SAN ANTONIO — Zoledronic acid infusions proved dramatically effective in preventing the pronounced bone loss that accompanies combination estrogen-reducing adjuvant endocrine therapy in premenopausal breast cancer patients, according to an update from a major Austrian clinical trial.
Indeed, the number of such patients who needed to be treated (NNT) with the third-generation bisphosphonate to prevent one additional case of osteopenia at 3 years was just 4.5 in the Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12), Dr. Michael Gnant reported at the San Antonio Breast Cancer Symposium.
Treatment-induced bone loss was particularly severe in participants who received goserelin plus the aromatase inhibitor anastrozole (Arimidex) without zoledronic acid (Zometa). By the time adjuvant therapy ended after 3 years, they averaged a 14% reduction from baseline in lumbar spine bone mineral density (BMD). Their BMD showed only partial recovery at 5 years—2 years after the conclusion of adjuvant therapy—with an 8% decrease from baseline.
In contrast, those patients randomized to a 15-minute, 4-mg infusion of zoledronic acid every 6 months for 3 years averaged a 3.1% increase over baseline in lumbar spine BMD at 5 years, said Dr. Gnant, professor of surgery at the Medical University of Vienna.
Prevention of bone loss in breast cancer patients treated with hormonal therapy is at present an off-label application for zoledronic acid.
The bisphosphonate's approved indications are treatment of patients with multiple myeloma, documented bone metastases from solid tumors, and hypercalcemia of malignancy.
The ABCSG-12 study involved 1,801 premenopausal women with stage I or stage II endocrine-responsive breast cancer and fewer than 10 positive lymph nodes. Dr. Gnant presented the 5-year results of the bone protection substudy, in which 404 patients on 3 years of goserelin were randomized to concurrent tamoxifen or anastrozole; half of those patients were randomized to twice-yearly zoledronic acid.
After 5 years, fewer than 50% of patients on goserelin plus anastrozole alone had normal bone health; the rest had osteopenia or osteoporosis. In contrast, roughly 70% of patients on anastrozole and zoledronic acid had normal bone health both at baseline and follow-up.
The NNT for zoledronic acid to prevent one case of osteoporosis at 3 years was 6.2, climbing to 15.5 at 5 years.
Expressed in terms of T scores, patients on goserelin and anastrozole alone averaged a 1.3-standard deviation loss at 3 years at the lumbar spine, with a half-standard deviation recovery by 5 years.
The BMD loss with goserelin plus tamoxifen alone, while less extensive, was still problematic: an average 9% decrease from baseline at 3 years and a 4.5% loss from baseline at 5 years. With zoledronic acid, however, BMD increased by 1% from baseline at 3 years and by 5.2% at 5 years. The NNT to prevent one case of osteopenia at 3 years in tamoxifen-treated patients was seven.
Dr. Gnant pronounced as excellent the safety and tolerability of zoledronic acid in this study. Bone pain, arthralgia, and fever were the only side effects that significantly increased in the bisphosphonate-treated group. There were three cases of osteonecrosis or osteomyelitis of the jaw, all in the zoledronic acid group. Dr. Gnant reported no relevant conflicts of interest.
“We believe that prevention of treatment-induced bone loss should be considered for premenopausal breast cancer patients receiving estrogen-reducing adjuvant therapies,” he concluded.
Audience member Dr. Mark Graham of the University of North Carolina at Chapel Hill congratulated Dr. Gnant on what he hailed as “certainly one of the most useful clinical studies presented in the last 5 years.”
Patients on goserelin and anastrozole alone averaged a 14% reduction from baseline in lumbar spine BMD. DR. GNANT