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COPD and Osteoporosis^*

^* From the Virginia Commonwealth University, Medical College of Virginia, Richmond, VA.

Correspondence to: Diane M. Biskobing, MD, 1101 East Marshall St, PO Box 980111, Richmond, VA 23298; e-mail: dmbiskob{at}hsc.vcu.edu

	Abstract

TOP Abstract Introduction Frequency of Osteoporosis in... Pathophysiology of Osteoporosis... Prevention and Treatment Recommendations and Summary References

 
Osteoporosis, with resulting fractures, is a significant problem in patients with advanced COPD. The etiology for the bone loss is diverse but includes smoking, vitamin D deficiency, low body mass index, hypogonadism, sedentary lifestyle, and use of glucocorticoids. Effective strategies to prevent bone loss and/or to treat osteoporosis include calcium and vitamin D, hormone replacement when indicated, calcitonin, and bisphosphonate administration. However, many patients remain undiagnosed until their first fracture because of the lack of recognition of the disease. With an increased awareness by pulmonologists and the increased use of preventive strategies, the impact of osteoporosis on those patients with COPD should decrease.

Key Words: COPD • fracture • glucocorticoids • osteoporosis

	Introduction

TOP Abstract Introduction Frequency of Osteoporosis in... Pathophysiology of Osteoporosis... Prevention and Treatment Recommendations and Summary References

 
In the care of patients with COPD, the primary focus of the physician is respiratory function. However, as COPD progresses and the patient becomes more debilitated, osteoporosis is a common finding.^{1 2 3} With progressive loss of bone mass, the patient is at high risk for vertebral or hip fractures. Fractures cause significant morbidity such as pain, worsened respiratory function, decreased mobility, and even mortality.^{4 5 6 7} While fractures occur more often in patients with advanced COPD,⁸ recognition of the problem early in the course of lung disease should occur so that preventive measures can be instituted before fractures develop.

	Frequency of Osteoporosis in COPD

TOP Abstract Introduction Frequency of Osteoporosis in... Pathophysiology of Osteoporosis... Prevention and Treatment Recommendations and Summary References

 
Low Bone Mineral Density
Osteoporosis is characterized by low bone mass accompanied by microarchitectural changes in bone that increase the susceptibility to fracture.^{9 10} The World Health Organization definition for osteoporosis is based on the measurement of bone mineral density (BMD).¹¹ Osteopenia is defined as a BMD between 1 and 2.5 SDs below the mean for young adults (ie, the T score), while osteoporosis is defined as a BMD of > 2.5 SDs below the mean for young adults.¹¹ This definition was developed for white postmenopausal women but appears to be valid in men as well.¹²

As many as 35 to 72% of patients with COPD have been reported to be osteopenic, and 36 to 60% of patients with COPD have osteoporosis.^{1 2 3} As the severity of COPD progresses, the proportion of patients with osteoporosis increases.^{2 8} Those patients requiring oral glucocorticoid therapy have lower T scores and more fractures than those treated with bronchodilators only.^{2 8} Patients receiving oral glucocorticoid therapy (average [± SD] cumulative dose, 19.5 ± 24.8 g) have been found to have a 1.8-fold (95% confidence interval [CI], 1.08 to 3.07) increased incidence of one or more vertebral fractures.⁸ However, glucocorticoid use does not fully account for the low BMD in these patients. Praet et al¹³ studied BMD in men with chronic bronchitis. Vertebral BMD in the study population was lower than that in age-matched control subjects. Patients were divided into the following two groups: those who had been receiving long-term oral glucocorticoid therapy for at least 1-year, with an average cumulative dose of prednisolone of 11,388 mg; and those who were currently receiving bronchodilator therapy only. In patients receiving chronic oral glucocorticoid therapy, the lumbar spine BMD was 1.4 SDs below that of age-matched control subjects (z score, -1.4; p < 0.01), while in those patients with no current exposure to glucocorticoids the z score was -1.0 (p < 0.05). However, the results are confounded by the fact that some of the bronchodilator patients had received intermittent oral corticosteroid therapy in the past. The cumulative dose of corticosteroids or the percentage of patients who previously had been exposed to corticosteroids was not given. Preliminary data from a more recent study by del Pino-Montes et al¹⁴ reported that both hip and spine BMDs were significantly lower in a group of men with COPD without prior exposure to glucocorticoids compared to age-matched control subjects. The z score for BMD at the lumbar spine was -1.27 ± 0.29 in the group with COPD compared with -0.34 ± 0.25 in the control group (p < 0.01). In a group of male subjects at a Veterans Affairs medical center,² subjects with chronic lung disease, regardless of treatment, were five times more likely to have osteoporosis than were control patients with hypertension. This increased risk was seen in subjects with no previous exposure to oral or inhaled corticosteroids. Subjects with more severe compromise in lung function requiring inhaled glucocorticoids (FEV₁, 59 ± 3.7%) or oral glucocorticoids (FEV₁, 50.6 ± 2.8%) had a ninefold (95% CI, 1.8 to 44) increased risk of osteoporosis compared to the control group. Interestingly, the risk did not differ between inhaled glucocorticoid users (cumulative steroid dose, 430 ± 70 mg prednisone per 4 years) vs oral glucocorticoid users (cumulative steroid dose, 4,121 ± 617 mg prednisone per 4 years).² A recent study³ of 104 consecutive patients admitted to the hospital for a COPD exacerbation revealed a prevalence of osteoporosis of 60%. Of the patients with osteoporosis, 60% were men. The majority of patients (79%) with osteoporosis had received inhaled glucocorticoids for at least 4 months, and 45% had received oral glucocorticoids for at least 4 months.³

