February 2009
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Importance of Awareness of Glucocorticoid-Associated Adverse Events
Glucocorticoid-induced osteoporosis is the most common type of iatrogenic osteoporosis and a frequent cause of secondary osteoporosis.Reviewed by Kenneth Saag, MD, MSc
Glucocorticoid therapy was introduced in the 1950s and since that time has been widely used to treat various rheumatic and inflammatory diseases. Although an important therapy, this medication is associated with significant side effects.1 Our group recently conducted a literature review to characterize glucocorticoid-associated adverse events. The full text of this review appeared in Current Opinion in Rheumatology (2008;20:131Ð137); the following is a summary.
USE AND PREVALENCE
Between 1% and 3% of adults worldwide receive long-term glucocorticoids.2 A prednisone-equivalent dose of <7.5 to 10 mg per day is considered low, and as such, doses below this level are associated with lower rates of adverse events such as osteoporosis, myopathy, cardiovascular disease, and glaucoma.3 Studies have revealed, however, that one-third of UK patients taking glucocorticoids for >2 years were receiving a prednisone-equivalent dose >7.5 mg daily. As many as 20% of patients take oral glucocorticoids for >6 months, and almost 5% of patients are on daily therapy for >5 years.2 In the United States, 14% of patients take glucocorticoids for skin and musculoskeletal conditions,4 and their use is as high as 38% among rheumatoid arthritis patients.5
There are many well-known adverse effects associated with glucocorticoids (Table 1).6 Even though these adverse events are now being been well studied, separating the effects of glucocorticoids from the outcomes of the underlying disease they are used to treat remains difficult and controversial.3,7
GENERAL SIDE EFFECTS
A large population-based study among members of a managed care organization obtained data on 2,446 patients who were long-term glucocorticoid users. Weight gain was the highest reported side effect, experienced by 80% of patients in the highest quartile of glucocorticoid use. Other commonly reported events were skin bruising/thinning, sleep disturbance, cataracts (15% overall), and fractures (12% overall).8 Because almost two-thirds of vertebral fractures are asymptomatic in postmenopausal women, the fracture percentage is probably underreported. This study found a strong dose-response relationship between glucocorticoids and adverse events, with acne, skin bruising, weight gain, and cataracts significantly associated with longer duration (>90 days) of low-dose glucocorticoid use. Increasing daily dose, on the other hand, was more strongly associated with sleep disturbance and fractures than was increased duration of use.9
GLUCOCORTICOID-INDUCED OSTEOPOROSIS
The most common type of iatrogenic osteoporosisÑand a frequent cause of secondary osteoporosisÑis glucocorticoid-induced osteoporosis,10 according to meta-analyses. Gudbjornsson et al estimated that half of patients who receive glucocorticoid therapy >6 months will develop secondary osteoporosis.11 Moreover, for patients aged ≥65 years, the absolute risk is even higher given their increased baseline risk of fracture.
Oral glucocorticoid therapy is responsible for an accelerated decrease in bone mineral density (BMD) that is the most pronounced in the first year of use.12 Studies have revealed12 decreased BMD at the lumbar spine, femoral neck, and whole body, with the greatest loss seen in the trabecular lumbar vertebrae after only 2 months of high-dose glucocorticoids.
This high incidence of glucocorticoid-induced osteoporosis has led to more scrutiny with regard to screening and treatment of this adverse effect. Fewer than 50% of patients who receive long-term glucocorticoids are evaluated for osteoporosis and <25% have been treated, according to a review.13 Physician awareness of glucocorticoid-induced osteoporosis varies widely, as does the standard of care for prevention and treatment of this condition.13 Shah et al found that, among prednisone-treated patients with no additional osteoporosis risk factors, screening, prophylaxis, or treatment was 38.1%.14
STANDARD OF CARE
Our group looked at 3,125 men and women on long-term glucocorticoid therapy. Although bone mass measurements increased among postmenopausal women from 10% in 1996 to 1997 to 19% in 2000 to 2001, the rate remained <6% at all time periods among men and women aged <50 years. Antiosteoporotic therapy was administered in almost 50% of postmenopausal women; the biggest increase of use was among women aged ≥65 years. We found that the specialty of the treating physician was associated with the likelihood of testing and treatment. The odds of patients receiving a bone mass measurement and antiosteoporotic medication was three to four times higher if the treating physician was a rheumatologist versus an internist or family practitioner, we found.15
As many as 30% to 50% of patients receiving long-term glucocorticoid therapy experience fracture, an expensive and debilitating adverse effect.16,17 Additionally, patients with glucocorticoid-induced osteoporosis are likely to experience fracture at higher BMDs than patients who are not being treated with such agents.18 Steinbuch et al reported a sevenfold increased risk of hip fractures and a 17-fold increased risk of vertebral fractures among patients taking >10 mg prednisone for >90 days compared with age-matched control patients.4
DeVries et al analyzed data from the UK General Practice Research Database and found that patients treated with <7.5 mg per day glucocorticoids experienced a 60% increased risk of osteoporotic fracture,19 and patients treated with 7.5 to 15 mg per day had a 115% increased risk. Within 3 months of stopping treatment, however, the risk of fracture rapidly decreased and within 6 months returned to baseline levels (patients exposed to <1-gram prednisone equivalent). It took 15 months for patients to return to baseline risk if they were exposed to >1-gram prednisone equivalent.
DETERMINING THE RISK
It is clear that bone health is adversely affected by glucocorticoid use, however, teasing out the risk has proved problematic. Glucocorticoids are used to treat diseases that also contribute to osteopenia and osteoporosis. This has been shown in a cross-sectional study by Lee and colleagues looking at 307 patients with systemic lupus erythematosus. They found that low BMD correlated with disease activity but not prior glucocorticoid use.20 Additionally, age, underlying disease, disease severity, other medications, and duration of therapy are all significant confounding factors.3 Therefore, the difficulty of comparing studies is compounded by numerous variables. We believe that, as no evidence exists defining a safe minimum dose or duration of glucocorticoid exposure, the lowest effective dose should be used.21
CONCLUSION, IMPLICATIONS FOR PRACTICE
Glucocorticoid therapy is an important and useful treatment for a variety of inflammatory diseases; however, among long-term users and at high doses it can cause morbidity. It is important that physicians are aware of the adverse effects associated with this treatment and decrease unnecessary glucocorticoid exposure by using glucocorticoid-sparing therapies and tapering treatment to a minimal effective dose.
Patients too need increased awareness of adverse effects before they begin treatment with this agent. They should be evaluated for conditions that can be worsened with glucocorticoid treatment, such as diabetes, hypertension, hyperlipidemia, heart failure, glaucoma, and peptic ulcer disease.22 Glucocorticoid treatment should be accompanied by physician vigilance for adverse events, and patients receiving long-term therapy should be given calcium and vitamin D supplementation. Among patients at high risk for glucocorticoid-induced osteoporosis, bisphosphonates or other antiosteoporotic medications during therapy should be considered. More research is needed to elucidate safe glucocorticoid doses for various adverse events, identify the independent effects of these agents on different outcomes, and to seek better ways to administer glucocorticoids more effectively and safely.
Kenneth Saag, MD, MSc, is Professor of Medicine in the Division of Clinical Immunology and Rheumatology, at the University of Alabama at Birmingham (UAB) School of Medicine, and Professor of Epidemiology, at the UAB School of Public Health. He is Director of the Deep South Musculoskeletal Center for Education and Research on Therapeutics and is Associate Director of the Multidisciplinary Clinical Research Center. Dr. Saag may be reached at kenneth.saag@ccc.uab.edu.
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