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Abstract & Commentary
Synopsis: Inhaled glucocorticoid therapy was associated with a dose-related decline in hip bone density in premenopausal women.
Source: Israel E, et al. N Engl J Med. 2001;345: 941-947.
Inhaled glucocorticoids are the mainstay of treatment for asthma and other respiratory conditions. It is widely held that their use poses minimal long-term health risks. Israel and colleagues sought to determine the effects, if any, upon bone density. To this end, they performed a prospective cohort study of premenopausal women. They recruited 3 groups: those not taking inhaled glucocorticoids; those taking 4-8 puffs daily; and those taking more than 8 puffs daily. Also, 109 women with 10 or more menses annually were enrolled between the ages of 18-45 years. Smokers were excluded as were those with any other medical conditions known to influence bone mass. Women who required oral glucocorticoids were excluded as were those taking any other substances known to influence bone density. All women were given calcium plus vitamin D (400 IU) supplements. Bone density was determined at baseline and at 0.5, 1, 2, and 3 years by dual-photon absorptiometry (Hologic®) in a single laboratory. A single investigator blind to subject status interpreted all results. Biochemical measures were also obtained at each visit.
There were no significant differences among the groups in respiratory status, physical activity, calcium intake, oral contraceptive use, or baseline bone density. There was a negative correlation between the average number of puffs per day of inhaled glucocorticoids and the annual change in bone density of total hip and at the trochanter. There was no association between glucocorticoid use or dose and bone density at femoral neck or lumbar spine across the 3-year observation interval. Urinary and serum measures of bone turnover (serum osteocalcin and parathyroid hormone and urinary N-telopeptide) were not consistently correlated with change in bone density. Israel et al note that a women who used inhaled glucocorticoids for 20 years premenopausally would experience sufficient bone loss to double her risk of hip fracture at age 65 based on bone density decline alone. However, they also note that women with osteopenia attributable to glucocorticoid use have a higher fracture rate than would be predicted from bone density alone. Glucocorticoid use apparently is a cause of bone fragility, which cannot be measured radiologically.
Comment by Sarah L. Berga, MD
Inhaled glucocorticoids are widely used for control of seasonal allergies, allergic rhinitis, and asthma. The prevailing assumption is that their use poses few medical risks, is devoid of nuisance side effects like sedation, is effective, and costs very little. There are studies, however, linking chronic inhaled or topical glucocorticoid use to an increased risk of osteoporosis and cataracts. For lipophilic compounds like steroids, systemic absorption from the lung is excellent. This is why there is reason to worry that the price one pays for short-term amelioration of respiratory conditions is long-term disability. The more serious the underlying respiratory condition, the more it may be worthwhile to assume these risks, particularly if there are no other equally effective medications. In weighing the pros and cons, it is important to remember that there are new medications that are especially effective for asthma control, namely, the leukotriene receptor antagonists, such as montelukast (Singulair®). These newer medications are much more selective in their targets (respiratory epithelium) and have fewer systemic side effects, but they are also much more expensive. Thus, health plans that offer pharmacy coverage tend to restrict their coverage of these selective compounds. The importance of this study is that it provides concrete data regarding the potential risks of inhaled glucocorticoids. In so doing, it creates the rationale for the use of safer, more targeted medications.
Another take-home message from this study is that the use of inhaled glucocorticoids should be added to the list of factors that increase the risk of osteoporosis. At midlife, women who have relied on inhaled glucocorticoids for the treatment of respiratory conditions should be offered an assessment of bone density, even if they had regular menses during their reproductive years. If they began the use of inhaled glucocorticoids in adolescence or childhood, the risk of osteoporosis and bone fragility is particularly heightened. It is not clear if there is any agent that can fully counteract the effect of glucocorticoids in women who must use them. After childbearing is complete, the use of bisphosphonates can be contemplated. Their use prior to the completion of childbearing is contraindicated because bisphosphonates are incorporated into the bone and then they slowly leach out. Therefore, even remote use may lead to incorporation of bisphosphonates into fetal bone during pregnancy. During reproductive years, the most that one can offer is oral contraceptives and adequate mineral and vitamin D intake. Exercise also stimulates bone accretion. While it is not clear that any combination of these prophylactic measures will fully counteract the effects of ongoing glucocorticoid exposure, one would recommend them anyway. In summary, it is particularly important to counsel women who use inhaled glucocorticoids about the potential risks of long-term osteoporosis and bone fracture. When feasible, an alternative treatment plan should be encouraged. It may fall to gynecologists to be the ones who sound the alarm and provide counseling about alternative medications and prophylactic measures.