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Recognizing and Treating Glucocorticoid-Induced Osteoporosis in Patients With Pulmonary Diseases^*

^* From the Department of Medicine (Dr. Gluck), University of Arizona College of Medicine, Tucson, AZ; and Pulmonary, Critical Care and Respiratory Services (Dr. Colice), Washington Hospital Center, The George Washington University School of Medicine, Washington, DC.

Correspondence to: Gene Colice, MD, FCCP, Washington Hospital Center, 110 Irving St NW, Washington, DC 20010; e-mail: Gene.Colice{at}Medstar.net

	Abstract

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Glucocorticoids are frequently used to treat patients with pulmonary diseases, but continuous long-term use of glucocorticoids may lead to significant bone loss and an increased risk of fragility fractures. Patients with certain lung diseases, regardless of pharmacotherapy—particularly COPD and cystic fibrosis—and patients waiting for lung transplantation are also at increased risk of osteoporosis. Fragility fractures, especially of the hip, will have substantial effects on the health and well-being of older patients. Vertebral collapse and kyphosis secondary to glucocorticoid-induced osteoporosis (GIO) may affect lung function. Identification of patients with osteopenia, osteoporosis, or fragility fractures related to osteoporosis is strongly recommended and should lead to appropriate treatment. Prevention of GIO in patients receiving continuous oral glucocorticoids is also recommended. In patients receiving either high-dose inhaled glucocorticoids or low- to medium-dose inhaled glucocorticoids with frequent courses of oral glucocorticoids, bone mineral density measurements should be performed to screen for osteopenia and osteoporosis. A bisphosphonate (risedronate or alendronate), calcium and vitamin D supplementation, and lifestyle modifications are recommended for the prevention and treatment of GIO.

Key Words: alendronate • bisphosphonate • glucocorticoids • osteoporosis • risedronate

	Introduction

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Continuous administration of oral glucocorticoids is used for the long-term management of a variety of inflammatory and autoimmune diseases, including pulmonary disorders, rheumatic diseases, and organ transplantation.¹ National and international guidelines recommend oral glucocorticoids for managing acute exacerbations of COPD²³⁴ and asthma.³⁵⁶ Although treatment courses with oral glucocorticoids for the acute exacerbations of pulmonary disease should be short,²³⁴⁶ COPD and asthma patients often remain on these medications for extended periods of time. Oral glucocorticoids are the primary pharmacologic approach for managing deterioration in lung function in sarcoidosis and certain interstitial lung diseases.⁷⁸ Treatment courses with oral glucocorticoids for these diseases may last months to years.

The benefits of oral glucocorticoids in reducing respiratory symptoms, improving lung function, and possibly saving lives are partially offset by their potential for systemic toxicity.⁹¹⁰¹¹ A major adverse event due to long-term use of oral glucocorticoids is osteoporosis.^12131415 As many as 90% of long-term glucocorticoid recipients lose a significant amount of bone and therefore have an increased risk of fractures.¹⁶¹⁷ The risk of hip and vertebral fracture is increased two to five times with continuous oral glucocorticoid treatment.¹⁸¹⁹ Inhaled glucocorticoids are used in an effort to reduce the systemic effects of oral glucocorticoids, but they have also been associated with many of the untoward effects described with oral glucocorticoids, including glucocorticoid-induced osteoporosis (GIO).^{1142021222324}

This review has four objectives. First, it is intended to heighten awareness of GIO among pulmonary physicians prescribing oral and inhaled glucocorticoids. Second, it provides a brief review of the pathogenesis of, and diagnostic methods for recognizing GIO. Third, it evaluates the dose-response relationship between oral and inhaled glucocorticoids and GIO. Fourth, it updates previous recommendations on the management of GIO in patients with pulmonary diseases^1142526 to ensure consistency with guidelines from other medical societies interested in the larger issue of osteoporosis.²⁷²⁸²⁹

	GIO and the Pulmonary Physician

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Frequency of Use of Glucocorticoids
In the United States, pharmacists fill approximately 18 million prescriptions for oral glucocorticoids each year, mostly for prednisone. Respiratory diseases are common reasons for the use of oral glucocorticoids. In surveys³⁰³¹ of large populations in health maintenance organizations, pulmonary diseases were the most common reasons for exposure to oral glucocorticoids. In a survey of general practices in Nottinghamshire, Walsh et al³² found that asthma was the third most common reason for the continuous use of oral glucocorticoids and that rheumatologic diseases, specifically rheumatoid arthritis and polymyalgia rheumatica, were the most common diseases treated with continuous oral glucocorticoids. van Staa and colleagues¹⁹ found in a very large retrospective cohort study in the United Kingdom that respiratory disease accounted for 40% of the oral glucocorticoid use in general medical practice. In the United States, > 27 million prescriptions are filled by pharmacists each year for inhaled glucocorticoids, which are used exclusively by patients with pulmonary diseases. Clearly, oral and inhaled glucocorticoids are extensively relied on for managing various pulmonary diseases.