Decreased BMD has been reported with therapy using both inhaled and oral corticosteroids. Oral corticosteroid use is a well-documented cause of bone loss.^{15 16 17} The more contentious issue is whether therapy with inhaled steroids induces bone loss. An evaluation of this issue, specifically in patients with COPD, is difficult since most of the studies have been performed in asthmatic patients. There are two large studies of inhaled steroid use in COPD patients. A recent randomized, prospective, 3-year study¹⁸ in 359 patients with COPD showed a 2 ± 0.35% loss in femoral neck BMD with therapy using inhaled triamcinolone (1,200 µg/d) compared to a 0.22 ± 0.32% loss in those patients receiving placebo (p < 0.001). However, another large study failed to find a significant effect on BMD. In a prospective study of 286 patients with COPD who were randomized to inhaled budesonide (800 µg/d) or placebo, Pauwels et al¹⁹ reported no significant change in BMD in either group after 3 years. The remainder of the studies on the effect of inhaled glucocorticoid therapy on BMD have been performed in asthmatic patients.²⁰ Several retrospective case control studies have reported decreased BMD in inhaled steroid users compared to control subjects.^{21 22 23 24} Two of these studies^{25 26} have suggested a dose-dependent decrease in BMD. However, these results are confounded by the past use of oral glucocorticoids in many of the patients. There are also numerous studies^{27 28 29 30 31} showing no significant loss in BMD in asthmatic patients receiving inhaled glucocorticoids (see Table 1 for details of the studies in both asthmatic patients and COPD patients, with information on the type of inhaled glucocorticoid, doses, and duration of use). An interpretation of the results is difficult because of differences in the inhaled steroid used, the doses of the inhaled steroids, the type of inhalation devices, and the duration of use. In summary, inhaled glucocorticoid therapy appears to have less effect on BMD than does oral administration. Short-term use (ie, 1 to 2 years) of low-dose inhaled steroids appears to have a minimal effect on bone. However, retrospective studies^{22 24 25} and a recent prospective study¹⁸ suggest that the long-term use of high-dose inhaled steroids may be associated with bone loss and decreased BMD.

Vertebral fractures are common in patients with COPD. In a study of patients awaiting lung transplantation,¹ the prevalence rate was 29%. Another study⁸ of patients with COPD revealed a prevalence of vertebral fractures of 49% in those who had never received any glucocorticoids to as high as 63% in those patients receiving systemic glucocorticoid therapy. Thoracic vertebral fractures were more common than lumbar fractures in all patients. Multiple fractures were more common in the systemic steroid users. A study¹⁹ of patients with mild COPD (ie, FEV₁, 2.54 L [77% of predicted]; FEV₁/slow vital capacity ratio, 62%) with no history of glucocorticoid use reported vertebral fractures in 12.4% of patients. However, another group reported³³ no increase in vertebral fractures in patients with COPD who did not have a history of long-term glucocorticoid use. The prevalence of vertebral fractures in a retrospective cohort study³⁴ was found to be increased in all users of oral glucocorticoids, with a relative risk of 2.6 (95% CI, 2.31 to 2.92) compared to control subjects. In a similar study, the same group recently reported³⁵ a relative risk for vertebral fractures of 2.5 (95% CI, 1.63–2.92) in users of high-dose (ie, > 700 µg/d beclomethasone) inhaled corticosteroids compared to control subjects. However, the risk was not increased compared to users of bronchodilators, suggesting that the increased risk is more related to the underlying lung disease than to the treatment.

