Long-term use of inhaled corticosteroids (ICS) at high doses was associated with a modest increase in risk for bone fractures in both men and women with chronic obstructive pulmonary disease (COPD), reported Canadian researchers.
Use of inhaled corticosteroids for 4 years or more at doses of ≥1 mg per day of fluticasone or equivalent was associated with a slightly higher risk of hip and upper extremity fractures, but not non-vertebral fractures, according to Anne Gonzalez, MD, of McGill University Health Centre in Montreal, and colleagues.
The dose-dependent, negative impact of inhaled corticosteroids on bone mineral density (BMD) is well known, but the research is among the first to show an increase in bone fractures in a COPD population, they wrote in Chest.
For this population-based cohort study, the researchers examined 1990-2005 data from two health care databases in Quebec, Canada to identify COPD patients, ages ≥55. The patients were followed until 2007 for hip and upper extremity fractures.
A nested case-control analysis was conducted to match each fracture case with 20 controls for age, sex, and follow-up time. Prescriptions for inhaled corticosteroids during the follow-up period were identified. Conditional logistic regression analysis was used the estimate the adjusted rate ratio of fractures with usage of inhaled corticosteroids.
There were 240,110 patients, ages ≥55, with newly-treated COPD identified between 1990 and 2005. During a mean 5.3 years of follow-up, 19,393 fractures were reported, for a rate of 15.2 cases per 1,000 per year.
The authors reported that any use of inhaled corticosteroids was not associated with an increased rate of fracture (relative risk 1.00, 95% CI 0.97-1.03).
Use of an inhaled corticosteroid for >4 years at daily doses of 1,000 mcg or more in fluticasone-equivalents was associated with a slight increase in risk (RR 1.10, 95% CI 1.02-1.19).
The observed risk increase was similar for men and women.
“Since fractures are more frequent in women than men, our study suggests that the excess number of fractures associated with ICS will be greater in women even though we did not find that the risk increase was particularly higher in women than in men,” said co-author Samy Suissa, PhD, of McGill University’s Lady Davis Institute.
He added that an even larger cohort study would be needed to quantify this excess number.
The researchers concluded that the benefits and risks of prescribing inhaled corticosteroids to patients with COPD need to be carefully considered, and the prescribed dose should be as low as possible in patients who receive the treatment.
In an accompanying editorial two COPD researchers noted that the findings are consistent with that of a trial showing a significant decline in BMD among patients with asthma after 3 years of inhaled corticosteroids treatment, but not 1 year.
“Together, these and other data suggest that long-term ICS therapy in COPD leads to accelerated bone mineralization and increased risk of long-bone and vertebral fractures, particularly among female patients who may have underlying osteopenia or osteoporosis,” wrote Yu Ji Cho, MD, PhD, of the University of British Columbia in Vancouver, and Don D. Sin, MD, of the National University School of Medicine in Jinju, South Korea.
They noted that inhaled corticosteroids are still commonly use in the treatment of COPD, despite calls for large reductions in inhaled corticosteroids use among patients who are not frequent exacerbators.
“For the large majority of COPD patients, ICS is not required; they can be managed with short or long acting bronchodilators,” Cho and Sin wrote, adding that the treatment should be used at the lowest effective dose in patients who require inhaled corticosteroids therapy. Also, patients taking inhaled corticosteroids should undergo regular monitoring for BMD and fracture risk.
“ICS therapy is useful in patients who experience frequent exacerbations. However, they are fraught with significant side effects, which may be dose-dependent,” they wrote. “It is now well established that ICS has deleterious effects on bone that increase the risk of fractures, a side effect that is largely avoidable and can be mitigated by careful monitoring and most importantly by reducing (and in vast majority eliminating) the use of ICS for COPD patients in the community.”
The study had limitations including the fact that data on smoking, BMI, pulmonary function, level of physical activity, and diet were not available in the analyzed databases.
Switching from salmeterol/fluticasone (SFC) to indacaterol/glycopyrronium (IND/GLY) improved lung function in patients with symptomatic, moderate-to-severe, chronic obstructive pulmonary disease (COPD), with a tolerability profile similar to SFC, themulticentre, double-blind, double-dummy, parallel-group phase IV FLASH study has shown.
“The findings reinforce the latest GOLD recommendations which support the use of dual bronchodilation therapy for the majority of symptomatic COPD patients and to limit the use of steroid-containing therapies to specific patient types,” said study investigator Dr Dina Diaz from the Lung Center of the Philippines, Manila, Philippines, who presented the results at APSR 2017 in behalf of principal investigator Professor Peter Frith from the Repatriation General Hospital, Daw Park, Australia. The findings are even more significant as patients were switched to IND/GLY without a washout period, which mimics normal clinical practice.