Little information is available on the number of patients using oral glucocorticoids on a long-term continuous basis. Data from the UK surveys suggest that between 0.5% and 0.9% of the adult population may be receiving oral glucocorticoids at any given time.³²³³ However, a smaller percentage of these patients, possibly one fifth, were receiving oral glucocorticoids on a sustained long-term basis.³³ In a review³⁰ of the Kaiser of Northern California Health Plan pharmacy database, 1.1% of covered patients received > 2 g of oral glucocorticoids, usually prednisone, between January 1998 and December 1999. Assuming from the observation by van Staa et al¹⁹ that perhaps 0.2% or slightly more of the adult population will be receiving long-term oral glucocorticoids and extrapolating from an estimated US population of 270 million adults, possibly 500,000 to 1,000,000 American adults would be receiving oral glucocorticoids on a sustained basis.

The extensive use of oral and inhaled glucocorticoids emphasizes the need for pulmonary physicians to be well aware of the adverse effects of glucocorticoids, particularly GIO. Pulmonary physicians should be well versed on the topic of osteoporosis for two other specific reasons. Independent of whether patients are being treated with oral glucocorticoids for underlying lung diseases, GIO may adversely affect lung function. Certain lung diseases may be associated with an increased risk of osteoporosis, regardless of whether glucocorticoids have been used in their treatment. Pulmonary physicians should also understand in general the consequences of osteoporosis, because fragility fractures cause an enormous impact on the health and well-being of older patients.

Effects of GIO on Lung Function
The hip, wrist, and thoracic and lumbar vertebral spine are the bones most susceptible to GIO-related fractures. Although fractures of the hip and wrist do not directly affect lung function, they can cause substantial morbidity and mortality.³⁴ Vertebral fractures are an important cause of back pain and functional disability (Fig 1 ).³⁵³⁶ They also cause spinal kyphosis and a loss of the normal lumbar lordosis through a decrease in vertebral body height and a limitation of spinal motion.³⁶³⁷ Kyphosis secondary to osteoporosis-related vertebral fractures may have a significant adverse effect on lung function. Leech et al³⁸ studied 74 women referred to an osteoporosis clinic in Canada. They found that the FVC was significantly lower in women with vertebral fractures than in women without these fractures. The effect of one or two vertebral fractures on FVC was minimal, but in a small group of women, three or more vertebral fractures were associated with a restrictive ventilatory defect (mean total lung capacity of 75% predicted and mean FVC of 68% predicted). A significant inverse relationship was found between the degree of thoracic hyperkyphosis and loss of height and the FVC in this study. Schlaich et al³⁹ showed that reductions in FVC occurring secondary to spinal osteoporotic fractures were related to height loss and hyperkyphosis and not to attendant chronic low back pain. Rib mobility and inspiratory muscle function may also be impaired in patients with kyphosis from osteoporosis.⁴⁰⁴¹

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Lateral chest radiograph shows multiple vertebral fractures (arrows) with hyperkyphosis.

Work showing that patients with COPD have an increased prevalence of vertebral fractures supports the link between COPD and osteoporosis. In a large prospective study⁴⁷ that examined the benefit of inhaled glucocorticoids in COPD, 653 patients had radiographs of the spine taken at baseline and 81 patients (12%) were found to have vertebral fractures. In a cross-sectional survey⁴⁸ of 117 patients with COPD who had not received glucocorticoids, 48.7% were found to have vertebral fractures on standard lateral radiographs of the spine. The explanation for the dissimilar fracture rates in these two studies relates to the populations studied. The prospective study enrolled mostly men in their early 50s with approximately a 40 pack-year smoking history. The cross-sectional study included only men in their late 60s with approximately a 65– to 70–pack-year smoking history. The difference in age and smoking history probably explains the higher fracture rate in the study by McEvoy et al.⁴⁸ McEvoy et al also observed that fracture rate was significantly associated with earlier-onset smoking.

In both of the studies cited above in patients with COPD, the prevalence of vertebral fractures in men was higher than anticipated. In the Dubbo (Australia) Osteoporosis Epidemiology Study,⁴⁹ the incidence of atraumatic vertebral fractures was very low for men < 75 years old. Age-adjusted vertebral fractures occur much less frequently in men than in women.⁵⁰ To give a perspective, in a large study³⁵ of postmenopausal women 65 years old, 1,416 of 7,223 women were found to have vertebral fractures at the baseline examination, yielding a prevalence rate of 20%; 11% of the patients were current smokers.

Unlike COPD, there does not seem to be a relationship between asthma and reduced BMD. Several small studies²²⁵¹⁵² have presented data showing that BMD measurements are normal in patients with asthma who have not received inhaled or oral glucocorticoids. In a cross-sectional study of a large group of women from Finland, Laatinkainen et al⁵³ found that patients receiving only bronchodilators to control asthma had BMD measurements similar to normal control subjects.

Another lung disease associated with an increased risk of osteoporosis is cystic fibrosis. Pancreatic insufficiency, poor nutrition, impaired absorption of calcium and vitamin D, reduced physical activity, and decreased production of sex hormones predispose the patient with cystic fibrosis to osteoporosis.⁵⁴⁵⁵ In a cross-sectional study⁵⁶ of 70 adults with cystic fibrosis, all patients were found to have significantly decreased BMD; 33 patients (47%) had vertebral compression fractures detected on chest radiographs and 62% had hyperkyphosis. In another study⁵⁷ of 30 patients with cystic fibrosis, age, weight, and body mass index were strongly correlated with BMD, whereas glucocorticoid therapy and pulmonary function were not. Other studies⁵⁸⁵⁹ have associated pulmonary infections and secondary release of inflammatory cytokines with increased bone resorption and diminished bone formation in cystic fibrosis.