Vertebral fractures can be asymptomatic and, when they occur, may seem of little significance. However, both symptomatic and asymptomatic vertebral fractures can cause significant morbidity due to back pain and decreased functional performance.^{36 37} This pain can be distressing to the patient who is already struggling to breathe. Additionally, progressive kyphosis due to thoracic vertebral fractures may decrease lung volume, causing a restrictive ventilatory defect.^{6 38} In a group of nine nonsmokers with severe kyphoscoliosis, FVC was 29% of predicted and total lung capacity was 44% of predicted, although the FEV₁/FVC ratio was within normal limits.⁷ In addition, respiratory muscle function was significantly impaired.⁷ In a study of 74 women with osteoporosis, each thoracic vertebral fracture decreased FVC by approximately 9%.⁶ Another study³⁸ looked at lung volumes in 15 women with osteoporosis compared to those in 15 healthy women of the same age. Vital capacity, total lung capacity, and inspiratory capacity were all significantly decreased in the women with osteoporosis (p < 0.05). Lateral and vertical rib expansion was also significantly decreased.³⁸ While these changes in lung volumes may have less effect on someone with normal lung function, the effect on someone with COPD may be significant. Furthermore, the relative risk of death has been found to be increased after vertebral fractures in two separate studies.^{39 40} There are currently no studies that have specifically looked at the consequences of vertebral fractures in patients with COPD.

Hip fractures are the most serious consequence of osteoporosis. The risk for hip fracture varies inversely with BMD and also increases with the presence of one or more chronic conditions.⁴¹ Even the use of inhaled corticosteroids increases the risk for hip fracture, with a relative risk of 1.22 (95% CI, 1.04 to 1.43) compared to a control population.³⁵ A dose response was demonstrated with the increased relative risk of 1.77 (95% CI, 1.31 to 2.4) seen in those receiving high-dose (ie, > 700 µg/d beclomethasone) inhaled corticosteroid therapy.³⁵ Hip fracture rates have not been specifically reported in those patients with COPD who are receiving oral corticosteroids but have been evaluated in users of oral corticosteroids for all reasons. The relative risk of hip fracture was found to be 1.61 (95% CI, 1.47 to 1.76) in a retrospective cohort study³⁴ comparing all users of oral corticosteroids to subjects in a control group who had used topical steroids. The risk increased with increasing doses of corticosteroids. Those patients receiving a relatively low dose of prednisone (ie, 2.5 to 7.5 mg/d) had a 1.77-fold increased risk of fractures (95% CI, 1.55 to 2.02), and those patients receiving > 7.5 mg/d prednisone had a 2.27-fold increased risk (95% CI, 1.94 to 2.66).³⁴ Hip fractures have significant morbidity, often resulting in decreased mobility and independence for the patient.⁴² In the severely dyspneic COPD patient, further loss of mobility after a hip fracture may lead to increased dependence on the caretaker. Up to 35% of previously independent-living patients require nursing-home care after hip fractures due to the loss of independence.^{5 42} There is an increased mortality rate after hip fractures as well. The overall in-hospital mortality rate after a hip fracture for patients who are > 65 years of age is reported to be 4.9%.³² As the number of other medical diagnoses increases, the in-hospital mortality rate increases as well.³² Studies in the United States⁴ and Switzerland⁵ of patients in the first year after a hip fracture have reported mortality rates of 17 to 21% in women and 34 to 35% in men compared to mortality rates of 4 to 5% and 5.1 to 8%, respectively, for all-cause mortality. The rate of hip fractures and mortality has not been specifically studied in COPD patients.