At week 12, patients switched to IND/GLY had significantly higher mean trough forced expiratory volume in 1 second (FEV1, treatment difference 45 mL; p=0.028). Forced vital capacity (FVC) also significantly improved with IND/GLY (p=0.002). Patients switched to IND/GLY also had numerical improvements in transition dyspnoea index (TDI, 0.46; p=0.063). The proportion of patients with clinically important improvement in TDI (≥1 point; odds ratio [OR],1.27; confidence interval [CI], 0.81–1.97) were also higher in those switched to the dual bronchodilator therapy. [APSR 2017, abstract AOL011]
Previous head-to-head studies have shown the superiority of IND/GLY vs SFC in reducing pulmonary exacerbations in patients with moderate-to-severe COPD. [N Engl J Med 2016;374:2222-2234; Int J Chron Obstruct Pulmon Dis 2017;12:339-349] FLASH is the first randomized controlled study to demonstrate the benefits of directly switching from SFC to IND/GLY.
The study included 502 patients with moderate-to-severe COPD and daily symptoms, but infrequent exacerbations (<2 within 1 year), who were receiving SFC 50/500μg twice daily for >3 months. They were randomized in a 1:1 ratio to continue SFC or switch, without a washout, to IND/GLY 110/50μg once daily. The primary endpoint was pre-dose FEV1 at week12.
After 12 weeks of treatment, rescue medication use (-0.04 puffs/day; 95 percent CI, 0.20–0.13; p=0.662) and CAT scores (-0.4; 95 percent CI, -1.3–0.4; p=0.319) were comparable between IND/GLY and SFC. Both treatments were well tolerated with similar safety profile. Of note, the proportion of patients with exacerbations was lower with IND/GLY vs SFC (10.1 percent vs 13.2 percent) during the treatment period.
IND is a long-acting beta agonist (LABA) which relaxes and opens air passages in the lungs. Together with the antimuscarinic GLY, it works to ease breathlessness in patients with COPD such as chronic bronchitis and emphysema. The combined therapy is approved in 90 countries as a maintenance bronchodilator treatment to relieve COPD symptoms in adults.
What the current study adds to the current evidence is that directly switching from SFC to IND/GLY, which happens in everyday practice, also have some benefits.
Before starting these techniques, ask your Health Care Provider if they are right for you.
Having COPD makes it harder to breathe. And when it’s hard to breathe, it’s normal to get anxious, making you feel even more short of breath.
There are two breathing techniques that can help you get the air you need without working so hard to breathe: Pursed-lips Breathing and Diaphragmatic (also called Belly or Abdominal) Breathing.
Better Breathing Tip: It’s normal to hold your shoulders tense and high. Before starting any breathing technique, take a minute to drop your shoulders down, close your eyes, and relax.
- Slows your breathing down
- Keeps airways open longer so your lungs can get rid of more stale, trapped air
- Reduces the work of breathing
- Increases the amount of time you can exercise or perform an activity
- Improves the exchange of oxygen and carbon dioxide
To do purse-lips breathing:
- Breathe in through your nose (as if you are smelling something) for about 2 seconds.
- Pucker your lips like you’re getting ready to blow out candles on a birthday cake.
- Breathe out very slowly through pursed-lips, two to three times as long as you breathed in.
Diaphragmatic (Abdominal/Belly) Breathing
The diaphragm is the main muscle of breathing. It’s supposed to do most of the work. When you have COPD, the diaphragm doesn’t work as well and muscles in the neck, shoulders and back are used. These muscles don’t do much to move your air. Training your diaphragm to take over more “work of breathing” can help.
Diaphragmatic breathing is not as easy to do as pursed-lips breathing. It is recommended that you get instruction from a respiratory health care professional or physical therapist experienced in teaching it.
This technique is best used when you’re feeling rested and relaxed, and while sitting back or lying down.
- Relax your shoulders.
- Place one hand on your chest and the other on your belly.
- Inhale through your nose for about two seconds.
- As you breathe in, your belly should move outward. Your belly should move more than your chest.
- As you breathe out slowly through pursed-lips, gently press on your belly. This will push up on your diaphragm to help get your air out.
Better Breathing Tip: Stop, Reset, Continue
When you are feeling short of breath during exercise or regular activities, use these 3 steps:
- Stop your activity.
- Reset by sitting down, relax your shoulders, and do pursed-lips breathing until you catch your breath.
- Continue activity, doing pursed-lips breathing as you go. Go at a slower pace if you need to.