Sarcoidosis may be associated with increased intestinal absorption of calcium, hypercalcuria and, infrequently, hypercalcemia. Osteopenia and osteoporosis have been described in a high percentage of patients with sarcoidosis, but whether the changes in BMD were due to sarcoidosis or concomitant treatment with high-dose oral glucocorticoids is unclear.⁶⁰⁶¹ Vertebral fracture rates have not been described in patients with sarcoidosis.

Numerous studies^626364656667 have shown that patients awaiting lung transplantation have a very high rate of osteoporosis. Osteoporosis has been found in all subsets of patients awaiting lung transplantation, including patients with COPD, cystic fibrosis, and pulmonary hypertension. In one study⁶⁸ of 70 patients with a variety of different lung diseases awaiting lung transplantation, a subgroup of 50 patients underwent spinal radiographs and 8 patients (16%) were found to have vertebral fractures; osteoporosis and vertebral fractures were significantly associated with pretransplantation use of high-dose continuous oral glucocorticoid treatment in these patients. Following lung transplantation, morbidity from fragility fractures is an important concern.⁶⁶⁶⁷

Impact of Osteoporosis on Health and Well-being of Elderly Patients
Osteoporosis is a well-recognized major public health concern because of its association with fragility fractures. The impact of fragility fractures on morbidity and mortality in older patients can be most clearly seen with hip fractures. Hip fracture rates increase markedly with age. It is estimated that the lifetime risk of hip fracture in 50-year-old men and women is 6.0% and 17.5%, respectively. Approximately 300,000 hip fractures occur annually in the United States. Approximately 8% of men and 3% of women > 50 years old will die during the initial hospitalization for a hip fracture. By 1 year after hip fracture, on average, 36% of men and 21% of women > 50 years old will be dead. These rates are much higher than anticipated from standard life expectancy tables. Higher mortality rates are seen in the elderly and in patients with comorbid conditions. An estimated 30,000 excess deaths per year can be associated with the complications of hip fracture.⁶⁹

Discharge to a nursing home after the initial hospitalization for hip fracture occurs in 14% of those aged 50 to 55 years and in 55% of nonagenarians. By 1 year following hip fracture, 40% cannot walk independently, 60% need help with basic activities such as dressing and bathing, and 80% require assistance with driving and shopping. The social impact of these complications is substantial. Depression and social isolation are well-recognized problems following hip fracture. The medical costs of osteoporosis and fragility fractures have been estimated at $20 billion per year in the United States, with hip fracture accounting for one third of this total.⁶⁹

	Pathogenesis of GIO

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Bone maintenance depends on a careful balance between bone formation by osteoblasts and bone resorption by osteoclasts. These processes are regulated by many mediators, including hormones, cytokines, and other signaling agents.⁷⁰ Osteoporosis occurs when the complex homeostatic cellular and hormonal mechanisms that control bone formation and resorption are disrupted. This disruption can occur in either of two basic ways, increased bone resorption (increased bone remodeling) or decreased bone formation (decreased bone remodeling). Glucocorticoids have a biphasic effect on bone, initially stimulating bone resorption and, after long-term use, suppressing bone formation. The net effects lead to osteoporosis and an increased susceptibility to fragility fractures. Histologic features of GIO are decreased rate of bone formation, decreased trabecular wall thickness, and apoptosis of bone cells.⁷¹⁷² Glucocorticoids affect bone formation and bone resorption through local as well as systemic effects on bone cells (Table 1 ).⁷⁰⁷³⁷⁴

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Cytokines, PTH, and vitamin D stimulate osteoblasts and stromal cells to release RANK-L and osteoprotegerin. RANK-L binds to its receptor, RANK, on monocytes and pro-osteoclasts, inducing osteoclastogenesis in the presence of M-CSF. Osteoprotegerin acts as a decoy receptor for RANK-L, inhibiting osteoclastogenesis.

Osteocytes, the principal stable cells within mature cortical bone, are also affected by glucocorticoids that induce apoptosis.⁷² In metaphyseal cortical bone, apoptotic osteocytes are much more prevalent than apoptotic osteoblasts. Accumulation of apoptotic osteocytes may be the pathologic mechanism of osteonecrosis, which results in femoral head collapse in many patients receiving glucocorticoids.⁷² Other proresorptive actions of glucocorticoids on bone include enhanced expression of collagenase-3 and inhibited transcription of insulin-like growth factors and their binding proteins.⁷⁰

Indirect Effects on Bone
Glucocorticoids reduce the production of gonadal hormones by acting on the pituitary glands, gonads, and adrenal glands via a negative feedback effect on the hypothalamic-pituitary-gonadal axis.⁷⁴⁷⁸⁷⁹ Because sex hormones are important regulators of bone metabolism, inhibition of their synthesis and release by long-term glucocorticoid therapy is another factor contributing to the development of GIO. Glucocorticoid-related malabsorption of calcium through the intestine and decreased reuptake of calcium through the kidney will further impair bone density maintenance.⁷⁴

