BOSTON—The use of inhaled glucocorticoids can lead to bone loss at the hip, investigators at Brigham and Women’s Hospital and Harvard University recently demonstrated.[1]

Although both oral and parenteral glucocorticoids are known to cause bone loss, whether this adverse effect also applies to the inhaled drugs “has been controversial,” said Elliot Israel, MD, a coauthor of the study. “There had always been a question as to whether there was an effect. These data make it quite clear that there is,” added Dr. Israel, who is also Director of Respiratory Therapy and Director of Clinical Research at Brigham and Women’s Hospital in Boston.

CLINICAL IMPLICATIONS

Based on their study data, Dr. Israel and his colleagues estimated that a woman who begins taking 1,200 mg/d of inhaled glucocorticoids to control airway inflammation at age 30 will likely have 0.106 g/cm2 less bone mass at the trochanter when she enters menopause at age 50 than would an untreated woman of a similar age. This degree of bone loss more than doubles the risk of hip fracture (relative to that in a 65-year-old woman with normal bone mass for her age). The hip fracture risk would increase even further with continued use of inhaled glucocorticoids.

For their prospective cohort study, the investigators recruited 109 premenopausal women with asthma, ages 18 to 45 years. “The reason we chose premenopausal women,” Dr. Israel explained, “is that we didn’t want confounding by the variable rate of bone loss that occurs with menopause.” Excluded from the study were women who had received more than two short courses (two weeks or less) of oral or parenteral glucocorticoids within the preceding year or oral or parenteral glucocorticoid therapy (of any duration) within the preceding three months.

The study participants were divided into three groups: those not taking inhaled glucocorticoids at enrollment or for the preceding six months (28 women); those taking four to eight puffs/d of inhaled glucocorticoids (39 women); and those taking more than eight puffs/d (42 women). Use of triamcinolone acetonide (100 mg/puff) during the study period was recorded with patient diaries and automated actuator-monitoring devices.

Women who had a calcium intake of less than 1,000 mg/d and a vitamin D intake of less than 400 IU/d received supplementation. Bone density at the total hip, trochanter, femoral neck, and lumbar spine was measured at baseline, at six months, and at one, two, and three years.

DOSE-RELATED EFFECTS

A decrease in bone density occurred yearly at the total hip and at the trochanter (Table 1). At both sites, a negative linear association was noted between the average number of daily puffs of triamcinolone acetonide and yearly bone loss.

For each additional daily puff of the glucocorticoid, bone density decreased another 0.00044 g/cm2 per year. This association persisted even after adjustment for the use of oral or parenteral glucocorticoids (at a level below the threshold for exclusion), the concurrent use of topical nasal glucocorticoids, the age of the study subjects, and the use of oral contraceptives.

Because the decline in bone density was dose-related, it is important to prescribe the lowest dosage needed to achieve effective control, Dr. Israel noted. “We have made progress in making physicians and patients aware of the need for anti-inflammatory medications to control asthma,” he said. “What we have not done as well is emphasize that, once control is achieved, we need to find the minimum effective dose when it comes to inhaled corticosteroids. That dose is frequently less than that required to achieve initial control and also may vary by season or environmental influences. The bottom line is that it looks like [the bone loss effect] accumulates. We really need to work to make sure that patients are on the minimum dose.”

No significant bone loss was seen at the spine or the femoral neck. One possible explanation is that inhaled glucocorticoids have different effects in the hip than in other bones.[2,3] “We know that oral corticosteroids can affect different areas of the skeleton differently. Depending on the study, sometimes one area is affected, sometimes another. So we weren’t surprised when we saw [bone loss] only in one area. But the hip is obviously an important area because of hip fracture and the morbidity that occurs with hip fracture,” noted Dr. Israel.

Wide variations in the rate of bone loss were seen among the women studied; however, serial measurements of biochemical markers of bone homeostasis or adrenal function (serum osteocalcin and parathyroid hormone as well as urinary N-telopeptide, cortisol, and calcium excretion) did not predict which women would experience the greatest bone loss.

What explains the variations in bone loss? “Could it be an interaction between agent and a genetic predisposition?” Dr. Israel asked. “Yes, it could be,” he said, but “it’s speculative.”

CLINICAL RECOMMENDATIONS

Given the lack of known predictors for inhaled glucocorticoid–induced bone loss, Dr. Israel recommends that clinicians:

• Ensure that all patients who are using inhaled glucocorticoid therapy receive an adequate amount of calcium and vitamin D, either through their diet or with supplementation.

• Order bone density testing for patients who are taking moderately high doses of inhaled glucocorticoids (eg, more than 1,000 to 1,200 mg/d of most agents or more than 500 to 600 mg/d of fluticasone) and who have been using inhaled glucocorticoids for 10 years or longer to determine whether they are losing bone mass rapidly; institute medical intervention if it is necessary. This determination should be made earlier if patients have received courses of oral or parenteral glucocorticoids over the years or if they have other risk factors for osteoporosis (eg, physical inactivity, a history of early menopause).

Dr. Israel emphasized that the results of his study should not lead patients who have asthma to stop using inhaled glucocorticoids. The findings do, however, allow clinicians “to quantify what the risks are and

understand them better.” Inhaled glucocorticoids are lifesaving for many patients, he explained. “They are good and safe, effective drugs. [The new research] allows us to use them ‘smarter’ and to institute preventive measures and strategies for potential complications.”

—Christine M. Olsen, PhD