Amgen has reported that denosumab improved bone density and reduced the risk of vertebral fracture in men with nonmetastatic prostate cancer receiving androgen-deprivation therapy (ADT).¹

Men treated with uninterrupted ADT have significant loss of bone mineral density in the first 24 months after starting therapy. Bone loss increases the risk of osteoporosis, bone fracture, pain, hospitalization, and immobility, and increases medical costs. There is evidence that bone loss due to ADT can be reduced by early bisphosphonate therapy. However, there are still no clear guidelines for intervention for men with non-metastatic disease (bisphosphonates are advised for men with metastatic disease).

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 three or six 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 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.³ Patients in this study (n=255) were randomly allocated to receive one of five dose levels of denosumab or to receive an intravenous bisphosphonate. Researchers from the United States and Canada reported that denosumab consistently increases bone mineral density in women with non-metastatic breast cancer being treated long-term with aromatase inhibitors. These results were presented at the 2007 annual San Antonio Breast Cancer Symposium (SABCS).⁴

To evaluate the effect of denosumab among prostate cancer patients receiving ADT, researchers conducted a Phase III clinical trial among more than 1,400 men with nonmetastatic prostate cancer. In addition to ADT, men were assigned to receive either denosumab or a placebo.

• Compared with men treated with placebo, men treated with denosumab experienced significantly greater increases in bone mineral density at the lumbar spine and other skeletal sites.
• Men treated with denosumab experienced significantly fewer vertebral fractures than men treated with placebo.
• The rate of adverse events was generally similar between men treated with placebo and men treated with denosumab.

These results suggest that denosumab may provide a new approach to improving bone density and reducing fracture risk among prostate cancer patients treated with ADT.

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

Related News:

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

New Analysis Suggests Finasteride Prevents Prostate Cancer Without Increased Risk of High-grade Cancers (06/18/2008)

Fareston® Decreases Vertebral Fractures in Men with Prostate Cancer Receiving ADT (06/10/2008)

Reference: 

¹ Amgen Press Release. Amgen announces positive top-line results for denosumab treatment of bone loss in men with non-metastatic prostate cancer undergoing androgen deprivation therapy. Available at 1174433. Accessed July 14, 2008.

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

³ Lipton A, Steiger GG, Gigueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastasis. Journal of Clinical Oncology. 2007;25:4431-4437.

⁴ Ellis G, Bone HG, Chlebowski R et al. A phase 3 study of the effect of denosumab therapy on bone mineral density in women receiving aromatase inhibitors for non metatastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract #47.