Histology of GIO
Histologically, osteoporosis is characterized by reduced bone volume and disruption of the three-dimensional trabecular architecture. These abnormalities can be quantitatively expressed using stereologic methods. Chappard and colleagues⁸⁰ performed transiliac bone biopsies on 30 patients with asthma who had received continuous oral glucocorticoids. They found a decreased bone volume explained largely by trabecular thinning. With trabeculae < 70 µm in thickness, perforations in the trabecular network became apparent. As trabeculae become thinner and the trabecular networks develop perforations and disconnections, the risk for fracture will increase. Just as with any type of osteoporosis, as BMD decreases the threshold for fractures decreases in GIO.⁸¹

A more recent study⁸² has compared the histomorphometry of GIO with that found in postmenopausal osteoporosis. Transiliac biopsy samples were obtained in two groups of postmenopausal women with osteoporosis: those receiving continuous oral glucocorticoids for at least 6 months and those who did not. Microarchitectural differences between the two groups were not found. GIO was associated with trabecular thinning, perforations, and disconnections, just as was osteoporosis in postmenopausal women. Although qualitative differences were not found, there were quantitative differences. There was a greater reduction in osteoblastic activity and more extensive bone resorption with GIO. This finding may have important implications for the prevention and treatment of GIO. Transiliac biopsy samples in patients receiving continuous oral glucocorticoids were obtained before and after 1 year of bisphosphonate therapy.⁸³ Bisphosphonates reduced bone turnover, probably through decreases in osteoclast function, but did not affect decreased osteoblast function.

	Diagnosis of GIO

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Osteoporosis (glucocorticoid-induced or nonglucocorticoid-related) is a systemic skeletal disease characterized by low bone mass, microarchitectural deterioration of bone tissue, reduced bone strength, and increased fracture risk.⁸⁴ Bone strength is dependent on bone density and bone quality. BMD, expressed as grams of mineral per area or volume, is frequently used as a proxy measure for bone strength.⁸⁵ In any given individual, BMD is a function of peak bone mass and amount of bone loss.⁸⁶

Patients with fragility fractures, defined as fractures associated with trivial trauma, will invariably have osteoporosis. In patients without clinically determined fragility fractures, the World Health Organization operationally defines osteoporosis as a BMD 2.5 SDs below the young normal adult mean (T score – 2.5; Table 2 ).⁸⁷ Low bone mass, also referred to as osteopenia, is defined as a BMD value between 1 SD and 2.5 SDs below the young normal adult mean (T score between – 1 and – 2.5; Table 2).⁸⁷ In patients treated with glucocorticoids, a T score < – 2.5 and/or a fragility fracture defines GIO, and a T score between – 1 and – 2.5 defines glucocorticoid- induced osteopenia. For physicians unfamiliar with BMD testing, the diagnosis of osteopenia and osteoporosis, using the concept of "a chain is as strong as its weakest link," is based on the lowest site-specific T score.

BMD can be measured accurately by several techniques, including ultrasound, peripheral single- and dual-energy x-ray absorptiometry (DXA), and quantitative CT. DXA of the lumbar spine, hip, total body, and distal forearm is the preferred method for measuring BMD. Quantitative CT is not readily available and causes higher radiation exposure. Newer techniques using MRI are still being developed.⁸⁸

Biochemical Markers of Bone Turnover
Bone resorption is associated with an increase in serum and urinary markers of bone turnover. Elevated serum and urinary levels of type I collagen crosslinked N-telopeptide⁸⁹⁹⁰ and serum levels of free deoxypyridinoline⁸⁹ are associated with an increased risk of fracture in women who have osteoporosis. Compared with BMD measurements obtained at specific skeletal sites containing different ratios of cancellous and cortical bone, bone turnover markers provide a more representative index of the overall skeletal changes.⁹¹ However, biochemical marker assays cannot be used instead of a bone density test for diagnosing osteoporosis because the relationship between bone metabolism and total bone mass has not been established.⁹² Bone markers can be used in conjunction with BMD testing to help identify people at risk of hip and other fractures. Although the results can be variable, bone marker assays, such as osteocalcin, may also be used to detect dose-related effects of glucocorticoids on bone,⁹³ and to monitor treatment strategies for osteoporosis.⁹⁴

	Risk Thresholds for GIO

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Under normal conditions, the average amount of cortisol secreted daily by the adrenal gland in an adult is equivalent to 5 mg of prednisone.⁹⁵ Therefore, any glucocorticoid dose > 5 mg/d is supraphysiologic and may increase the risk of adverse events, including osteoporosis, over the long-term. Ledford and colleagues¹⁴ suggest that every patient receiving either oral or inhaled glucocorticoid therapy is at risk for bone loss regardless of age, ethnicity, gender, or other risk factors for nonglucocorticoid-induced osteoporosis.

Although alternate-day dosing reduces the incidence of most glucocorticoid-related adverse effects,⁹ it does not reduce the risk of osteoporosis.¹⁰ In several studies,¹⁰⁹⁶⁹⁷ oral prednisone administered on alternate days had a negative effect on bone similar to patients receiving daily prednisone.

Oral Glucocorticoids and Bone Loss
The American College of Rheumatology recommends that preventative and/or treatment measures against osteoporosis be implemented in patients beginning or receiving long-term glucocorticoid therapy if the dosage is the equivalent of 5 mg/d of prednisone.²⁹ However, there is no apparent lower dose threshold for bone loss. One study⁹⁸ reported that increases in fracture risk appeared to be smaller at daily doses < 5 mg/d compared with higher doses, but were still apparent. The increased risk of fracture observed in patients receiving oral glucocorticoids is strongly related to the daily glucocorticoid dose.⁹⁸ The risk of both hip and vertebral fractures was approximately doubled in patients receiving high daily doses ( 7.5 mg of prednisolone or equivalent) compared with those using low doses (< 2.5 mg of prednisolone or equivalent).

