Early Zoledronic Acid Beats Late for AI Bone Loss


SAN ANTONIO — Up-front administration of zoledronic acid in postmenopausal women taking an aromatase inhibitor to reduce their risk of recurrent breast cancer is significantly more effective at preventing bone loss than a strategy of delayed initiation of zoledronic acid, according to 36-month data from Z-FAST, the Zometa-Femara Adjuvant Synergy Trial.

This Z-FAST finding casts into question the current guideline-recommended strategy of reserving bisphosphonate therapy for the subset of breast cancer patients who experience marked loss of bone mineral density (BMD) or a fracture while on an aromatase inhibitor (AI). A routine of prophylactic bisphosphonates from the onset of AI therapy appears to be a better way to go, Dr. Adam Brufsky asserted at the annual San Antonio Breast Cancer Symposium.

On the other hand, Z-FAST didn't show a significant difference in fracture rates with up-front—as compared with delayed—initiation of zoledronic acid (Zometa), and fractures are the key end point in clinical practice, audience members countered.

Z-FAST was an open-label trial that involved 602 postmenopausal women with early-stage, hormone-receptor-positive breast cancer at 94 U.S. and Canadian sites who were placed on 5 years of adjuvant therapy with the AI letrozole (Femara), along with calcium and vitamin D supplements. The women were randomized to up-front intravenous zoledronic acid at 4 mg twice yearly or to delayed initiation of the third-generation bisphosphonate.

Women in the delayed-initiation group were placed on zoledronic acid if their lumbar spine or total hip BMD T score fell below −2.0 standard deviations or if they experienced a clinical fracture or an asymptomatic spinal fracture detected on a mandatory x-ray, which was part of the study protocol. Through 36 months, 20% of patients in the delayed-initiation group qualified.

The primary study end point was change in lumbar spine BMD, compared with baseline. The up-front therapy group showed a mean 3.72% increase; the delayed group showed a 2.95% decrease, for a highly significant absolute 6.7% difference favoring up-front therapy. When patients in the delayed-initiation group who had been placed on zoledronic acid were excluded, this difference climbed to 8.2%. Markers of bone turnover were effectively suppressed in the up-front therapy group only.

The fracture rate was 5.7% in the up-front group and 6.3% in the delayed zoledronic acid group, a nonsignificant difference. However, Z-FAST wasn't powered to detect a difference in fractures, stressed Dr. Brufsky of the University of Pittsburgh.

The rate of recurrent breast cancer was 3.5% in the up-front zoledronic acid arm and 6.9% in the delayed group. “These numbers are fairly small—9 versus 16 patients—and did not achieve statistical significance. And these data are only exploratory. But they are rather interesting,” he observed.

There were two episodes of grade I/II renal insufficiency believed related to zoledronic acid. However, there were no significant differences between the two study arms in arthralgia, myalgia, fever, or other side effects. And among the 602 study participants, there was not a single confirmed case of osteonecrosis of the jaw, a side effect that has been reported with bisphosphonates.

Audience member Dr. Hope S. Rugo of the University of California, San Francisco, asked if, in light of the lack of a major reduction in fractures in the up-front zoledronic acid group, it would be more prudent to stick to the delayed-initiation strategy. That strategy is in accord with current American Society of Clinical Oncology guidelines, which recommend individualized therapy.

Dr. Brufsy replied that, had Z-FAST been a 3,000- or 4,000-patient trial, he suspects—based upon the highly significant differences observed in surrogate end points—that the trend for fewer fractures with up-front therapy would have achieved significance.

“I'm not certain that every woman [on an AI] should get these drugs, but I'm becoming more convinced of that over time,” he added.

Dr. Brufsky is a member of an international expert panel that develops alternative evidence-based guidelines for prevention of AI-associated bone loss in breast cancer patients. In a separate presentation at the symposium, fellow panelist Dr. Peyman Hadji outlined the group's recommendations.

Based on a systematic literature review, the panel recommends that, in addition to calcium and vitamin D supplements, any breast cancer patient initiating AI therapy with a baseline T score below −2.0 should be placed on zoledronic acid.

Moreover, up-front zoledronic acid also will be recommended by the expert panel for patients receiving an AI who have any two of the following risk factors: a T score below −1.5, age greater than 65 years, a personal history of a fragility fracture after age 50 years, a family history of hip fracture, or a history of more than 6 months of oral corticosteroid therapy, added Dr. Hadji of Philipps University, Marbug, Germany.


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