While you’re here, look over these topics to learn tips on how to live better with your COPD.+
Lung function is a heritable trait. Heritability estimates posit that approximately30%–50% of the phenotypic variation in FEV1 is explained by genetics,1–3 and genome-wide association studies (GWAS) of lung function4–11 have discovered multiple genetic variants that are associated with cross-sectional measurements in adults of FEV1, FVC and FEV1/FVC ratio at genome-wide significance levels. Many of these same loci have also been implicated in GWAS of COPD. Additional work is required to link these loci to pathophysiology. Functional studies on GWAS loci involving HHIP,12 ,13 FAM13A,14 HTR4,15 AGER16 and IREB217 have already provided important insights into the biological mechanisms for genetic determinants of COPD and/or lung function.
Longitudinal change in lung function (ΔFEV1, ΔFEV1/FVC) is also heritable,18 albeit perhaps to a lesser degree than cross-sectional lung function levels. Although studies of longitudinal lung function have discovered a few loci associated with ΔFEV1 at genome-wide significance levels, none were robust to replication in the available populations. While at first glance the genetic determinants of FEV1 level and ΔFEV1 might be expected to show significant overlap, a recent study of COPD by Lange et al19 and a complementary study in asthma by McGeachie et al20 have suggested that low maximum attained lung function and accelerated lung function decline are distinct processes that can exert independent effects on the risk for chronic airflow obstruction. Therefore, it would not be surprising if different genetic determinants influenced cross-sectional and longitudinal lung function change. Longitudinal measurements of lung function are highly informative for identifying these separate processes.
Former smokers have a higher risk of small cell lung cancer (SCLC), which, in some cases, is partially mediated by chronic obstructive pulmonary disease (COPD), according to a large, multinational study.
Compared to non-smokers, former and current smokers had a significantly higher risk of SCLC (odds ratio [OR], 6.21, 95 percent CI, 5.21-7.41 and OR, 26.72, 95 percent CI, 22.54-31.68, respectively; p<0.001).
Smokers who have COPD had a 1.86 times higher risk of SCLC (95 percent CI, 1.61-2.16; p<0.001) than smokers without COPD. Among former smokers, COPD indirectly mediated the risk of SCLC (OR, 1.03; p<0.001), though this only occurred in less than 10 percent of cases. [EBioMedicine 2015;doi:10.1016/j.ebiom.2015.09.031]
A longer period of cessation greatly reduced the risk of SCLC in a dose-response manner (OR, 0.57, 95 percent CI, 0.45-0.73 for individuals who had quit for 5-9 years versus OR, 0.11, 95 percent CI, 0.09-0.14; p<0.001 for those who had quit for more than 20 years).
Previous studies have shown that even after years of cessation, the risk of SCLC remains higher than that of non-smokers, which has been attributed to irreversible lung damage. [Resp Res 2013;14:97]
The association between COPD and overall lung cancer is well-established, and newer studies have demonstrated the link between cigarette smoking and concurrent COPD and NSCLC. [Ann Intern Med 1987;106:512-518; Int J Cancer 2014;134:961-970]
To investigate the impact of smoking and the specific role of COPD on SCLC risk, researchers analyzed data from 24 studies from the International Lung Cancer Consortium (ILCCO) that included 4,346 patients with SCLC and 37,942 without the disease.
According to the researchers, SCLC has a high mortality and relapse rate, which raises the need for preventive measures. This is the largest study investigating the link between multiple smoking risk factors, COPD and SCLC risk, as well as the first to look into COPD as a mediator between smoking and SCLC.
Study limitations include potential underdiagnosis of COPD leading to overestimation of smoking patterns. The use of corticosteroids or statins which improve COPD and reduce lung cancer risk may also have distorted the results. Researchers called for further investigation into the role of genetics and the pathways by which COPD, smoking and lung cancer are connected in order to enable early diagnosis of SCLC.
Smoking causes damage to the airways of the lungs. This video provides an overview of how the lungs work and the effects smoking can have on their bronchioles and alveoli, leading over time to chronic bronchitis and emphysema, collectively known as chronic obstructive pulmonary disease (COPD)..
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is associated with significant morbidity and disability caused by impaired pulmonary function and dyspnea. Nonrespiratory factors are implicated in the development of disability, with evidence to suggest that COPD is a systemic disease, rather than solely a pulmonary disease. The systemic nature of COPD results in the development of both physical and cognitive comorbidities.1Cognitive impairments were reported more than 15 years ago, with moderate-to-severe dysfunctions evident in 42% of patients with COPD compared with 19% of controls. Results from other studies suggest that as few as 12% and as many as 88% of patients with COPD experience cognitive impairments 2 that can manifest globally or in single cognitive domains.3
“Severity and duration of COPD are important factors that increase the risk of cognitive dysfunction,” says Balwinder Singh, MD, MS, research fellow in the Department of Neurology, Mayo Clinic, Rochester, Minn. “The risk of mild cognitive impairment (MCI) increases with a longer duration of COPD such that individuals who have COPD for more than 5 years have a 2.5-fold increased risk of developing nonamnestic MCI.”
