NEW YORK (Reuters Health) - Compared with zoledronic acid, the monoclonal antibody denosumab is more effective in delaying skeletal-related events in women with breast cancer that has metastasized to bone, according to the results of a new study.

The finding is reported in the November 8 online issue of the Journal of Clinical Oncology by Dr. Alison T. Stopeck with the University of Arizona and Arizona Cancer Center, Tucson, and an international team.

“Denosumab offers a new therapy for the treatment of bone metastases that is more effective, more convenient, and less toxic for patients,” Dr. Stopeck commented in an email.

The investigators observe that breast cancer metastases to bone induce osteoclast activity that results in skeletal-related events (SREs) such as palliative radiation therapy for pain or surgery for fractures. Intravenous treatment with zoledronic acid reduces the rate of SREs but requires renal function monitoring.

Denosumab, which was approved in June this year by the US Food and Drug Administration for the treatment of osteoporosis in women at high risk for fracture, binds RANK ligand and inhibits osteoclast activity.

In the current study, Dr. Stopek and colleagues randomly assigned 2046 breast cancer patients with bone metastases to treatment with subcutaneous denosumab 120 mg or intravenous zoledronic acid 4 mg every 4 weeks, along with the opposite placebo by IV or subcutaneous injection. The primary end point was time before a first SRE, defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression.

“Median time to first on-study SRE was 26.4 months for the zoledronic acid group and has not yet been reached for the denosumab group,” according to the report. The hazard ratio for a first SRE with denosumab compared to zoledronic acid was 0.82 (p=0.01),

The mean skeletal morbidity rate was 0.45 events per patient per year with denosumab compared with 0.58 with zoledronic acid (p=0.004).

As for safety, rates of severe or serious adverse events were similar in the two groups and were mostly attributed to the effects of chemotherapy or underlying disease. However, renal toxicity (8.5% vs 4.9%) and acute-phase reactions (27.3% vs 10.4%) were more common with zoledronic acid.

“The improved renal safety profile is important for patients who are receiving potentially nephrotoxic antitumor agents and older patients who often have decreased renal function,” Dr. Stopeck pointed out.

Hypocalcemia was less frequent with zoledronic acid than with denosumab treatment (3.4% vs 5.5%), but this was not a major concern. “No, it was typically treated with oral calcium supplements,” Dr. Stopeck said, “and is probably a reflection of the mechanism of action of the drug, i.e. osteoclast inhibition.”

Summing up, she added: “The fact that the therapy is administered subcutaneously and does not need renal monitoring is particularly important as it will spare patients the inconvenience of waiting for renal function results to return as well as the infusion time required for the intravenous therapies.”

Still, Dr. Stopek noted, “The long-term risks of (denosumab) are still unknown so we will have to continue to monitor our patients.”

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study
J Clin Oncol 2010.