	Pathophysiology of Osteoporosis in COPD

TOP Abstract Introduction Frequency of Osteoporosis in... Pathophysiology of Osteoporosis... Prevention and Treatment Recommendations and Summary References

 
There are numerous risk factors that contribute to the pathophysiology of osteoporosis seen in COPD patients. These risk factors include smoking, vitamin D deficiency, low body mass index (BMI), hypogonadism, and decreased mobility as the disease progresses (Table 2 ). In addition to these risk factors, glucocorticoid use in many patients with COPD is thought to be a contributing factor in the development of osteoporosis. However, since osteoporosis has been reported in COPD patients who have no history of corticosteroid use,^{2 13 14} the other risk factors must also play a significant role in the progression of the disease.

The combination of tobacco and alcohol use markedly increases the risk for osteoporosis. Alcohol use has been shown to be independently related to bone loss in a dose-dependent manner (ie, greater rates of bone loss are seen in those persons who consume higher amounts of alcohol).⁴⁸ Slemenda et al⁴⁸ have demonstrated the highest rate of bone loss in those patients with high alcohol and tobacco use. Vertebral fracture risk is markedly increased in those who both smoke and drink alcohol, and magnifies the aging-related risk. In nonobese smokers and drinkers aged 60 to 69 years, the relative risk for vertebral fracture was 3, and in those aged 70 years, the relative risk increased to 20.2.⁴³

Vitamin D Deficiency
Vitamin D plays a vital role in the normal mineralization of the bone matrix.⁵¹ Vitamin D deficiency, which may lead to decreased mineralization of bone and contribute to decreased BMD,^{52 53} appears to contribute to the declining BMD that is associated with COPD. Riancho et al³³ reported significantly decreased 25-hydroxyvitamin D levels in a group of men with COPD who were not receiving long-term glucocorticoid therapy compared to control subjects of a similar age. The authors documented a correlation between sun exposure and the 25-hydroxyvitamin D level. In another group of patients with severe lung disease who were awaiting lung transplantation, 35% of the COPD patients had markedly low 25-hydroxyvitamin D levels (ie, 10 ng/mL).¹ Thus, vitamin D deficiency may contribute to the decreased BMD associated with COPD due to less sun exposure and poor nutrition as a result of decreased functional status.

BMI
Bone mass is directly correlated with BMI.^{9 54} Both men and women with high BMIs have higher BMD. This is thought to be partially due to the effect of the greater weight-bearing load on the bone.⁵⁵ In addition, estrogen levels tend to be higher in obese people due to the increased aromatization of testosterone to estrogen in adipose tissue.⁵⁵ The resulting higher estradiol levels may help to explain the higher BMD in obese persons, since estradiol levels in both men and women correlate with BMD.^{56 57} Malnutrition, as well, may contribute to the low BMD associated with low BMI, as demonstrated in a recent study of otherwise healthy subjects.⁵⁸ Many patients with end-stage COPD lose weight as the disease progresses due to decreased intake and increased energy requirements.⁵⁹ Iqbal et al² reported that the lowest BMD was seen in a group of patients with BMI below the normal median and reported an independent correlation between BMI and BMD (r = 0.34; p < 0.05). Another recent study³ of osteoporosis in COPD found that BMI was the strongest predictor of osteoporosis, with a BMI 22 having an odds ratio of 4.18 (95% CI, 1.19 to 14.71).

Hypogonadism
Hypogonadism is a significant cause of osteoporosis. Chronic illness as well as glucocorticoid therapy can cause hypogonadism in both men and women.^{60 61} Studies^{62 63 64} of healthy young men treated with high-dose glucocorticoids have demonstrated up to a 47% suppression of testosterone levels. The mechanism for the hypogonadism is an effect of corticosteroids on both the pituitary gland and the gonads. Corticosteroid use decreases gonadotropin (ie, leutenizing hormone and follicle-stimulating hormone) secretion from the pituitary gland.^{60 61 65} In addition, there is a direct effect of glucocorticoids to decrease estrogen and testosterone production in response to gonadotropins.⁶⁶ The combination of these effects results in hypogonadism. If left untreated, this will contribute to accelerated bone resorption as well.

