Abstract: Smoking cessation is still the most important intervention in patients with chronic obstructive pulmonary disease (COPD), regardless of sex. There is some evidence that nicotine replacement therapy may be less effective in women than in men. However, women may derive greater benefits from a sustained quit attempt. For example, one study found that compared with men, women who were sustained quitters had a greater initial rise and a slower age-related decline in forced expiratory volume in 1 second. Men and women do not appear to differ in their response to bupropion or to the various types of bronchodilators. A number of factors contribute to the increased risk of osteoporosis in women with COPD. Both smoking and the degree of airflow obstruction have been identified as important risk factors for osteoporosis. Women may be particularly susceptible to the effects of smoking on bone metabolism. Immobility and decreased physical activity have also been shown to accelerate bone loss. (J Respir Dis. 2006;27(3):115-122)
As the popularity of smoking has increased in women, so has the incidence of chronic obstructive pulmonary disease (COPD). Anatomic differences and increased bronchial hyperreactivity may predispose women to symptomatic airways obstruction, and although controversial, some data suggest that women may be more susceptible than men to COPD. As the number of COPD-related hospitalizations and deaths in women continues to rise, health care providers must be aware of the unique challenges that face women with this disease.
In the February 2006 issue of The Journal of Respiratory Diseases, we reviewed the epidemiology of COPD and sex differences in COPD pathophysiology. In this article, we will address management issues. We also will discuss the risk of osteoporosis in women with COPD.
To date, only one intervention has been shown to change the natural history of COPD: smoking cessation. All other therapies, such as bronchodilators, provide only relief of symptoms. Investigations are under way to determine whether other therapies, such as inhaled corticosteroids, inhaled long-acting bronchodilators, and phosphodiesterase E4 inhibitors, may alter the course of COPD by slowing the rate of decline of forced expiratory volume in 1 second (FEV1), possibly reducing mortality.
In one review, Perkins1 concluded that nicotine replacement therapy was less effective in women than in men. This conclusion was based on a meta-analysis of 3 nicotine patch trials involving 632 persons, which revealed that women's cessation rates were significantly lower than those of men.2
The Lung Health Study, which used nicotine gum, found that male sex predicted successful cessation at 36 months (odds ratio [OR], 1.24), but not at 12 months.3 This may suggest that women are more likely to be "late relapsers." Compared with men, women have a flattened nicotine dose-response curve.4 They seem to benefit less from nicotine replacement therapy, and they may experience less physiologic addiction and greater behavioral dependence; as a result, they might benefit more from behavioral counseling.5
In contrast, bupropion appears to be equally effective in men and women.6 This may be related to some of the unique issues that women face when they attempt to quit smoking; these include weight gain, tension, and irritability, which vary with the menstrual cycle.7 As a result, women may perceive more barriers to smoking cessation than men. It has been suggested that women should plan their quit attempt to occur during the follicular phase rather than the late luteal (premenstrual) phase.7
Bupropion reduces the amount of weight gained with a quit attempt. However, its benefit is short-lived--after the 2-week course of bupropion, the weight gain begins. Women participating in the Lung Health Study gained more weight after a smoking cessation attempt than the men did. In the first year, women gained an average of 5.2 kg, compared with 4.9 kg in men. Among the sustained quitters, women gained 4.9 kg and men gained 3.4 kg more than the group initiating an attempt.
Despite the increased barriers that women face with a smoking cessation attempt, they appear to derive greater benefits from a sustained quit attempt.8 Connett and coworkers8 showed that the women in the Lung Health Study who were sustained quitters had a greater initial rise and a slower age-related decline in FEV1 than men (Figure 1).
As a result of the challenges that many women face with a smoking cessation attempt, a program that uses bupropion as the first-line pharmacotherapy and includes intensive counseling may be especially helpful.
The data on sex differences in response to bronchodilators are difficult to interpret because of the smaller lungs of women. Few bronchodilator trials have published data stratified by sex, and such data often are not corrected for percent of predicted FEV1. Lima and coworkers9 demonstrated this in a study of response to oral albuterol (Figure 2). Although the FEV1 response of men was twice that of women, the change in percent of predicted FEV1 was equivalent.9
One study10 showed that men and women with COPD had equivalent responses to the combination of fluticasone (250 µg) and salmeterol (50 µg) when the response was measured by milliliters of FEV1, but the analysis did not correct for percent of predicted FEV1. Vestbo and colleagues11 evaluated the efficacy of fluticasone (500 µg) and salmeterol (50 µg) in a similar population of COPD patients stratified by sex. The data were not corrected for percent of predicted FEV1; however, the 127-mL increase in FEV1 that women derived from therapy was 15% of their baseline FEV1, while the 152-mL increase achieved by men was only 9% of their baseline FEV1.11 There was no significant difference between men and women in the rate of exacerbations of COPD.
