Exemestane for Breast Cancer Prevention Weakens Bones

Zosia Chustecka

February 06, 2012

February 6, 2012 — New data from a subset of postmenopausal women participating in a landmark trial that established exemestane for the prevention of breast cancer show that the drug significantly worsens age-related bone loss.

When the exemestane results from the Mammary Prevention 3 (MAP.3) trial were reported last year, experts welcomed a new option for the chemoprevention of breast cancer, and several called for its widespread use in women who are at high risk for breast cancer. They noted that exemestane, an aromatase inhibitor, appeared to be safer and more effective than the selective estrogen-receptor modulators found to be effective in this setting — tamoxifen and raloxifene.

However, new data from a subset of patients taking part in that trial, published online on February 7 in the Lancet Oncology, show that exemestane weakens bones.

The subset data were collected from 351 women, representing 7.6% of the MAP.3 cohort (n = 4569). The subset study specifically examined bone effects of the drug; it measured bone mineral density (BMD) at baseline and after 2 years of therapy using high-resolution peripheral quantitative computed tomography (CT) screening and the more usual method of dual-energy x-ray absorptiometry (DXA).

The extra CT screening provided information on bone infrastructure and showed large decreases in cortical bone. These changes cannot be seen on DXA, the researchers explain.

"Exemestane worsens age-related decreases in bone mineral density by about 3 times, even in the setting of adequate calcium and vitamin D intake," noted lead author Angela Cheung, MD, from the University Health Network in Toronto, Ontario, Canada.

In an interview with Medscape Medical News, Dr. Cheung explained that each woman will have to weigh the benefits of taking the drug — substantially reducing the risk for invasive breast cancer — against the deleterious effects of the drug on bone seen in this new study. The clinical significance of these bone effects is not yet clear, she said, noting that longer-term studies are needed.

In the 2-year period of this subset study, there was no increase in fractures in the exemestane group, but the numbers are small and the time period is short, she emphasized.

"The bone changes that we saw on CT were real," Dr. Cheung said, "but whether they will increase the risk of fracture — time will tell."

Results of this study are important.

"Results of this study are important," writes Jane Cauley, DrPH, professor of epidemiology at the University of Pittsburgh, Pennsylvania, in an accompanying editorial.

This is the first study of the bone effects of an aromatase inhibitor that has used high-resolution peripheral quantitative CT. It sheds light on how bone is affected by these agents.

These results show that exemestane substantially affects the loss of cortical bone, compared with trabecular bone, Dr. Cauley notes. "This finding is important because 80% of our bone mass is cortical, and 80% of all fractures occur in nonvertebral sites that are mainly cortical."

"Cortical bone is not solid, but is riddled with pores that are active sites of bone remodeling," she explains. Cortical porosity increases with age, and most of the bone loss that is seen after 65 years of age occurs in this cortical component.

"If aromatase inhibitors increase cortical porosity, this effect could be a key cause of loss of bone strength and nonvertebral fractures associated with their use," Dr. Cauley notes. "Thus, one might not be too reassured about the use of exemestane in the prevention setting."

Study Underpowered for Fracture Outcome

The MAP.3 study was conducted in healthy postmenopausal women who were at moderately high risk of developing breast cancer, and showed that exemestane more than halved the risk for invasive breast cancer (65% reduction).

As reported at the time by Medscape Medical News, these results were presented at the 2011 annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine (2011;364:2381-2391). In that paper, the MAP.3 researchers note that the "absence of excess clinical fractures in patients treated with exemestane in this study is reassuring."

However, in her editorial, Dr. Cauley argues that the study was underpowered for a clinical fracture outcome, in part because of the underlying high risk for breast cancer in the participants. "Women with higher BMD have a higher risk of breast cancer than do women with lower BMD," she notes.

Closer Look at Bone Effects

In the MAP.3 subset study, Dr. Cheung and colleagues specifically set out examine the effects of exemestane on the skeleton.

The substudy involved 3 participating centers in Canada, and focused on 351 healthy postmenopausal women with an average age of 61 years. This is about a year younger than the main MAP.3 trial cohort, but otherwise the subset participants had similar characteristics, the researchers note. As with all the participants in the MAP.3 trial, those in the subset were taking calcium and vitamin D supplements.

The women in the subset study were not osteoporotic at baseline (BMD T score above –2.0 at the lumbar spine, total hip, and femoral neck).

The DXA results showed a small but significant decrease in areal BMD at the lumbar spine and at the total hip and femoral neck in women taking exemestane for 2 years, compared with those taking placebo. The magnitude of this loss of BMD is similar to that reported with exemestane in other trials, including other studies conducted in healthy postmenopausal women and studies conducted in women with breast cancer, the researchers note.

However, the results from the CT screening showed much larger decreases in BMD than those seen on DXA, the researchers note, demonstrating large and significant decreases in total volumetric BMD at the distal radius and distal tibia. More specifically, these CT scans showed decreases in cortical volumetric BMD and cortical thickness in women who were taking exemestane, which "implicate the loss of cortical bone," the researchers explain.

The loss of bone in women taking exemestane was about 3 times greater than in those taking placebo. Dr. Cheung noted that the loss measured with DXA was about 2.4% in the exemestane group and 0.8% in the placebo group; the loss measured with CT screening was about 6.1% in the exemestane group and 1.8% in the placebo group.

However, not all women showed bone loss. The deleterious effects of exemestane on bone were seen in about 65% of those on the drug, Dr. Cheung noted, but the extent of bone loss varied from woman to woman.

Thus, the risk for this deleterious effect on bone will be different for each individual woman. The impact of these changes will depend on the state of the bones before therapy begins, which needs to be taken into consideration when this treatment is being contemplated, she said. It also reinforces the need for monitoring of bone health, so that the women who are experiencing bone loss can be identified, she added.

Funding for this subset study came from the Canadian Breast Cancer Research Alliance. Dr. Cheung's coauthor, P.E. Goss, reports serving as a consultant for Pfizer. The remaining researchers and Dr. Cauley have disclosed no relevant financial relationships.

Lancet Oncol. Published online February 7, 2012. Abstract, Editorial

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