News

Breast Cancer Drug Exemestane Linked to BMD Loss

View on the News

Adverse Bone Effects ‘Substantially Underestimated’ Until Now

"Results of this study suggest that effects of aromatase inhibitors on bone strength might have been substantially underestimated because all previous data relied on dual-energy x-ray absorptiometry," which cannot assess volumetric bone density or trabecular and cortical microarchitecture, said Dr. Jane A. Cauley.

In contrast, high-resolution quantitative CT allowed separate examination of the cortical and trabecular compartments and found that exemestane substantially increased loss of cortical bone compared with trabecular bone. "This finding is important because 80% of our bone loss is cortical and 80% of all fractures occur in nonvertebral sites that are mainly cortical. These fractures account for most of the disability and costs due to fracture," she wrote.

Dr. Cauley is with the University of Pittsburgh. She reported no financial conflicts of interest. These remarks were taken from her editorial comments accompanying Dr. Cheung’s report (Lancet Oncol. 2012 [doi:10.1016/S1470-2045(12)70030-X]).


 

FROM THE LANCET ONCOLOGY

Exemestane significantly decreases bone mineral density in healthy postmenopausal women who take it to reduce their risk of breast cancer, according to a study published online Feb. 7 in The Lancet Oncology.

Two years of daily oral treatment with the steroidal aromatase inhibitor was found to worsen age-related decreases in BMD "by about three times, even in the setting of adequate calcium and vitamin D intake," said Dr. Angela M. Cheung of the University Health Network in Toronto and her associates.

Dr. Cheung and her colleagues performed a safety substudy as part of the National Cancer Institute of Canada’s Mammary Prevention Trial 3 (MAP.3), a double-blind randomized study showing that exemestane significantly reduced the development of breast cancer in high-risk women, compared with placebo. Previous studies had suggested that exemestane exerted a small protective effect and caused less bone loss than other, nonsteroidal aromatase inhibitors such as anastrozole and letrozole.

This substudy focused on the drug’s effect on bone health and involved 351 subjects with T-scores above 2.0 at the lumbar spine, total hip, and femoral neck at baseline. The women had adequate dietary intake of calcium and vitamin D but received supplements as well. This was not a large enough sample to assess fracture risk directly, so the researchers instead assessed the intermediate end points of bone density and structure.

Theirs is the first study to use high-resolution peripheral quantitative CT scanning as well as the usual dual-energy x-ray absorptiometry to examine bone. Unlike the latter method, high-resolution peripheral quantitative CT captures aspects of bone fragility, including microarchitectural, geometric, and material properties that heavily influence fracture risk, the investigators noted.

The study subjects were treated and followed at three medical centers in Canada and two in the United States; median age was 61 years. A total of 176 were randomly assigned to receive daily oral exemestane and 175 to receive placebo.

The primary end point, percent change in total volumetric BMD at the distal radius after 2 years, was significantly greater with exemestane (mean loss of 6.1%) than placebo (mean loss of 1.8%). Exemestane also decreased cortical volumetric BMD at the distal radius by 4.6%, compared with 1.9% for placebo.

The drug also decreased total volumetric BMD at the distal tibia (loss of 5.0%) and cortical volumetric BMD at the distal tibia (loss of 5.3%), compared with placebo (losses of 1.3% and 2.3%, respectively).

In addition, exemestane was associated with a loss of 7.9% in mean cortical thickness at the distal radius (compared with –1.1% with placebo) and a loss of 7.6% in cortical thickness at the distal tibia (compared with –0.7% with placebo). Exemestane also cut mean total area and mean cortical area at both sites, compared with placebo, Dr. Cheung and her associates said (Lancet Oncol. 2012 [doi:10.1016/S1470-2045(11)70389-8]).

With exemestane, more women had clinically significant areal BMD loss at the lumbar spine (45%), total hip (26%), and femoral neck (22%), compared with placebo (20%, 19%, and 6%, respectively). Moreover, 65% of women taking exemestane showed clinically significant areal BMD loss at one of these three sites, compared with only 35% of women taking placebo.

These changes in bone strength, however, were not reflected in fracture rates during this relatively short study. There were no significant differences between the two study groups in fractures deemed to be attributable to bone fragility (1 with exemestane and 3 with placebo) or in total fractures (6 with exemestane and 11 with placebo), and the difference in height reduction (2 mm for exemestane vs. 1 mm for placebo) also was not significant, the researchers noted.

More importantly, "the minor areal BMD changes detected by dual-energy x-ray absorptiometry did not reflect the underlying structural deterioration seen with high-resolution peripheral quantitative CT. Although dual x-ray absorptiometry is the current clinical gold standard for skeletal assessment of fracture risk, it does not capture bone geometry, microarchitecture, or biomechanical properties, which also contribute to fracture risk," Dr. Cheung and her colleagues noted.

Unfortunately, this CT technique is not yet available for routine clinical care, they added.

This study was limited in that it involved healthy, predominantly white women with normal BMD and adequate calcium and vitamin D intake, so the findings may not be generalizable to women with osteoporosis, women with breast cancer, or nonwhite women. Also, follow-up was only 2 years; longer follow-up (up to 5 years) is needed to assess exemestane’s long-term effects on bone, the researchers said.

Nonetheless, the findings do reinforce the importance of monitoring bone health in these patients, they said.

Pages

Recommended Reading

BRCA1/2 Mutations Tied to Better Ovarian Cancer Survival
MDedge Internal Medicine
Gastric Cancer Subtype May Affect Bevacizumab Benefit
MDedge Internal Medicine
Bevacizumab Boosts Treatment Responses in Early Breast Cancer
MDedge Internal Medicine
Oral HPV Infection More Prevalent in Men Than Women
MDedge Internal Medicine
Cancer Screening Falls Short of Federal Targets
MDedge Internal Medicine
Head/Neck Cancer Treatments Less Effective in HIV Patients
MDedge Internal Medicine
Re-Excision Rates After Breast-Conserving Surgery Vary Greatly
MDedge Internal Medicine
ASCO GU to Spotlight Prostate Cancer Drugs MDV3100 and Radium-223
MDedge Internal Medicine
MDV3100 Cuts Risk of Death in Advanced Prostate Cancer
MDedge Internal Medicine
ALSYMPCA Trial: Radium-223 Prolongs Life in Some Prostate Cancers
MDedge Internal Medicine