Immobility and Decreased Muscle Strength
Normal weight-bearing activity has been shown to be required for maintenance of bone mass. Complete immobilization such as in paralysis or in experimental settings has been shown to accelerate bone turnover, resulting in decreased BMD.^{67 68} Most patients with COPD are not completely immobilized; however, advanced COPD often is associated with decreased functional status and mobility.^{69 70} The decreased exercise tolerance is due to multiple factors, including dyspnea and deconditioning due to respiratory and peripheral skeletal muscle weakness.⁷⁰ The decreased activity and muscle strength may increase their risk for falls and fractures since several studies^{49 71 72} have demonstrated an inverse correlation between hip fracture risk and activity level. Decreased activities such as standing, walking, stair climbing, and housework, as well as decreased grip strength and ability to rise from a chair, have been shown to be associated with a significantly increased risk for hip fracture in postmenopausal women.^{49 71 72}

Glucocorticoids
Glucocorticoid-induced osteoporosis is well-documented in the literature.^{15 16 17 20 73} Patients placed on high-dose glucocorticoid therapy exhibit a rapid loss of BMD within the first 6 months.^{62 74} Normal bone metabolism is a result of the equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts.^{10 75 76} The mechanism of bone loss induced by glucocorticoids is twofold, with decreased bone formation and increased bone resorption (Table 3 ).

The accelerated bone resorption seen with glucocorticoid therapy appears to be due to secondary hyperparathyroidism.^{60 61 77} Glucocorticoids decrease intestinal calcium absorption and increase urinary calcium excretion, causing a rise in parathyroid hormone levels, which stimulates bone resorption. The elevation in parathyroid hormone level activates osteoclasts and accelerates bone resorption.^{60 61 77} In vitro evidence⁸³ also has suggested that glucocorticoid therapy stimulates osteoclast differentiation through direct effects on the osteoblast. After exposure to glucocorticoids, the expression of osteoclast differentiating factor by the osteoblast is increased while the expression of osteoprotegerin, a cytokine that inhibits osteoclast differentiation, is decreased.⁸³ This change in expression of these two modulators of osteoclast differentiation results in increased osteoclast formation and potentially increased bone resorption.

	Prevention and Treatment

TOP Abstract Introduction Frequency of Osteoporosis in... Pathophysiology of Osteoporosis... Prevention and Treatment Recommendations and Summary References

 
The prevention of osteoporosis in COPD patients is dependent on an awareness of the magnitude of the problem. There is little impetus for screening and/or preventive therapy because patients are generally asymptomatic until they experience a fracture. However, early recognition and the institution of preventive therapy are essential in avoiding fractures. Patients who are being started on long-term inhaled or oral glucocorticoid therapy should be considered for preventive therapy since steroid-induced bone loss occurs very early in the course of treatment.

Some have suggested² that all patients with COPD should be screened with measurements of BMD. There is evidence to support this recommendation. The prevalence of osteoporosis in men and women with COPD,^{1 2} irrespective of treatment, is similar to that in postmenopausal women.⁸⁴ If up to half of all COPD patients have decreased bone mass, then the screening of all patients to identify those who are at high risk for fractures would be indicated.

Nonpharmacologic Therapies
Nonpharmacologic therapies such as physical therapy can be beneficial in the prevention of falls and fractures in patients with osteoporosis.⁸⁵ Patients with COPD have been shown to have decreased activity levels due to muscle weakness and deconditioning.⁷⁰ To reverse the decreased muscle strength and instability, which is manifested by the inability to rise from a chair, slow gait speed, decreased grip strength, and increased risk for hip fracture,^{49 72} a physical therapy program should be designed to increase exercise endurance, muscle strength, and balance. This will not only improve the quality of life and functional status but also will decrease the risk for falls and subsequent fractures.^{70 86}

Calcium and Vitamin D
Calcium and vitamin D supplementation have been shown in some, but not all, studies to be beneficial in patients receiving long-term corticosteroid therapy. In a randomized 2-year study of patients with rheumatoid arthritis who were receiving relatively low doses of prednisone (average dose, 5.5 mg/d), those receiving calcium and vitamin D had significantly higher BMDs than those receiving placebo.⁸⁷ High-dose 25-hydroxy-cholecalciferol significantly increased vertebral BMD by 4.9% in cardiac transplant patients after 18 months.⁸⁸ However, another study⁸⁹ failed to show a benefit of calcium and vitamin D in patients receiving higher doses of prednisone (average dose, 18.9 mg/d). In general, calcium and vitamin D alone are insufficient to completely prevent the bone loss associated with high-dose glucocorticoid treatment,⁹⁰ and additional therapy is required. Furthermore, vitamin D therapy can lead to hypercalciuria, and urinary calcium excretion should be monitored.⁹⁰