A prospective study compared cognitive status in 3 groups of participants (N=110): the COPD-E group was awaiting discharge following hospitalization for an acute exacerbation of COPD; the COPD-S group included patients with stable COPD and no history of exacerbations in the previous 8 weeks; and age-matched healthy individuals recruited from the local community. Cognitive function in the 3 groups was compared to age-matched controls, population-derived normal values, and the patients’ own estimated premorbid level of cognitive function. Patients in the COPD-E group performed significantly worse on all cognitive measures when compared with healthy controls and had greater impairment on all but 3 cognitive tests compared with patients in the COPD-S group. Cognitive scores of patients in the COPD-E group were in the impaired range when compared to population norms, with the most significant deficits evident for Trail Making Test performance and visuospatial ability. Furthermore, 20% of those in the exacerbation group had evidence of a pathologic loss of cognitive processing speed; there was no evidence of diminished processing speed or working memory among patients in the COPD-S group, however. Patients in the COPD-E and COPD-S groups completed follow-up assessments 3 months after their initial evaluations, and there was no evidence of improvement in cognitive function in the COPD-E group. More severe cognitive deficits in the COPD-E group were significantly correlated with greater impairment of health status and hospital stays. 4
An observational, prospective, population-based study compared different domains of cognitive abilities between individuals affected and unaffected by obstructive lung disease (OLD). 3 Complete data on cognitive functioning and spirometry were available for all participants. Those with a fixed ratio of forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) <0.70 were classified with OLD (13.4%); the comparison group had FEV1/FVC ≥0.70. After adjustment for confounders, significantly greater cognitive deficits were evident for individuals with OLD in prospective memory, visuospatial memory, numeric short-term memory, and cognitive processing speed. 3
Many factors are implicated in the etiology of cognitive impairments associated with COPD, including brain damage, decreased levels of physical activity, and exacerbations. 2 An evaluation of hippocampal volumes and performance on the Mini-Mental State Exam (MMSE) in patients with COPD of varying severity revealed significantly lower MMSE scores in patients with mild-to-moderate and severe COPD compared with healthy controls (P<.01 for both comparisons). MMSE scores were also significantly lower for patients with severe COPD compared with those who had mild-to-moderate disease. 5 Hippocampal atrophy was evident on magnetic resonance imaging, with significantly smaller right and left hippocampal volumes detected in patients with mild-to-moderate and severe COPD (P<.01 for both right and left sides in both COPD severity groups).
When asked about factors that might contribute to the development of cognitive dysfunction in patients with COPD, Fiona Cleutjens, researcher at the Centre of Expertise for Chronic Organ Failure in the Netherlands, said, “In recent years, the literature on cognitive functioning in COPD has postulated several causes for cognitive impairment, including brain damage, smoking, inflammation, alveolar hypoxia and consequent hypoxemia, hypercapnia, atherosclerosis, reduced physical activity, and exacerbations.”
“The variance in cognitive impairment in COPD,” she added, “could also be explained by comorbid conditions such as obstructive sleep apnea syndrome and major depressive disorders, which also decrease cognitive performance.”
Patients with COPD and cognitive impairments appear to be vulnerable to deficits in memory, attention, and concentration, which may result in a decreased ability to perform activities of daily living. For example, the loss of executive function skills may trigger improper use of inhaled medications, problems with the management of comorbidities, and negative effects on efforts to stop smoking. Deficits in verbal memory may contribute to poor medication adherence. Importantly, patients with COPD and comorbid cognitive dysfunction have a higher frequency and longer duration of hospitalizations, and they also experience higher mortality rates compared with those who have better cognitive performance. 2
“It’s important to regularly assess cognitive function among people who have COPD. Look for cognitive problems, particularly in attention, planning, and executive function,” says Dr. Singh.
“Don’t take cognitive symptoms lightly,” he adds. “Act early.”
To reduce limitations in their daily lives, patients with COPD and cognitive impairments may benefit from interventions that address smoking cessation, environmental adaptations, social support, and the development of coping and self-management skills.
- Mild-to-moderate and severe cognitive impairments affect many patients with COPD, with deficits reported in prospective memory, visuospatial memory, numeric short-term memory, cognitive processing speed, executive function, and verbal memory.
- To reduce limitations in their daily lives, patients may benefit from early and aggressive treatment of COPD, regular assessment of cognitive function, interventions to promote smoking cessation, environmental adaptations, and the development of coping and self-management skills.