Continuous administration of high-dose oral glucocorticoids (equivalent to 7.5 mg/d of prednisone) causes a rapid decrease in BMD, which is detectable within 3 months of commencing treatment⁹⁹ and is maximal during the first 6 months of treatment.¹⁰⁰ In patients with sarcoidosis, those receiving glucocorticoids experienced a mean 4.5% decrease in BMD after 1 year.¹⁰¹ Bone loss continues at a slower rate thereafter, but the rate is still two to three times higher than that observed in patients not receiving glucocorticoids.¹⁰²

Inhaled Glucocorticoids
The relationship between use of inhaled glucocorticoids and development of osteoporosis has been evaluated in cross-sectional surveys and prospective studies performed in populations with asthma and COPD. Unfortunately, design issues limit the value of many of these studies. Sample sizes tended to be small, especially in the cross-sectional surveys, with inadequate power to test the hypothesis of an effect by inhaled glucocorticoids on either BMD or fracture rates. Control groups were often inappropriate. In some studies,^103104105 control groups were mixed collections of patients receiving nonglucocorticoids and low-dose inhaled glucocorticoids. Prospective studies^{47106107108109} in some cases were too short to adequately evaluate the effects of inhaled glucocorticoids on BMD and fracture rates over time. Serial evaluations over years may be required to detect the full effects of inhaled glucocorticoids.

A variety of other factors confound analyses of the effects of inhaled glucocorticoids on BMD and fractures. Smoking and COPD seem to have independent effects on BMD and fracture rates. Sex hormone status (eg, changes in postmenopausal women and hypogonadal men) will influence bone homeostasis. Other factors influencing bone homeostasis are activity level, body weight, sunlight exposure, and calcium and vitamin D intake. Often these factors are difficult to control during clinical trials. Use of inhaled glucocorticoids prior to study entry, nasal glucocorticoids for rhinitis, and intermittent courses of oral glucocorticoids for exacerbations of airway disease may obscure the effects of inhaled glucocorticoids during a study. An underappreciated issue is the difference in systemic potency of the various inhaled glucocorticoid preparations.¹¹⁰ Contributing to these potency differences are the characteristics of the glucocorticoid, the formulation, the inhalation device, and deposition characteristics. Even factors as simple as the use of a spacer or rinsing the mouth after inhalation may influence the systemic absorption and effects of an inhaled glucocorticoid.

Despite these study design issues and other confounding factors, increasing evidence seems to point toward a relationship between use of inhaled glucocorticoids and reduced BMD. Initial small cross-sectional surveys^22232451 of patients with asthma did not consistently find reductions in BMD of the spine and/or hip in inhaled glucocorticoid users. Wisniewski et al¹¹¹ found no difference in BMD between 47 patients with asthma receiving inhaled glucocorticoids and 34 control patients with asthma not receiving inhaled glucocorticoids, but they did note on multivariate analysis an inverse relationship between cumulative use of inhaled glucocorticoids and BMD in women. In a larger follow-up study¹¹² of 196 adults with asthma, this group confirmed an inverse relationship between cumulative dose of inhaled glucocorticoid used and BMD in both men and women and estimated its effect. These authors calculated that receiving 2,000 µg/d of an inhaled glucocorticoid for 7 years would result in a BMD 1 SD lower than that of a patient receiving only 200 µg/d. This effect on BMD is large enough to double the fracture rate in postmenopausal women. In a recent case-control analysis¹¹³ of patients with hip fractures in a general practice database, this group confirmed that use of inhaled glucocorticoids was associated with a small increase in hip fracture rates in a dose-dependent manner. The limitation of these studies, though, is that they largely reflect experience from the United Kingdom with primarily beclomethasone. A large survey study⁵³ of Finnish women noted that BMD was normal in patients with asthma receiving inhaled glucocorticoids, but again found a significant inverse relationship between duration of inhaled glucocorticoid use and BMD of the spine.

Cross-sectional surveys of patients with COPD found inconsistent effects of inhaled glucocorticoids on BMD and fracture rates. Iqbal et al⁴³ found that the risk of osteoporosis was just as high in users of inhaled glucocorticoids as oral glucocorticoids. In another small study,¹¹⁴ changes in BMD were noted with inhaled glucocorticoid use, but only in women. In one study,⁴⁸ 57.1% of patient with COPD receiving inhaled glucocorticoids had vertebral fractures noted on lateral lumbar and thoracic radiographs, a higher rate than found in patients with COPD not receiving glucocorticoids (ie, 48%). van Staa and colleagues,¹¹⁵ in a retrospective review of a large UK primary-care database, found a dose-related increase in relative rates of nonvertebral, hip, and vertebral fractures in inhaled glucocorticoid users. The effect was significant in patients receiving > 700 µg/d of inhaled glucocorticoids; however, when the relationship between inhaled glucocorticoid use and fractures was controlled for bronchodilator therapy, the effect was no longer significant. This suggested that it was the underlying lung disease and not the use of inhaled glucocorticoids that accounted for the increased fracture rates.