The available data show no difference between men and women in response to tiotropium, salmeterol, or ipratropium.12
Most COPD medications are given via inhalation. Technique when using metered-dose inhalers has been reported to be poor among both men and women, but it is generally worse in women.13 Goodman and coworkers13 evaluated 59 persons (26 women and 33 men) and found that only 25% of all inhalation maneuvers met acceptable criteria. When maneuver acceptability was stratified by sex, only 4% of women's inhalation maneuvers met acceptability criteria, compared with 43% in men (P < .001).
Inhaler technique can be improved with teaching; however, studies have shown that good inhaler technique must be periodically reinforced.14
The Global Initiative for Chronic Obstructive Lung Disease guidelines recommend pulmonary rehabilitation for all patients with moderate to severe COPD.15 Studies suggest that men benefit more than women from extended rehabilitation programs. In a study of 118 persons, the benefit derived from a rehabilitation program was measured by the Chronic Bronchitis Respiratory Questionnaire. The results indicated that men improved at 3 months and incrementally more at 18 months; in contrast, women improved at 3 months, and that improvement was sustained but not incrementally better at 18 months.16 Frey17 found that men tended to participate longer in pulmonary rehabilitation programs than women (median of 20 vs 4 months, respectively).
Women are at higher risk than men for osteoporosis,18 and clinicians should be particularly aware of this when considering the long-term management of COPD in women. However, men and women share many excess risks for smoking- related diseases, such as osteoporosis, cancer, cardiovascular disease, and COPD.19 In turn, persons with COPD have several risk factors that may predispose them to accelerated bone loss and osteoporosis.20
Although the exact mechanism for the increased risk of osteoporosis in adults with COPD has not been identified, several factors probably contribute. These may include the direct effects of smoking on bone metabolism, hypogonadism and premature menopause, vitamin D deficiency, low body mass index, immobility, and long-term corticosteroid use.20
Osteoporosis is characterized by compromised bone strength that predisposes a person to fractures.18 The World Health Organization defines osteoporosis as a bone mineral density (BMD) of more than 2.5 SDs below the mean for young white women (T score, below 2.5). Osteopenia is defined as a BMD of 1 to 2.5 SDs below the mean (T score, 21 to 22.5). Osteopenia has been reported in 35% to 72% of patients with COPD, and as many as 36% to 60% of patients with COPD have osteoporosis.21,22
As expected, the rate of osteoporosis in women with COPD has been found to be higher than that in men with COPD.21 Incalzi and associates21 reported osteoporosis in 69% of women with COPD and 54% of men with COPD.
Osteoporosis and airflow obstruction
The degree of airflow obstruction has been identified as an important risk factor for osteoporosis. Using data from NHANES III, Sin and colleagues23 established that in both men and women, the prevalence of osteopenia and osteoporosis increased linearly with the degree of airflow obstruction. Osteoporosis was found in 11% of men and 33% of women with severe airflow obstruction (FEV1 less than 50% of predicted), compared with 3.9% of men and 10.3% of women with mild airflow obstruction (FEV1 of 80% of predicted). The presence of any degree of airflow obstruction increased the risk of osteoporosis by nearly 2-fold compared with the absence of airflow obstruction (OR, 1.9).
Iqbal and associates24 showed that men with obstructive lung disease who had not been exposed to corticosteroids had reduced vertebral and hip BMD compared with men without evidence of obstructive lung disease. However, Riancho and associates25 failed to show any significant difference in vertebral deformity score or metacarpal indices between those with COPD and those without COPD.
Effects of smoking on bone metabolism
Smoking has been shown to be an independent risk factor for osteoporosis in both men and women.20 Slemenda and colleagues26 reported that the lumbar vertebral BMD was 12% lower in smokers who had a greater than 20-pack-year history, compared with nonsmokers. In a group of COPD patients awaiting lung transplantation, Shane and coworkers22 found that the average T score fell within the osteoporotic range (22.7 ± 0.3).
Although the exact mechanisms responsible for lower BMD in smokers remain unclear, some effects of smoking on bone metabolism seem to be mediated by alterations in calcium and vitamin D metabolism.27 Lower serum calcitriol and parathyroid hormone levels in smokers result in decreased absorption of calcium and accelerated bone loss. In one series, 20% of patients with COPD awaiting lung transplantation were found to have vitamin D deficiency (25- hydroxyvitamin D levels of 10 ng/mL).22 However, the levels of 25-hydroxyvitamin D did not correlate with BMD.
