A study of Amgen’s denosumab osteoporosis drug showed it increased bone density throughout the skeleton in postmenopausal women with breast cancer that had not yet spread and who were being treated with aromatose inhibitors, a type of cancer drug that can reduce bone density.

The results of the phase 3 trial were presented at this year’s 30th Annual San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas on Friday 14th December.

Dr Georgiana Kehr Ellis, Associate Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Seattle, said that:

“The risk of bone loss for women with breast cancer is a genuine concern and needs to be proactively managed when treating with aromatase inhibitors.”

The researchers presented results from the Phase 3 HALT Breast Cancer 135 study which showed that the human monoclonal antibody denosumab, given as a twice yearly injection, increased bone density that had deteriorated because of adjuvant aromatase inhibitor (AI) therapy to treat non-metastatic breast cancer.

The results showed that bone mineral density (BMD) increased throughout the skeleton, including cortical bone, the dense outer shell of the skeleton that supports and protects it, and trabecular bone, the spongy bone tissue that fills the inner cavity of long bones.

Most people think of the skeleton as a dead and static structure that stops us falling inside our skin. But bone tissue is very much alive, going through complex processes of continual renewal where old tissue is broken down and resorbed, and new bone tissue is formed.

The balance between resorption and formation is usually disrupted by AI therapy in postmenopausal breast cancer patients, who may already be in a state of increasing bone loss.

The balance is upset when osteoblasts, the cells that break down and resorb the old bone tissue, become overstimulated, resulting in too much resorption and not enough formation of new bone. Over time this leads to progressive loss of bone tissue, which weakens the cortical framework of the skeleton as well as the matrix of spongy trabecular tissue inside.

Denosumab targets RANK Ligand, the chemical messenger that binds to the RANK receptors on the surface of pre-osteoblast cells in all parts of trabecular and cortical bone, and helps turn them into full blown osteoblasts ready to break down bone tissue.

In other words denosumab slows down osteoblast production, which slows down bone tissue resorption and restores the balance between bone elimination and formation so that bone density is retained at the right level.

In this study, researchers compared BMD results of the drug group (127 participants) and a placebo group (125 participants) at several time intervals for various parts of the skeleton.

The researchers said that after only one month into the trial, the denosumab group was already showing a significant increase in lumbar spine BMD compared to placebo.

At month 12 there was a highly significant difference of 5.5 per cent lumbar spine BMD in favour of the denosumab group compared to placebo.

Also, total hip BMD was 3.7 per cent higher in the drug group, and femoral neck BMD was 2.5 per cent higher, compared to placebo at the 12 month point.

Denosumab also showed higher BMD results compared with placebo for a number of other exploratory targets, including distal radius and total body.

The drug was generally well tolerated, said the researchers, with overall adverse events being comparable between drug and placebo groups.

The most common adverse side effects were as expected for AI therapy, and included arthralgia (pain in joints), pain in extremity, back pain, fatigue, constipation, cough, and insomnia.

Dr Roger M. Perlmutter, executive vice president of Research and Development at Amgen, said:

“The results of this pivotal study provide a promising glimpse of the potential of denosumab to help manage bone disease in multiple tumor types and stages of disease in the cancer setting.”

“This data on denosumab evaluating its effect on BMD throughout the skeleton, including cortical sites, should be encouraging to clinicians who witness the devastating effects of cancer and cancer treatment on their patients’ bones,” he added.

Ellis added that:

“In this study, denosumab data looks promising, and as a clinician, I look forward to having a potential alternative to existing therapies.”

Denosumab is also being investigated in treatment-related bone loss in prostate cancer patients, and there are trials looking at the drug’s potential for delaying bone metastases and bone destruction across several stages of cancer.

Click here for San Antonio Breast Cancer Symposium.

Click here to learn more about bone resorption and formation (University of Washington course notes).

Written by: Catharine Paddock