Prospective studies of the effect of inhaled glucocorticoids on BMD have been influenced by the dose of inhaled glucocorticoid and the duration of follow-up. Studies using low-dose inhaled glucocorticoids¹¹⁶¹¹⁷ or with follow-up for 12 months¹⁰⁷¹¹⁸ in general did not find negative effects on BMD. Studies with higher-dose inhaled glucocorticoids^{47108109119120} and longer-term follow-up¹⁰⁴¹⁰⁵ tended to find decreases in BMD. Israel et al¹²¹ performed a rigorous study of the effects of regular use of inhaled triamcinolone over 3 years in premenopausal women. They found a clinically meaningful effect on BMD of the hip and trochanter, but not the spine or femoral neck with use of higher doses of this inhaled glucocorticoid. They estimated that this effect on BMD would potentially translate into a doubling of the risk of hip fracture at age 65 years in these women. This study was notable for the large variations in BMD occurring over time. Although in some patients BMD increased, in others there were large decreases in BMD, emphasizing that individual BMD responses to use of inhaled glucocorticoids are difficult to predict.

There is little information available on the combined effect of inhaled glucocorticoids and intermittent courses of oral glucocorticoids on BMD. However, in one small study,²² decreases in BMD were found in patients receiving this combination similar to those patients receiving regular doses of oral glucocorticoids. In another small study,¹¹⁷ inhaled glucocorticoid users who had received frequent (> 2.5 courses per year) short courses of oral glucocorticoids for exacerbations of airway disease in addition to regular treatment with lower doses of inhaled glucocorticoids were found to have had significantly greater changes in BMD than patients receiving high-dose inhaled glucocorticoids alone.

Two well-designed, prospective, placebo-controlled studies¹²²¹²³ on the effect of inhaled glucocorticoids on lung function in COPD are available. These studies included measures of BMD as part of the safety evaluation. In the Lung Health Study,¹²² significantly greater decreases in BMD were found in the lumbar spine and femoral neck in the inhaled glucocorticoid treatment group (receiving triamcinolone) compared with the placebo group after 36 months of regular use, although no effect on BMD was seen after 1 year of use. Confounding the interpretation of this finding, however, is the observation that BMD increased in the placebo group over the 3 years of the study and decreased, but only minimally, in the inhaled glucocorticoid group. Pauwels et al¹²³ found no change in BMD over time and no increase in total fractures in their patients treated with inhaled budesonide. Unfortunately, only 102 of the 643 patients randomized to inhaled glucocorticoids (16%) underwent bone density measurements in this study, and approximately 29% did so in the Lung Health Study.¹²² As bone density measurements were secondary safety objectives of both studies, these findings should be interpreted cautiously.

In summary, there is increasing concern that continuous, long-term use of inhaled glucocorticoids may reduce BMD and increase the risk of fragility fractures. Although there is insufficient evidence at present from both cross-sectional surveys and prospective studies to fully characterize the dose-related effect of inhaled glucocorticoids on BMD, patients receiving high dose inhaled glucocorticoids may be at risk for reductions in BMD. Limited data suggest that lower doses of inhaled glucocorticoids may result in decreases in BMD if frequent courses of oral glucocorticoids are also administered.

	Glucocorticoid Dosage Recommendations

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
To minimize the occurrence of adverse events, including GIO, the lowest possible dose and shortest duration of therapy of oral and inhaled glucocorticoids to achieve the desired therapeutic benefit should be used. Use of inhaled glucocorticoids will reduce the risk of adverse effects, including GIO, compared with oral therapy. For certain inhaled glucocorticoids, which are not adequately cleared by hepatic metabolism, the risk of GIO may be further decreased with the use of spacer devices and rinsing the mouth after inhalation. The relationship between characteristics of the inhaled glucocorticoid, based on its lung deposition properties, potency, or half-life, and risk of GIO has not been studied. However, increasing systemic exposure or potency of an inhaled glucocorticoid should be expected to increase the risk for adverse events on BMD.

	Prevention and Treatment of GIO

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Because osteoporosis may complicate certain pulmonary diseases and because clinically significant bone loss may result from oral and inhaled glucocorticoid therapy, a proactive strategy for prevention and treatment of osteoporosis is warranted in patients with severe pulmonary disease who are receiving continuous long-term glucocorticoid therapy. Whether GIO may be reversible on discontinuation of long-term glucocorticoid treatment, as suggested by small studies,¹²⁴¹²⁵ is not clear. The urgency of recognizing the possible risk is based on the histomorphometric studies of bone biopsies that suggest that thinning and disconnectivity of bone trabeculae may become irreversible in certain patients with GIO.⁸²

Bisphosphonates
Bisphosphonates are synthetic, stable pyrophosphate analogues that are potent inhibitors of bone resorption.¹²⁶¹²⁷ The two oral bisphosphonates available in the United States are risedronate (Actonel; Procter & Gamble; Cincinnati, OH) and alendronate (Fosamax; Merck; West Point, PA). Risedronate, 5 mg/d, is approved for the prevention and treatment of GIO.¹²⁸ Alendronate, 5 mg/d, is approved for the treatment of GIO; alendronate, 10 mg/d, is approved for the treatment of GIO in postmenopausal women who are not receiving estrogen.¹²⁹ Etidronate (Didronel; P&G Pharmaceuticals; Cincinnati, OH) has not been approved for use in the United States, but has been effective at a dose of 200 mg po bid for 2 weeks in 3-month cycles in preventing GIO.¹³⁰ Both risedronate and alendronate are pregnancy category C and should be used with caution in premenopausal women because bisphosphonates may cross the placenta and affect bone development in the fetus. Whether bisphosphonates appear in human milk is uncertain. Patients who are being considered for bisphosphonate therapy and of child-bearing age must be counseled regarding the use of appropriate contraception.²⁹

