Early Use of Zoledronic Acid Prevents Letrozole-Related Bone Loss

Paula Moyer, MA

March 24, 2006

March 24, 2006 (Nice, France) — Women who receive zoledronic acid (Zometa) at the initiation of breast cancer treatment with letrozole (Femara) have less bone loss than those for whom treatment is postponed, according to an international team of investigators who presented their findings here at the 5th European Breast Cancer Conference.

"It would appear from this study and others that zoledronic acid can prevent that bone mineral density loss," said principal investigator Nigel Bundred, MD. "Therefore, this may be a useful strategy for women at risk of cancer-associated bone loss." Dr. Bundred, a professor of surgical oncology at South Manchester University Hospital in the United Kingdom, reported on 12-month data from the Zometa-Femara Adjuvant Synergy Trial (ZO-FAST).

The study was designed to determine whether combining letrozole with zoledronic acid would preserve letrozole's ability to prevent breast cancer recurrence and yet minimize the bone loss that is known to occur with letrozole and all other aromatase inhibitors. The investigators also wanted to know whether timing made a difference, ie, whether initiating zoledronic acid therapy simultaneously with letrozole or after treatment with letrozole had been well established would be more effective.

The researchers recruited 1066 patients from 150 centers and 28 countries. Patients were postmenopausal and had estrogen receptor–positive breast cancer in stages I to IIIa. Eligible patients had a bone mineral density (BMD) T score of at least 2 standard deviations (SD) below normal.

Patients were randomized to receive intravenous zoledronic acid at a dose of 4 mg once every 6 months or to start receiving it after a delay. The delayed group received zoledronic acid when their BMD T score decreased beyond 2 SD below normal, or if they had a nontraumatic fracture, or if they were found to have an asymptomatic fracture when they were assessed at 36 months after starting letrozole therapy. At this interim point, the crossover rate was 15%, Dr. Bundred said.

The investigators identified a change in lumbar spine BMD as the primary end point, and they defined clinically significant bone loss as a 6% reduction in BMD per year, a cumulative reduction in BMD of 8% during any period of time, a T score exceeding 2.5 SD below normal, and a fracture or impending fracture on x-ray.

Of these patients, 573 had had prior adjuvant chemotherapy and 493 had not. The baseline BMD T score was less than 1 SD below normal in 718 patients and 1 to 2 SD below normal in 348. The median age of patients in this study was 58 years.

At this point, the most common adverse effect reported was arthralgia, reported by 21.3% of the women. Of the original participants, 90 (8%) withdrew from the study, of whom 42 (4%) had experienced adverse events.

At 12 months, women in the delayed group had lost an average of 3.5% BMD at the lumbar spine and 2% at the hip compared with a slight increase in BMD at those sites in the group receiving immediate treatment (P < .0001). Of women who were postmenopausal, the average total BMD loss in the delayed group was 6%, with virtually no change in women receiving immediate zoledronic acid treatment (P < .0001). Biomarkers such as N-teleopeptide and serum calcium, which can indicate an increased rate of bone resorption and therefore BMD loss, were increased in the delayed-treatment group and unchanged in the immediate-treatment group.

"At 12 months there is little difference in the groups' fracture rates," Dr. Bundred said. "However, we can see that immediate treatment with zoledronic acid when starting letrozole prevents BMD loss in women with early breast cancer who are being treated with letrozole." Dr. Bundred and coinvestigators will be following this cohort for several more years, he said.

"Aromatase inhibitors are better than tamoxifen at preventing recurrence, and they entail no risk of endometrial cancer," said Gordon McVie, MD, in an interview seeking outside comment. "However, because they're acting on different targets, they don't have the protective effect on bone that tamoxifen does. Fortunately, bisphosphonates are available." Dr. McVie is a senior consultant for research strategies and international affairs at the European Institute of Oncology in Milan, Italy.

"This study carries the logic one step further: prophylactic bisphosphonate versus delaying until later in management," Dr. McVie added. "Pretty predictably, the effect was seen straightaway, and it was quite impressive." However, to know whether prophylactic bisphosphonate treatment is appropriate for women commencing aromatase inhibitor therapy, an independent trial would be needed, and there are other bisphosphonates other than zoledronic acid that may be just as effective."

The study was sponsored by Novartis, the maker of Zometa and Femara.

5th EBCC: Abstract 12. Presented March 22, 2006.

Reviewed by Margie Miller

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