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| |  Denosumab Reduces Bone Turnover Markers in Patients With Various Cancers: Presented at ASCO By Ed Susman CHICAGO -- June 4, 2008 -- Regardless of prior use of IV bisphosphonates, cancer patients receiving the investigational denosumab have decreased markers in bone turnover, according to research presented here at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting. Denosumab is a fully human monoclonal antibody that binds and neutralises receptor activator of NF-kappa-B ligand (RANKL) pathway, which has been shown to accelerate bone turnover and to have harmful effects on bone volume and strength, said investigator Julie Gralow, MD, University of Washington Cancer Care Alliance, Seattle, Washington. "In patients still having active turnover despite being on IV bisphosphonates, being switched to denosumab gives a really dramatic and rapid decrease in markers of bone turnover," Dr. Gralow said in an oral presentation on June 1. "Ultimately, the combination of the 2 agents might prove to be more useful -- hitting the osteoclasts in a couple of ways." She noted that while IV bisphosphonates are the current standard of care, "they have limitations in both efficacy and safety." She said bisphosphonates are associated with renal toxicity, first infusion effects including fever and chills, and osteonecrosis of the jaw. To date, denosumab has demonstrated no renal toxicity, no first infusion effects, and no osteonecrosis of the jaw, Dr. Gralow said. To test whether prior exposure to IV bisphosphonates affects denosumab's ability to suppress bone turnover, Dr. Gralow and colleagues compared results from studies of denosumab versus IV bisphosphonates in 255 bisphosphonate-naive patients diagnosed with breast cancer and bone metastases and in 111 men or women with solid tumours and bone metastases or multiple myeloma with evidence of high levels of bone resorption despite IV bisphosphonate treatment. Patients were randomised to continue IV bisphosphonate therapy every 4 weeks (n = 37), to receive denosumab 180 mg by subcutaneous injection every 12 weeks (n = 36), or to denosumab 180 mg every 4 weeks (n = 38). In treatment-naive patients, serum C-telopeptide levels were reduced by 80% after 25 weeks of treatment with either bisphosphonates or denosumab. Among patients previously treated with bisphosphonates, C-telopeptide levels were decreased by 50% among patients randomised to bisphosphonate treatment during the study, but the reduction was 80% among patients randomised to denosumab. Viable osteoclasts (TRAP 5b) in IV bisphosphonate-naïve patients were reduced by 40% in patients randomised to bisphosphonates and by 60% in those randomised to denosumab. Among patients treated with IV bisphosphonate prior to the study, TRAP 5b levels were reduced by 10% among patients randomised to IV bisphosphonates but by 70% in those randomised to treatment with denosumab. "The marked difference in TRAP 5b levels suggests the persistence of functioning osteoclasts despite treatment with intravenous bisphosphonates," Dr. Gralow commented. Bone-specific alkaline phosphatase reductions were about 40% in both treatment groups and both agents. She noted that rates of adverse events were similar between groups. The researchers concluded that these study findings support further evaluation of denosumab in phase 3 trials in oncology.
[Presentation title: Denosumab in Patients With Bone Metastases From Prostate, Breast, and Other Cancers and Elevated Urinary N-Telopeptide (uNTx) During Intravenous Bisphosphonate (IV BP) Therapy: Final Results of a Randomized, Phase II Study. Abstract 3596]
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