Efficacy:
The effects of risedronate and alendronate on the risk of fracture in GIO are summarized in Table 3 . A placebo-controlled treatment trial in 290 patients with GIO demonstrated a significant 70% reduction in the risk of vertebral fracture after 1 year of treatment with risedronate compared with placebo (p = 0.04).¹⁷ A combined analysis of the prevention and treatment trials showed that risedronate, 5 mg/d, significantly reduced the risk of vertebral fracture by 70% compared with placebo (p = 0.01). The effect was more marked in postmenopausal women than in men.¹³¹

Changes in BMD in patients with GIO have also been assessed with risedronate and alendronate therapy (Table 4 ).^17132133134 Both agents produced statistically significant increases in BMD at different skeletal sites. In all of the trials, patients in both the treatment and placebo arms received calcium and/or vitamin D supplementation.

Adverse Effects:
In controlled clinical trials¹³⁹¹⁴⁰ investigating the use of risedronate or alendronate, each bisphosphonate had in general a safety profile comparable to placebo. However, in the original alendronate GIO clinical trial,¹³² upper-GI adverse effects were more common in patients receiving alendronate at 10 mg/d as compared with placebo. Bisphosphonate use may rarely be associated with more serious GI side effects, such as esophagitis and bleeding. Use of these drugs is contraindicated in patients with esophageal motility problems and strictures. At present, direct comparative information on the safety profiles of risedronate and alendronate are not available.

Calcium and Vitamin D Supplementation
Calcium and vitamin D supplementation can reduce early bone loss in patients with GIO,¹⁴¹ but are not adequate for prevention of fracture.¹⁴² Studies²⁹¹⁴³ clearly show that calcium and vitamin D should be used in conjunction with a bisphosphonate. If calcium and vitamin D are not administered with a bisphosphonate, there is a risk of hypocalcemia. Patients receiving activated forms of vitamin D should be monitored for hypercalcemia and hypercalcuria.²⁹

Hormone Replacement Therapy
Reduced production of estrogen and/or testosterone is a risk factor for osteoporosis, and sex hormone replacement therapy (HRT) is recommended in hypogonadal patients receiving continuous oral glucocorticoid therapy.²⁹ However, there is no evidence that HRT reduces the risk of osteoporotic fracture in patients with GIO.¹⁴⁴¹⁴⁵ Consideration should be given to recent evidence of the increased risks associated with HRT therapy in women in the large Women’s Health Initiative trial,¹⁴⁶ namely an increased risk of breast cancer, heart attacks, strokes, and pulmonary emboli.

Salmon Calcitonin
Calcitonin administered subcutaneously has been effective in preventing bone loss in asthma patients treated with oral glucocorticoids, but was not well tolerated.¹⁴⁷ In a study of sarcoid patients, salmon calcitonin administered as a nasal spray formulation effectively prevented loss of BMD during treatment with oral glucocorticoids.¹⁴⁸ Data on fracture prevention with salmon calcitonin are not currently available. Calcitonin has not been approved for use in GIO, and insufficient data are currently available as to its benefit in this population.

Parathyroid Hormone 1–34
Intermittent administration of low-dose recombinant parathyroid hormone (PTH) stimulates bone formation¹⁴⁹ and reduces the risk of new nonvertebral fractures in women with postmenopausal osteoporosis.¹⁵⁰ In women with postmenopausal osteoporosis who were receiving glucocorticoids and HRT, 1 year of treatment with PTH 1–34 resulted in an 11% increase in lumbar spine BMD (by DXA), an improvement that remained constant 1 year after discontinuation of PTH.¹⁵¹ Prospective clinical trials are still needed to determine fracture risk reduction with PTH 1–34 in patients with GIO.

	Recommendations for Identifying and Treating Patients With GIO

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Identifying Patients With Complications of Osteoporosis and Patients With Osteoporosis at Risk for Fractures
Recommendations for managing GIO follow a simple three-step process (Fig 3 ). The first step is to identify patients who already have complications of osteoporosis, specifically fractures. A careful history should elicit prior fractures. Hip, wrist, and/or vertebral fractures, especially those associated with trivial trauma, should suggest that the fracture was a complication of osteoporosis. Surprisingly, osteoporosis- related fractures are often not identified. Audits of hospital records from patients admitted with either hip or wrist fractures show that the diagnosis of osteoporosis was infrequently considered.^152153154 In one study,¹⁵² BMD measurements were obtained in only 32% of the 218 patients audited. Treatment for osteoporosis was offered to only 4 to 13% of patients in two other audit studies¹⁵³¹⁵⁴ and was most often simply calcium and vitamin D supplementation.

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Identifying and treating GIO.

