BCRF researchers ask: will bisphosphonates aid in reducing bone metastasis?

Bone metastasis is a dreaded diagnosis for breast cancer patients, but one that is all too common. BCRF grantee, Julie Gralow, MD, Associate Professor of Medical Oncology, University of Washington School of Medicine, cites the statistics. "For 35 to 40 percent of breast cancer patients, the skeleton is the initial site of recurrence. In women with metastatic breast cancer, bone involvement occurs 60 to 80 percent of the time." Gralow should know. She and her BCRF-funded colleague Peggy L. Porter, MD, of the Fred Hutchinson Cancer Center, working on behalf of the Southwest Oncology Group, are studying ways to diagnose, treat and avert bone metastasis in breast cancer. In the past two years, they've turned their attention to a class of drugs known as bisphosphonates.

Bisphosphonates have been around for a long time, and are in medical use for the prevention of osteoporosis-deterioration and loss of bone density, common among women as they approach and go through menopause. Their commercial names - Fosamax, Actonel, Boniva and Reclast - are well-known to many women taking the drugs. Like most of the body, bones are in an ongoing state of self-renewal. A process called resorption allows bones to shed old tissue and rebuild. Beginning in their 30s, women's bones start breaking down faster than they can be rebuilt. Bisphosphonates inhibit the normal process of resorption, and in turn preserve bone density. Turns out, the inhibitory power of bisphosphonates may also be good for breast cancer patients. In addition to bisphosphonates inhibiting the process of bone deterioration in osteoporosis due to normal aging, this class of drugs may also be able to disrupt the relationship between breast cancer cells and the bone environment during the early process of cancer spread (or metastasis). Gralow's study is designed to determine whether the unique class of drugs can delay or prevent metastases in high-risk patients with breast cancer but who have no evidence of metastatic disease.

Bisphosphonates are not without side effects. Recent case reports and a small, retrospective study, described on July 15 in The New York Times, have documented a rare leg fracture in non-cancer patients who have been taking Fosamax for more than five years to prevent osteoporosis. The fracture generally shears the bone of the upper thigh known as the femur with little or no impact. Another infrequent side effect of high-dose bisphosphonates taken intravenously by cancer patients to reduce the bone-weakening effects of some forms of chemotherapy is osteonecrosis of the jaw - in other words, a die-off (or disruption in healing) of the bone tissue there.

Testing the potential effectiveness of bisphosphonates in preventing or reducing bone metastases requires a high dose of the drugs. Gralow and Porter are cautious about the eventual dosage requirements of bisphosphonates as a treatment in breast cancer. For this reason, they, along with Dr. Susan Ott, an endocrinologist, have launched a sister study (funded in part by The Breast Cancer Research Foundation) in healthy, pre-menopausal women, to learn the effects of high-dose bisphosphonate use. The participants of this study have agreed to many forms of bone measurement over the three years of the study. The results will provide valuable information about the skeletal effects of bisphosphonates that have so far not been determined.

Given that the reported dramatic side effects are extremely rare and the positive impact of bisphosphonates in preventing osteoporosis so great, the drugs likely will remain in wide use. Doctors may modify their prescription of the drugs, making sure that only the women at highest risk for osteoporosis continue taking them past five years.

If the class of drugs proves useful in reducing and preventing bone metastases, oncologists like Gralow will use them, as wisely and precisely as possible. Preliminary studies suggest that bone recurrences and deaths due to breast cancer may be reduced by adding high doses of bisphosphonates to standard breast cancer therapy, but not all breast cancer patients are at risk for bone metastases. An additional ongoing study led by this group is evaluating patient- and tumor-specific features that would help predict a recurrence of cancer in the bone versus other locations. This would allow more specific use of bisphosphonates in patients most likely to benefit - those at risk for bone recurrence. These innovative studies meet a criterion that has improved outcomes in breast cancer and that so many doctors and researchers use as a mantra: treat the right patients with the right medicines.