Pharmacologic Therapies
The following section will discuss the pharmacologic therapies available to prevent and treat osteoporosis. The use of these agents for postmenopausal osteoporosis or male osteoporosis will not be elaborated on except in the context of hypogonadism. There are numerous review articles that discuss therapy for postmenopausal osteoporosis^{11 91 92} and male osteoporosis.⁹³ The effect of specific therapies for glucocorticoid-induced osteoporosis will be addressed, since many of COPD patients have been exposed to glucocorticoids. At the conclusion, the few studies that specifically address osteoporosis treatment or prevention in patients with lung disease will be discussed.

Hormone Replacement:
Due to the high incidence of hypogonadism with glucocorticoid use, all premenopausal women and men should be monitored for the development of hypogonadism.^{60 63} In premenopausal women, a history of amenorrhea suggests the development of hypogonadism, which can be treated with oral contraceptives or hormone replacement therapy (HRT).⁶¹ Postmenopausal women should be considered for HRT unless there is a contraindication.^{92 94 95} HRT has been shown in a small retrospective study⁹⁶ of 15 asthmatic women receiving oral corticosteroids to increase spine BMD by 4.1% compared to a 3.4% loss in the control group. An alternative to estrogen therapy is raloxifene, a selective estrogen receptor modulator.⁹⁷ In postmenopausal women, these agents have estrogen-like effects on the bone but do not increase the risk of breast cancer or endometrial cancer.^{97 98} Raloxifene has not been studied in patients with glucocorticoid-induced osteoporosis. Testosterone levels should be measured in all men who have osteoporosis. If the level is low, testosterone replacement therapy will be beneficial not only by improving BMD but also, possibly, by improving muscle mass and strength.^{99 100 101} Testosterone therapy has been shown to improve BMD in a crossover study⁶⁴ of 15 asthmatic men receiving oral glucocorticoid therapy. The spine BMD improved 5% after 12 months of testosterone therapy compared to no change in BMD after the 12-month control period.

Calcitonin:
Studies evaluating the effectiveness of calcitonin on glucocorticoid-induced bone loss have been mixed. Luengo et al³⁰ looked at the effect of nasal calcitonin on bone loss in asthmatic patients who were treated with long-term oral corticosteroid therapy (ie, 10 mg/d prednisone). Those patients receiving calcitonin showed an increase in lumbar spine BMD of 2.8% at 2 years. Those patients receiving calcium alone showed a loss of BMD of 7.8% after 2 years. The difference between the groups was statistically significant. In patients with sarcoidosis who were beginning prednisone therapy, bone loss at the spine was prevented in the group receiving calcitonin.¹⁰² In the first year, the control group lost 13.95 ± 2.1% of BMD, whereas the calcitonin group gained 0.2 ± 3.2% of BMD. However, other studies^{88 90 103} have shown no additional benefit for calcitonin when it is added to calcium. Healey et al¹⁰³ randomized patients who were beginning high-dose prednisone therapy to receive calcium plus vitamin D vs calcitonin plus calcium and vitamin D for 2 years. Neither group showed a significant loss in BMD in the spine or hip over the 2 years, and there was no difference between the groups.¹⁰³ Sambrook et al⁹⁰ randomized patients who were beginning high-dose prednisone therapy (average dose, 13.5 mg/d) to receive calcium alone, calcium plus calcitriol, or calcium plus calcitriol and calcitonin. After 1 year, the BMD in the spine was decreased 4.3 ± 5.5% in the calcium-alone group, 1.3 ± 5.6% in the calcium-plus-calcitriol group, and 0.2 ± 6.5% in the calcium-plus-calcitriol-and-calcitonin group. The groups receiving calcium plus calcitriol with or without calcitonin had significantly less bone loss than did those receiving calcium alone. However, there was no significant difference between patients receiving calcium plus calcitriol alone and those receiving calcium plus calcitriol with calcitonin added. Thus, the current data are not definitive regarding the benefits of calcitonin in preventing or treating glucocorticoid-induced osteoporosis.

