Doctors already use the drug to build up bone in patients receiving certain cancer treatments—aromatase inhibitors, for instance—that can cause bone loss. Zometa works by slowing down the activity of osteoclasts, the cells that break down bone tissue.

Findings from the AZURE trial, presented at the annual San Antonio Breast Cancer Symposium (SABCS) in December, suggested Zometa only works to prevent recurrence in women who are well into menopause. Not only do these select women have a lower risk of recurrence with Zometa, they also appear to live longer than women receiving standard treatment alone. 

When looking at the study’s 3,360 patients as a whole, there was no difference in disease-free survival after almost five years of follow-up, says Robert Coleman, MD, a professor of medical oncology at the University of Sheffield in England, who presented the findings. “That tells us that for patients, in general, with breast cancer, the use of [post-surgery] zoledronic acid can’t be supported.”

But among the 1,101 women who were at least five years past menopause or over age 60, adding Zometa to standard treatment led to a 29 percent reduction in the risk of death, with 120 deaths in the standard treatment-alone group and 86 deaths in the Zometa group. “Our conclusion would be that this is not an approach for all patients. But for those patients with established menopause or low estrogen levels, this does appear to be a treatment approach that should be considered,” Coleman says.

The differing results between AZURE and the Austrian study, known as ABCSG-12, may be explained by the minimal overlap in the type of patients enrolled and the treatment they received. Patients in AZURE had stage 2 or 3 breast cancer and received 19 total doses of Zometa over five years, whereas ABCSG-12 patients had stage 1 or 2 disease and received only seven doses over three years. But most notably, nearly all the pre- and postmenopausal women in AZURE received chemotherapy, while the treatment regimen for premenopausal women in ABCSG-12 included goserelin, a drug that switches off ovarian function and thus induces menopause.

“In both of those settings, women would have had very low estrogen levels—in our study, just by virtue of age; and in ABCSG-12, because they were given goserelin. The effect we’re seeing is on the host, not on the tumor,” Coleman says.

Even if the hormonal age of the patient is driving the difference in outcome, experts caution the concept is intriguing but not definitive. A number of other studies testing Zometa and related bone drugs will report findings over the next year, Coleman says. “I think they will greatly help us tease out this benefit or not.”

Julie Gralow, MD, director of breast medical oncology at Seattle Cancer Care Alliance and a professor of medical oncology at the University of Washington School of Medicine, says the findings won’t change how she treats patients. 

“For preservation of bone mineral density and prevention of fractures, I think it’s proven,” says Gralow, who was not involved in the studies. And if there happens to be disease benefit along the way, she’ll take it. “We try to do evidence-based medicine, but we also try to do the best for our patients.”

In an updated analysis of the ABCSG-12 study reported at SABCS, Zometa continues to protect patients from recurrence after more than five years of follow-up with a 32 percent risk reduction or a 3.8 percent absolute risk reduction.

For now, the AZURE study has raised more questions than it was hoping to answer. “I think our results will put a brake on the enthusiasm for adjuvant bisphosphonates that was engendered by the ABCSG-12 results,” Coleman said. “Inevitably it’s going to be a mixed message, and people are going to disagree or debate what the role is for some time to come.”

For more on updates from the 2010 San Antonio Breast Cancer Symposium, go to www.curetoday.com/sabcs2010.