Breast cancer can metastasize, or spread, to the bone. Finding new ways to prevent breast cancer from attacking bone is a major challenge in treating this cancer.

Clodronate, a drug used to prevent bone wasting in breast cancer patients, may also reduce the risk of bone metastases and increase survival, said a team of researchers in the Journal of Clinical Oncology (Vol. 20. No. 15: 3219-3224).

One of the co-authors of the study, Sandy Paterson, MD, of the Tom Baker Cancer Center and University of Calgary, in Alberta, Canada, explained that this oral drug has been used in some countries for several years.

Clodronate is used for treatment of bone tumors associated with other cancers because it "appears to have a direct [effect] on osteoclasts." Osteoclasts are cells that are associated with bone wasting.

Clodronate, which is one of a class of drugs called bisphosphonates, "doesn't kill cancer cells, but appears to have a bone bolstering effect, and that effect appears to offer a survival advantage," Paterson said.

But there are still many unanswered questions, Paterson said.

In the study, 1,069 women with breast cancer underwent traditional treatment: surgery, radiotherapy, chemotherapy, and/or tamoxifen as required. But within six months after treatment, 530 women were started on 1,600 mg of clodronate daily and 539 received inactive pill (placebo). The women were maintained on clodronate or placebo for two years.

During those two years of active treatment, about half as many women on clodronate had cancer spread to the bone compared to those taking the placebo.

But clodronate only appears to reduce the number of bone metastases "while women are actively taking the drug," said Paterson. When he and his colleagues considered the total follow-up period (about five and one-half years), the differences in bone metastases became too small to be considered important.

And there was no difference in the rate of metastases to other organs, with about the same number of women in both groups developing metastatic disease during the entire follow-up period.

Nonetheless, and somewhat surprisingly, there was a significant difference in survival: there were about one-fourth fewer deaths among those who took the clodronate.

So there are still several unanswered questions: How long should women be treated? Should a bisphosphonate be added routinely following breast cancer surgery? It this a real effect, or can it be explained by chance?

Many breast cancer experts hoped this most recent study would provide a final answer to those questions, explained Daniel Hayes, MD, clinical director of the breast oncology program a the University of Michigan Comprehensive Cancer Center.

Hayes, who wasn't involved in the clodronate study, said that two earlier studies had produced mixed results: a small study suggested bisphosphonates were beneficial and a larger study found no benefit.

"This is a very large trial and it was hoped that the results would provide a definitive answer," Hayes said.

Hayes believes the study by Paterson and colleagues may have been flawed from the outset because it recruited women who had only a small risk of developing bone metastases.

"We have these very small number of [metastases], which make it very difficult to consider these findings definitive," he said. Moreover, the survival benefit "comes late, so we don't know what to make of that either."

One of the reasons that doctors may be reluctant to routinely recommend bisphosphonates is that clodronate, although it is an old drug, is not approved for use in the US.

"The drugs [bisphosphonates] that we do have are not available as oral medications; they require IV infusion," said Hayes. "I don't think that many of us are anxious to tether women to two years of IV pamidronate [another bisphosphonate, which is approved in the US] every three weeks."

But Hayes said that doctors are "interested in a definitive study that can answer the questions raised by these early studies."

Paterson said answers may come from a new study that is currently underway. In the new study women will be randomized to active clodronate treatment or placebo for three years, "so we will find out if longer treatment will increase or sustain the benefit."

That study is about halfway through its recruitment phase, so Paterson predicted those results would be available in "about five years."

Meanwhile, both Paterson and Hayes agreed that women who are interested in adding bisphosphonates to breast cancer treatment should discuss this option with their treating oncologists. This is not, they point out, being promoted as standard treatment.