Denosumab

Denosumab is a new osteoporosis medication that was approved in June 2010 by the FDA for treatment of severe osteoporosis. This drug inhibits bone resorption. It is an antibody to RANK-Ligand, the factor made by osteoblasts that is necessary for the formation of mature osteoclasts. Here's how to remember the generic name:

The brand name is "Prolia"

Indications

The FDA approved this for severe osteoporosis in postmenopausal women.

Clinical trials have also suggested it is effective in rheumatoid arthritis and cancer with metastases to the bone.

On a physiological basis it would be a good choice for patients with any disease characterized by rapid bone resorption, especially when the cause of the resorption is temporary.

Contra-indications

Dose and duration of therapy

The dose is 60mg given as sub-cutaneous injection once every 6 months. Adequate calcium and vitamin D was given in all the clinical trials. The optimal duration is not known. Clinical trials lasted 3 to 4 years, and during that time the drug was safe and effective. However, the bone formation is markedly suppressed and this could lead to brittle bone after prolonged use. When denosumab is discontinued, the effect wears off about 6 months after the last injection, and then bone density decreases rapidly. If another dose is given, the bone density again increases.

Side effects

Bone pain and back pain were commonly reported but were not different from placebo-treated patients (35% with back pain, 12% with extremity pain, 4% with bone pain)

New cancers or opportunistic infections were not significantly higher than in placebo groups. However, there is theoretical concern about this because the RANK-RANK-ligand signalling system is used by other cells, particularly the white blood cells that fight infections and tumors. Therefore, denosumab should be used cautiously in patients at high risk for infection.

Atypical fractures were not described in the trials, but bone formation was suppressed. The bone formation rate on bone biopsies after 2 or 3 years of treatment was zero (no tetracycline labels) in 36% of the patients and almost zero the in the rest (Reid I). Tetracycline was present in the urine so it is certain that the patients took and absorbed the tetracycline. It is not known (and widely debated) whether low bone formation would eventually make the bone more brittle; within the first 3 years this was not observed.

Osteonecrosis of the jaw was seen in 2% of patients with metastatic cancer who were treated with high doses (compared to 1.4% in the zoledronic acid group). This side effect was not seen in the osteoporosis studies.

The following .pdf documents are from the FDA webpage. The FDA approved a medication guide that should be read by all patients prior to receiving the drug.

 
The Prolia Medication Guide for patients
Package insert
Summary of safety concerns
Background for the FDA advisory committee

These are graphs of the fracture effects as reported to the FDA:

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Summary of clinical trials

The table shows percent change since baseline for bone density

Rheumatoid Arthritis

A randomized clinical trial in patients with active rheumatoid arthritis who were receiving methotrexate included 226 patients. They were allowed to take bisphosphonates or glucocorticoids. All received supplemental calcium and vitamin D, depending on the initial levels. The change in erosion score measured by MRI was significantly better in the denosumab-treated patients compared to the placebo-treated patients (Cohen).
A sub-study of those who were receiving either bisphosphonates or glucocorticoids (N=75) found that the bone density increased in denosumab compared with placebo (Dore). The bone density after one year was similar in denosumab treated patients with or without glucocortoicoids. The combination of denosumab and alendronate was similar to denosumab alone and better than bisphosphonates alone.

Metastatic cancer

The bone lesions in metastatic cancer follow a viscous cycle. The malignant cells secrete factors that stimulate the bone resorption. The bone contains growth factors that are released by resorption, and these growth factors further stimulate the malignant cells. The cancer cells can secrete RANK-ligand directly or indirectly by other factors that activate the osteoblasts. Thus, a medicine than blocks RANK-ligand theoretically should help to prevent the growth of these metastatic lesions.

Body and colleagues reported the results of a study comparing denosumab with zoledronic acid for the treatment of breast cancer patients with bone metastases. They randomized 2046 women and followed them for 34 months. The doses were higher than used in osteoporosis (denosumab 120mg or zoledronic acid 4mg every 4 weeks). The number of skeletal-related events was lower in the denosumab group and the time to the first event was delayed. The side effects related to infections were similar. The renal toxicity was 4.9%, compared to 8.5% in the zoledronic acid group.

Osteonecrosis of the jaw occurred in 20 denosumab-treated patients (2%) and 14 zoledronic acid-treated patients (1.4%)

Denosumab has also been studied in men with prostate cancer, patients with myleloma, and patients with giant-cell tumor of the bone. It also increases bone density in women who are receiving aromatase inhibitors for non-metastatic breast cancer. In all of these reports the results were favorable.

Click for more details about denosumab, bone histology, and physiology.

Updated 7/19/2010