Continuing Concern about Bone Loss with Aromatase Inhibitors

BETHESDA, MD—The risk of breast cancer is reduced markedly when patients are switched from tamoxifen to such aromatase-inhibiting drugs as anastrozole, letrozole, and exemestane, but these newer drugs appear to have a detrimental effect on bones. “Patients on aromatase inhibitors should be closely monitored for bone mineral loss and advised of skeletal health-maintenance strategies,” said Katherine Weilbaecher, MD, Assistant Professor of Medicine, Pathology, and Immunology at Washington University School of Medicine. “Aromatase inhibitors have a negative impact on the skeleton when compared with tamoxifen.” Dr. Weilbaecher reviewed the data from three major studies—ATAC (Arimidex, Tamoxifen, Alone or in Combination); MA-17, which compared tamoxifen and letrozole and was conducted through the National Cancer Institute of Canada; and IES (Intergroupl Exemestane Study)—and found that in terms of the risk of fractures, there was either a significant difference or a trend that indicated a greater risk with the aromatase inhibitors than with tamoxifen. “Over the past three years in breast cancer treatment, aromatase inhibitors have come on the scene very powerfully,” she said. “If the cancer would just stay in the breast, we wouldn't be here at this meeting,” she said. “So we have therapies that try to decrease the risk of developing metastasis, and we use systemic therapies to do that. A big part of breast cancer therapy is trying to block estrogen production.” ATAC In the ATAC trial, the fracture rate was 11% in the anastrozole group and 7.7% for the tamoxifen group—an odds ratio of 1.49 for women taking anastrozole. “We saw no increase in hip fractures with anastrozole, which is important, but the fracture rate with anastrozole is still a concern,” said the lead investigator, Anthony Howell, MD, Senior Lecturer and Professor of Medical Oncology at the University of Manchester.Figure. Katherine Weilbaecher, MD: “Patients on aromatase inhibitors should be closely monitored for bone mineral loss and advised of skeletal health-maintenance strategies. Aromatase inhibitors have a negative impact on the skeleton when compared with tamoxifen.”“The other issue is fracture rate over time. I presented the data after six years, and the annual fracture rate is approximately 1.5% to 2% with tamoxifen and 2.5% with anastrozole. What surprised me was that during the fifth year of the trial, the fracture rate was lower in the anastrozole group than in the tamoxifen group, although not significantly lower,” he continued. “It seems that as soon as anastrozole is stopped, the fracture rate goes down. We had a bone subprotocol in which we evaluated lumbar spine and bone mineral density over time. In the first year, an approximately 2.5% drop in bone mineral density occurred in patients on anastrozole. At two years, it was slightly more than a 4% drop.” Canadian MA-17 Study In the MA-17 trial, there were more fractures in the letrozole group compared with the tamoxifen group but the difference did not reach statistical significance. Still, Dr. Weilbaecher said, the patients who received letrozole did have significantly decreased bone mineral density compared with those on placebo. Exemestane Results In the third study, as with the other two trials, there was a statistically significant increase in disease-free survival in the women who received exemestane. “When you look at the osteoporosis rate as measured by bone mineral density, patients who received the exemestane had a statistically higher incidence of osteoporosis,” Dr. Weilbaecher said. “And the exemestane group had slightly more fractures, although it did not reach statistical significance. Bone mineral density went down in the patients who received the exemestane compared with those who had tamoxifen.” Dr. Howell said that the data in the ATAC trial appear similar to that seen in the IES data with exemestane and the MA-17 data with letrozole. “The impact on bone mineral density is a class effect of aromatase inhibitors, and we need to learn how to manage it,” he said. ASCO Exemestane Study: After One Year, Bone Loss Temporary & Reversible A poster report at this year's ASCO Annual Meeting found that the bone mineral loss seen with exemestane was apparently reversed a year after treatment ended (OT, 6/25/05 issue). “These findings are good news because osteoporosis is such a large public health concern in breast cancer,” said the lead investigator, Per E. Lonning, MD, of Haukeland University Hospital in Bergen, Norway. The study (027) is the only placebo-controlled trial of an aromatase inhibitor conducted to date. In commenting on the study for OT, William Gradishar, MD, said, “The message is that if a woman is on exemestane therapy, there will not be a persistent adverse effect on bone. In the absence of head-to-head comparisons of the effect of different aromatase inhibitors on bone mineral density, one cannot say for sure that exemestane has the least adverse effects on bone over time, but this study tells us that exemestane would be a reasonable choice of aromatase inhibitor based on its effect on bone.”

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