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Zometa Counteracts Bone Loss From Endocrine Therapy

Zometa Counteracts Bone Loss From Endocrine Therapy

SAN ANTONIO—The bisphosphonate zoledronic acid (Zometa) effectively counteracts bone loss associated with combination endocrine treatment in premenopausal women with hormone-responsive breast cancer, Michael Gnant, MD, University of Vienna, said at the 27th Annual San Antonio Breast Cancer Symposium (abstract 6) on behalf of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).

Combination endocrine therapy for ovarian suppression using an LHRH analogue with tamoxifen yields benefits similar to chemotherapy in these patients, but treatment-induced bone loss is common and increases with treatment duration, he said. Aromatase inhibitors have generally superior toxicity profiles to tamoxifen but stronger adverse effects on bone. "Aromatase inhibitors are on the verge of replacing tamoxifen as adjuvant therapy for hormone-responsive breast cancer," Dr. Gnant noted.

ABCSG-12 Substudy

In ABCSG-12, with a planned enrollment of 1,800, premenopausal patients with stage I-II hormone-receptor-positive breast cancer are treated for 3 years with the LHRH analogue goserelin (Zoladex), 3.6 mg subcutaneously every 28 days, and randomized to one of four treatment groups: tamoxifen 20 mg/d plus placebo or IV zoledronic acid (4 mg every 6 months), or the aromatase inhibitor anastrozole (Arimidex), 1 mg/d, plus placebo or zoledronic acid. The trial design mirrors that of the ATAC trial for the premenopausal population.

Dr. Gnant and his colleagues conducted a substudy of 401 patients from ABCSG-12, to determine whether there is significant cancer-treatment-induced bone loss in patients treated with combination endocrine therapy. Their further question was whether zoledronic acid would counteract the bone loss. The 401 patients all had bone mineral density (BMD) measurements at baseline, 6 months, 1 year, and 3 years.

BMD Results

Analysis showed that most bone loss occurred in the first year. By 3 years, lumbar spine BMD in those patients receiving tamoxifen or anastrozole, but not zoledronic acid, was reduced by 14.4% (P < .0001): 11.6% in the tamoxifen/placebo group and 17.4% in the anastrozole/placebo group. BMD remained constant in those receiving zoledronic acid.

In addition, T-scores were significantly worse compared with baseline (P < .0001) in the anastrozole/placebo group (-1.7) than in the tamoxifen/placebo group (-1.1). For zoledronic acid, however, T-scores did not decline significantly. [A T-score is the number of standard deviations the BMD measurement is above or below the normal peak value for young adults. Osteoporosis is defined as a T-score of -2.5 or lower.]

The researchers also evaluated potential interactions with age or baseline BMD, and found no significant relationships. Furthermore, renal function was not affected by zoledronic acid, and no fractures have been reported to date.

The findings suggest, he said, that patients receiving combination endocrine therapy who have T-scores worse than
-2.5 or who lose a total of 10% of BMD within 12 months of treatment should receive a bisphosphonate. The trial’s further implication is that all such patients should have annual BMD measurements.

Responding to a question about news reports of mandibular necrosis in metastatic breast cancer patients receiving zoledronic acid, Dr. Gnant said that to date there have been no cases of mandibular necrosis reported in ABCSG-12, with 1,315 patients enrolled. He noted, however, that the trial involves younger patients "in a country where oral hygiene is not a problem."

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