oral; Adrenal Cortex Hormones; Adult; Budesonide; Case-Control Studies; Dose-Response Relationship, Drug; Female; Fractures, Bone; Humans; Male; Methylprednisolone; Middle Aged; Prednisolone; Prednisone; Registries; Risk

To determine whether children or adolescents who are exposed to inhaled corticosteroids (ie, beclomethasone, budesonide, fluticasone) are at a higher risk of having bone fractures compared with nonexposed individuals.. We performed a population-based nested case-control analysis using data from the United Kingdom-based General Practice Research Database. Within a base population of 273,456 individuals aged 5 to 79 years, we identified by International Classification of Diseases codes children or adolescents who were aged 5 to 17 years with a fracture diagnosis and up to 6 control subjects per case matched to cases on age, gender, general practice attended, calendar time, and years of history in the GPRD. We compared use of inhaled steroids before the index date between fracture cases and control patients.. We identified 3744 cases and 21,757 matched control subjects aged 5 to 17 years. Current exposure to inhaled steroids did not reveal a substantially altered fracture risk compared with nonusers, even in individuals with current longer term exposure (ie, > or =20 prescriptions; adjusted odds ratio 1.15; 95% confidence interval: 0.89-1.48). In individuals with current or previous exposure to oral steroids, the adjusted odds ratio for current long-term inhaled steroid use compared with nonusers was 1.21 (95% confidence interval: 0.99-1.49).. Exposure to inhaled steroids does not materially increase the fracture risk in children or adolescents compared with nonexposed individuals.

Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Androstadienes; Beclomethasone; Bronchodilator Agents; Budesonide; Case-Control Studies; Child; Child, Preschool; Databases, Factual; Female; Fluticasone; Fractures, Bone; Humans; Logistic Models; Male; Risk Factors; United Kingdom