Researchers from the United States and Canada reported that the fully human monoclonal antibody, denosumab (Amgen), consistently increases bone mineral density in women with non-metastatic breast cancer being treated long-term with aromatase inhibitors. These results appeared in an advanced publication in the Journal of Clinical Oncology on August 25, 2008 and were presented in part at the 2007 annual San Antonio Breast Cancer Symposium (SABCS).¹ 

Aromatase inhibitors have become increasingly common for the treatment of hormone receptor-positive breast cancer. Aromatase inhibitors confer a survival benefit when compared to Nolvadex® (tamoxifen) among these patients; however, one of the main concerns associated with aromatase inhibitors is bone loss and increased fracture risk. Bisphosphonates have been evaluated for the prevention or reduction of bone loss for patients treated with aromatase inhibitors; however, most bisphosphonates require intravenous administration and may cause renal complications as well as osteonecrosis of the jaw.

Denosumab is a fully human monoclonal antibody that specifically targets the receptor activator of nuclear factor kappa B ligand (RANKL), a key mediator of the resorptive phase of bone remodeling. Denosumab is being studied across a range of conditions, including osteoporosis, treatment-induced bone loss, rheumatoid arthritis, bone metastases, and multiple myeloma. A previous study published in the February 23, 2006 issue of the New England Journal of Medicine showed that the subcutaneous administration of denosumab (every 3 or 6 months) for 12 months in postmenopausal women with low bone mass increased bone mineral density and decreased bone resorption.² There were 412 women in this study who were randomly allocated to receive denosumab, alendronate (Fosamax®) or placebo. Denosumab was at least as effective as alendronate in increasing bone density, and in some measurements it was superior. A randomized Phase II study of denosumab in women with breast cancer-related bone metastasis suggested that subcutaneous denosumab was similar to intravenous bisphosphonates in suppressing bone turnover and reducing skeletal-related events. More recently, researchers affiliated with the international trial known as the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) Trial have reported that treatment with denosumab significantly reduces the risk of vertebral and hip fractures among postmenopausal women with osteoporosis.

To further evaluate the effects of denosumab on bone density, researchers conducted a Phase III randomized, double-blind, placebo-controlled clinical trial among women with non-metastatic breast cancer who were being treated with an aromatase inhibitor. This trial included 252 women, all of whom received 1,000 mg of calcium and at least 400 IU of vitamin D. All had low bone mass but did not have clinical osteoporosis. The trial lasted 24 months.

Throughout the duration of the study (24 months), patients treated with denosumab had consistent increases of bone density at trabecular and cortical sites. At one year, patients in the denosumab group had a 5.5% increase in lumbar spine bone density, and at 2 years this had increased to 7.6%. Similar increases were noted in the total hip and distal radius bone density measurements. Increases in bone mass could be detected as early as one month, and the duration of aromatose treatment had no impact on outcome. These researchers also reported that markers of bone turnover decreased in the denosumab group. Adverse events associated with denosumab were similar to those of placebo.

The researchers concluded that denosumab appears to be a very effective treatment for bone loss among women receiving treatment with aromatase inhibitors for non-metastatic breast cancer. Denosumab not only halted bone loss compared to placebo, but increased bone density among women who had evidence of bone loss upon initiation of the trial. Researchers eagerly await results from the planned clinical trial further evaluating denosumab. Those conducting this trial hope to enroll 8,000 women.

Comments: Denosumab appears to represent a major breakthrough in the treatment and prevention of bone loss from a variety of diseases.

Related News:

Denosumab Reduces the Risk of Bone Fractures (09/22/2008)

Denosumab Reduces Fractures in Postmenopausal Women with Osteoporosis (07/31/2008)

Denosumab Improves Bone Density in Prostate Cancer Patients (07/16/2008)

Denosumab Effective in Treating Bone Loss Induced by Aromatase Inhibitors (12/17/2007)

Reference:

¹ Ellis GK, Bone HG, Chelbowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. Journal of Clinical Oncology 2008; published early on-line on August 25.

² McClung MR, Lewiecki EM, Cohen SB. Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine. 2006; 354: 821-831.