Bisphosphonates:
In contrast, there is now substantial evidence that the initiation of bisphosphonate therapy when glucocorticoid therapy is begun will prevent a significant loss of BMD. In two randomized prevention studies^{104 105} of patients beginning long-term glucocorticoid treatment for rheumatologic diseases (average dose, 10 to 23 mg/d prednisone), intermittent etidronate therapy, when started within 3 months of glucocorticoid treatment, prevented bone loss compared to calcium alone. The etidronate groups showed a 0.3 to 0.6% increase in lumbar spine BMD vs a 2.79 to 3.23% decrease in the placebo groups. However, a small uncontrolled study⁸⁸ in cardiac transplant patients failed to show any benefit of therapy with etidronate over high-dose calcidiol. In a study¹⁰⁶ comparing the newer bisphosphonate alendronate vs calcium and vitamin D in patients receiving glucocorticoid therapy (average daily dose, 8.7 to 10 mg/d) for from < 4 months to > 12 months, alendronate significantly increased lumbar spine BMD by 2.9% compared to a 0.4% loss in the calcium-and-vitamin D group. More recently, risedronate has been shown to be effective in preventing bone loss in patients receiving glucocorticoid therapy (average dose, 11 mg/d prednisone) for 3 months. The lumbar spine BMD for the placebo group decreased 2.8%, whereas those patients receiving 5 mg risedronate showed a 0.6% gain in BMD.¹⁰⁷ Finally, there is one small study¹⁰⁸ of 27 patients evaluating IV pamidronate for the prevention of glucocorticoid-induced bone loss. The groups receiving pamidronate showed a significant increase in BMD at all sites compared to a significant loss in BMD in the calcium-alone group.¹⁰⁸ There was a trend toward decreased vertebral fractures in the bisphosphonate-treated groups in three studies,^{104 106 107} but because of the small number of fractures overall, the decrease did not reach statistical significance. While these studies were mainly in patients with rheumatologic diseases, they provide strong evidence that bisphosphonates can prevent steroid-induced bone loss.

There is also evidence that bisphosphonate therapy can improve BMD in patients with established bone loss due to glucocorticoid therapy. In a small treatment study¹⁰⁹ of 49 patients receiving glucocorticoid therapy (mean dose, 10.8 mg/d prednisone) for 6 months, patients were randomized to intermittent etidronate plus calcium vs placebo plus calcium. BMD in the placebo-treated patients was stable, whereas BMD in the etidronate group rose by 4%. Forty-three percent of the patients in the study were asthmatic. In the alendronate study mentioned above,¹⁰⁶ 44% of the participants had been receiving glucocorticoid therapy for > 12 months. Those in the alendronate group showed a 2.8% increase in spinal BMD compared to 0.2% in the placebo group.¹⁰⁶ A recent study¹¹⁰ demonstrated similar results with risedronate. Two hundred ninety patients receiving long-term glucocorticoid therapy were randomized to placebo, to 2.5 mg risedronate, or to 5 mg risedronate. After 12 months, the placebo group showed no significant change in lumbar spine BMD, whereas the 2.5-mg risedronate group had a 1.9% increase in lumbar BMD and the 5-mg risedronate group had a 2.9% increase in lumbar BMD. Fractures were decreased by 70%, and the decrease was significant when treatment groups were combined.¹¹⁰

Studies in Patients With Lung Disease:
There are only a few small studies^{111 112 113 114} specifically addressing osteoporosis treatment in patients with lung disease. Several small studies have shown improved BMD in asthmatic patients receiving oral corticosteroid therapy who were treated with a bisphosphonate. An uncontrolled study by Gallacher et al¹¹³ in 17 steroid-treated asthmatic patients (average dose, 14 mg/d prednisone) demonstrated a 3.4% increase in lumbar BMD in response to cyclic pamidronate infusions over 1 year. In an open-label etidronate study¹¹¹ of patients with glucocorticoid-induced osteoporosis, the subset of 22 patients with pulmonary disease demonstrated a 3.8% increase in spinal BMD after 1 year compared to a 3.6% loss in spinal BMD in the calcium group. Another small study¹¹⁴ evaluated the effect of calcium administered alone or in combination with intermittent etidronate therapy in asthmatic patients receiving high-dose inhaled steroid therapy (ie, 2.0 mg/d budesonide or beclomethasone). Those patients receiving calcium alone (n = 8) or with intermittent etidronate (n = 10) had a 2 to 3% increase in BMD after 18 months compared with a loss of 1% in those patients receiving no supplements (n = 10). There was no difference between the calcium-alone group and the calcium-and-etidronate group.¹¹⁴