In patients with recognized complications of osteoporosis, measurements of BMD to confirm the diagnosis and to allow accurate monitoring of the response to therapy are advised. If BMD does not increase with the standard regimen of bisphosphonates, calcium and vitamin D supplementation, and lifestyle changes, therapy with PTH should be considered. This is the only agent approved for use in the United States and known to increase BMD by its anabolic effect on osteoblasts.¹⁵¹

The second step is to identify patients who are being started on long-term courses of continuous oral glucocorticoids (> 5 mg/d of prednisone for > 3 months). Because these patients will have significant bone loss within the first weeks to months of treatment, therapy with a bisphosphonate should be initiated along with the oral glucocorticoids to prevent GIO. This recommendation is consistent with those from the American College of Rheumatology.²⁹

The third step is to identify patients who are at risk for fractures and other complications of osteoporosis. Studies have simplified the approach to identifying at-risk patients. A large-scale longitudinal observational study¹⁵⁵ strongly supported the value of BMD measures as highly predictive of fracture risk. The use of BMD measures as an accurate predictor of fractures in the short-term has been endorsed by multiple organizations.^2885156157

Groups of patients who are at sufficiently high risk for osteoporosis to warrant routine screening with BMD measurements have been identified. The two most important subgroups are postmenopausal women > 65 years old and postmenopausal women aged 60 to 64 years with a body weight < 70 kg.²⁸ However, it is clear that patients with certain types of lung disease are also at a sufficiently high risk of osteoporosis to warrant routine screening. The most susceptible group is patients with COPD. Men in their mid to late 60s with a significant smoking history (> 60 pack-years) have a prevalence rate of vertebral fractures similar to, and possibly greater than, postmenopausal women 65 years old.⁴⁸ Postmenopausal women aged 60 to 64 years with COPD and a significant smoking history should also be expected to have increased risk, regardless of body weight. Adult patients with cystic fibrosis and patients awaiting lung transplantation have an extremely high prevalence rate of vertebral fractures. Regardless of pharmacologic therapy for lung disease, men and women with COPD and a significant smoking history, adults with cystic fibrosis, and patients awaiting lung transplantation should undergo routine BMD screening for the purpose of identifying osteoporosis.

Currently, data are not clear on the relationship between use of inhaled glucocorticoids and development of GIO. However, it is reasonable to suggest that patients who are being treated on a sustained basis with either high-dose inhaled glucocorticoids or low-to-medium doses of inhaled glucocorticoids with frequent short courses of oral glucocorticoids should have routine BMD testing performed. If osteopenia or osteoporosis were identified, appropriate treatment would be recommended.

Treatment of Patients With Osteopenia/Osteoporosis and Complications Related to Osteoporosis
In patients with osteopenia or osteoporosis identified by BMD measurements or with fractures related to osteoporosis, multiple approaches should be considered to reduce further bone loss and the risk for future fractures (Table 5 ).²⁹¹⁵⁸ Lifestyle modifications are important issues. Smoking cessation, minimization of alcohol intake, muscle strengthening, and balance exercises and steps to avoid falls should all be encouraged.

Risedronate and alendronate are recommended as first-line therapy for the prevention and treatment of osteopenia and osteoporosis.²⁹ If these two drugs are to be considered for premenopausal women, counseling regarding use of appropriate contraception is recommended. Although not approved by the US Food and Drug Administration for the prevention and treatment of GIO, salmon calcitonin nasal spray may be considered as second-line therapy for patients contraindicated or intolerant to bisphosphonates.²⁹ Other secondary options include fluorides and PTH 1–34.²⁹

	Conclusions

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 
Continuous treatment with oral glucocorticoids is associated with GIO and an increased risk of fracture. There is also the risk of GIO with use of either high-dose inhaled glucocorticoid therapy or low-to-medium-dose inhaled glucocorticoid therapy accompanied by frequent short courses of oral glucocorticoids. Smokers with COPD > 60 years old, adults with cystic fibrosis, and patients awaiting lung transplantation will also be at increased risk for osteoporosis. Vertebral fractures and hyperkyphosis secondary to osteoporosis are of particular concern in pulmonary patients because they can further compromise lung function.

Patients who receive sustained treatment with oral glucocorticoids should be started on concomitant antiresorptive therapy. Patients receiving either high-dose inhaled glucocorticoids or low-to-medium-dose glucocorticoids with intermittent short course therapy ("bursts") with oral glucocorticoids should undergo BMD testing. Patients with osteopenia, osteoporosis, or a fracture related to osteoporosis should receive appropriate therapy to prevent further complications. For most patients, the regimen of choice is lifestyle modifications and risedronate or alendronate in conjunction with calcium and vitamin D supplementation.

	Footnotes

 
Abbreviations: BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; GIO = glucocorticoid-induced osteoporosis; HRT = hormone replacement therapy; M-CSF = macrophage colony-stimulating factor; PTH = parathyroid hormone; RANK = receptor activator of nuclear factor B; RANK-L = receptor activator of nuclear factor B ligand

Dr. Gluck has served as a consultant to Merck, Eli Lilly, and the Alliance for Bone Health (Procter & Gamble and Aventis).

Dr. Colice has acted as a consultant to Aventis, GlaxoSmithKline, Novartis, Om, Kos, and Sepracor.

Received for publication February 14, 2003. Accepted for publication July 16, 2003.

	References

TOP Abstract Introduction GIO and the Pulmonary... Pathogenesis of GIO Diagnosis of GIO Risk Thresholds for GIO Glucocorticoid Dosage... Prevention and Treatment of... Recommendations for Identifying... Conclusions References

 

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