Women may be particularly susceptible to the effects of smoking on bone metabolism, since the deleterious effects of smoking on bone appear to be mediated partly through an estrogen-lowering effect. Through increased hepatic metabolism of estrogen28 and increased production of sex hormone-binding globulin,29 cigarette smoking results in decreased concentrations of biologically active estrogens and, in turn, predisposes women to osteoporosis.18
Smoking has also been shown to affect normal ovarian function. Women who smoke are more likely to have irregular menses and to have anovulatory cycles.30 These effects have been shown to decrease fertility in women and may result in premature menopause, which increases the risk of osteoporosis.19
Other mechanisms may explain the increased risk of osteoporosis in female smokers. Long-term smoking in postmenopausal women has been shown to increase serum cortisol levels, resulting in effects similar to those of hypercortisolism on bone.31 In addition, smoking has been shown to increase serum concentrations of the adrenal androgens androstenedione and dehydroepiandrosterone, which may enhance its antiestrogenic effects.
Effects of immobility
Immobility and decreased physical activity have been shown to accelerate bone loss resulting in decreased BMD, and advanced COPD is often associated with decreased physical activity and functional status.20 Gregg and associates32 showed that physical activity in community-dwelling women reduced the risk of hip fracture.
Similarly, Cummings and associates33 showed that decreased functional status, such as the inability to rise from a chair without using one's arms, was associated with an increased risk of hip fracture. McSweeny and colleagues34 showed that patients with COPD and chronic hypoxemia (PaO2 less than 60 mm Hg) reported an approximate 25% impairment in mobility and ability to ambulate.
Effects of corticosteroids on bone
The importance of corticosteroid-induced osteoporosis is widely recognized, and careful consideration of this complication in patients with chronic underlying lung disease should be the norm. In one meta-analysis, van Staa and coworkers35 concluded that there was a strong correlation between daily doses of corticosteroids and risk of fracture and between cumulative doses and loss of BMD, which appeared to be independent of underlying disease, age, and sex. The risk of fracture increased within 3 to 6 months of initiating therapy in daily doses exceeding 5 mg of prednisolone (or equivalent).
In a group of 117 adults who were taking oral corticosteroids for chronic lung disease,36 the presence of vertebral fracture was strongly related to cumulative prednisolone dose and seemed to be independent of any corticosteroid-mediated reductions of BMD. The cumulative prednisolone doses ranged from 3.4 to 175 g, with a linear association between dose quartiles and vertebral fracture (OR, 4.4 between the highest and lowest quartiles of 47 to 175 g and 3 to 12 g, respectively).
The effects of inhaled corticosteroids on bone have not been as clearly determined, and 2 reviews have reached different conclusions. Leone and colleagues37 concluded that inhaled corticosteroids generally do not cause a significant reduction in BMD in adults with asthma, but they noted that the effects may become more clinically apparent in patients receiving high doses for an extended period. In contrast, Richy and coworkers38 concluded that all inhaled corticosteroids affect bone metabolism and BMD in adults with asthma or COPD.
Two studies looked specifically at the effects of inhaled corticosteroids in patients with COPD. In a randomized prospective study of 359 patients, the Lung Health Study Research Group39 showed a 2% ± 0.35% loss in BMD of the femoral neck in patients using inhaled triamcinolone (1200 µg/d), compared with a 0.22% ± 0.32% loss in patients receiving placebo (P < .001). However, a similar prospective trial of 286 patients with COPD who were randomly assigned to inhaled budesonide (800 µg/d) or placebo failed to show a significant effect on BMD after 3 years.40
Data from the United Kingdom General Practice Research Database have shown that inhaled corticosteroid use is associated with an increased risk of fracture. In a case-control analysis of 16,341 patients with hip fractures and 29,889 controls, the risk of hip fracture was associated with exposure to inhaled corticosteroids (OR, 1.19).41
Using the same database, van Staa and associates42 compared the risk of fractures in 170,818 inhaled corticosteroid users, 108,786 bronchodilator users, and 170,818 controls. They showed a relative risk of hip, vertebral, and all nonvertebral fractures of 1.22, 1.51, and 1.15, respectively, in inhaled corticosteroid users compared with controls. There was no difference between inhaled corticosteroid users and bronchodilator users, so the authors concluded that the increased risk of fractures in these groups may be related more to the underlying respiratory disease than to inhaled corticosteroid use.
Baseline and follow-up BMD scans are recommended for women with COPD. In those who do not have evidence of osteoporosis or osteopenia, exercise and calcium and vitamin D supplements are recommended. Postmenopausal women with established osteoporosis or osteopenia are candidates for bisphosphonates, a selective estrogen receptor modulator, estrogen, or calcitonin.
In conclusion, smoking cessation is critical for all smokers who have COPD or osteoporosis/osteopenia. The use of systemic corticosteroids should be avoided, as much as possible, in patients with osteoporosis or osteopenia.
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