	Recommendations and Summary

TOP Abstract Introduction Frequency of Osteoporosis in... Pathophysiology of Osteoporosis... Prevention and Treatment Recommendations and Summary References

 
Preventive strategies to decrease osteoporotic fractures in those patients with COPD should begin with screening for the disease. All patients receiving long-term oral glucocorticoid therapy (> 7.5 mg prednisone/d) should have BMD testing. Ideally, BMD should be measured prior to initiating therapy, especially in those patients at highest risk such as postmenopausal women. BMD measurement also should be considered in COPD patients at high risk for osteoporosis such as those receiving high-dose inhaled glucocorticoid therapy, postmenopausal women, premenopausal women, or men with hypogonadism, low BMI, or a history of osteoporotic fracture (see Table 4 ). The Bone Mass Measurement Act provides for Medicare part B coverage for BMD measurement in estrogen-deficient women who are at risk for osteoporosis, in those receiving corticosteroid therapy 7.5 mg/d prednisone for > 3 months, and in those with vertebral fractures.¹¹⁵ The guidelines allow for the measurement of BMD prior to the initiation of long-term glucocorticoid therapy. To assess the response to therapy, follow-up BMD testing can be performed every 2 years in most patients but more frequently in those receiving long-term oral glucocorticoid therapy (ie, every 6 to 12 months).

In those patients who have low BMD or fractures due to any etiology, treatment should be initiated since they are at high risk for further bone loss and fractures. The National Osteoporosis Foundation recommends treatment in postmenopausal women with T scores of -2 or -1.5 with at least one risk factor for osteoporosis.⁹² Risk factors include a family history of osteoporosis, white or Asian ancestry, smoking, thin build, and a history of osteoporotic fractures.^{11 116} Currently, there are no specific recommendations concerning treatment in men who are not receiving glucocorticoid therapy. However, the generally accepted standards would be to initiate therapy in men with T scores -2.5.⁹³

Preventive therapy should be considered in all patients receiving long-term oral corticosteroid therapy. The decision on whether to begin pharmacologic therapy other than calcium and vitamin D will depend on the BMD level of the patient and on the presence of other risk factors for osteoporosis and fracture. The American College of Rheumatology recommends¹¹⁷ treatment for those patients with a T score of -1. Patients with normal BMDs and no other risk factors for osteoporosis should be monitored for bone loss with a repeat BMD measurement in 6 to 12 months. Postmenopausal women with normal BMDs who are at high risk for osteoporosis and fractures can be offered either HRT or a bisphosphonate. The more difficult issue is whether patients receiving inhaled glucocorticoid therapy should be placed on any preventive therapy. One prospective study¹¹⁴ has suggested that calcium supplements alone are sufficient to prevent significant bone loss. Since the bone loss from inhaled glucocorticoid therapy is generally less than that seen with oral steroid therapy, more conservative management may be adequate as long as patients are observed closely with a measurement of BMD in 12 to 18 months.

Prevention and treatment options other than gonadal HRT include therapy with bisphosphonates or calcitonin. Those patients who exhibit significant bone loss despite receiving gonadal hormone therapy should be placed on additional therapy. The evidence is strongest for the use of bisphosphonates; they have been shown to improve BMD and to decrease the fracture rate in postmenopausal women, patients with glucocorticoid-induced osteoporosis, and in men.^{118 119 120 121 122 123} Calcitonin can prevent bone loss in postmenopausal women and in patients receiving glucocorticoid therapy, but a decrease in vertebral fractures has been shown only in postmenopausal women.^{61 92 124 125}

In summary, osteoporosis and subsequent fractures are common problems in patients with COPD. Fractures can produce significant comorbidity in patients with COPD. While the use of glucocorticoids increases the frequency of osteoporosis, the problem also is seen in patients who have not been treated with glucocorticoids. Awareness of the problem and of strategies to prevent the development of osteoporosis during the course of COPD therapy are essential to increase BMD and, likely, to decrease the incidence of fractures in these patients.

	Footnotes

 
Abbreviations: BMD = bone mineral density; BMI = body mass index; CI = confidence interval; HRT = hormone replacement therapy

Received for publication January 2, 2001. Accepted for publication June 4, 2001.

	References

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