Denosumab treatment significantly increased bone density in the lumbar spine compared to placebo, in addition to the hip, the wrist and the total body. In another study, the drug also seemed to protect bone from erosion in rheumatoid arthritis patients.
Denosumab is a monoclonal antibody which targets RANK Ligand, a cell mediator that break down bone. RANK Ligand is found in many parts of bone.
What I find interesting is that Amgen is also looking at the effect of denosumab on bone erosions in rheumatoid arthritis in a Phase 2 study. RANK Ligand-driven osteoclast activity — osteoclasts being those cells which erode the bones — has been implicated in the destructive bone erosions which are characteristic of rheumatoid arthritis and other forms of erosive arthritis such as psoriatic arthritis.
A rheumatoid arthritis study looked at over 200 patients who received different dosages of denosumab by injection every 6 months. X-rays of hands and feet were taken at the start of the study and then at 6 and 12 months. The study showed that there was a reduction in the progression of destructive bone erosions compared to placebo.
So, it appears that there may be an important future role for denosumab, a potent osteoclast inhibitor, in the treatment of rheumatoid arthritis patients. However, it should be noted that the place of denosumab in the treatment of rheumatoid arthritis is far form clear, because we still do not know if denosumab improves how a patient feels: Does denosumab improve, for example, fatigue, pain or morning stiffness?
It also is not clear as to whether denosumab helps to treat or prevent steroid-induced osteoporosis. If it did, this would be so important, because many rheumatoid arthritis patients are taking or have taken corticosteroids such as prednisone at some point in the course of their illness. The corticosteroids can of course make worse the osteoporosis that many rheumatoid arthritis patients suffer from — often due to the lack of physical activity, which is in turn due to the inflammatory joint activity and the pain from the swelling.
Interestingly, osteoclasts are an important part of the cell cocktail which migrates to the inflamed joint. Denosumab targets these cells, and makes for an attractive therapeutic tool for treating rheumatoid arthritis.
And even though RANK Ligand blockade appears to not inhibit inflammation, there are several reasons for targeting RANK Ligand:
- Structural damage in rheumatoid arthritis often progresses despite the use of disease-modifying drugs such as methotrexate or sulfasalazine, especially in patients who are NOT being treated with biologic drugs such as Enbrel or Humira.
- Structural damage is a major cause of decreased joint function and disability in rheumatoid arthritis patients; effective therapy is therefore needed to preserve the normal joint.
- Targeting RANK Ligand directly affects the mechanism responsible for the loss of cartilage and bone in long-term rheumatoid arthritis.
We should keep it well in our mind’s eye that rheumatoid arthritis is a disease that destroys bone. Physicians must remember that the job at hand is to not simply control inflammation, but also to halt or prevent structural damage (for example, erosions). Structural damage has its basis in rheumatoid arthritis on the formation of osteoclasts in and around the joint, which in turn take away mineralized cartilage and bone. The generation of osteoclasts depends on RANK Ligand.
Inhibition of RANK Ligand is a novel way of improving the rheumatoid arthritis patient. It is a novel way of treating osteoporosis, a common affliction of the rheumatoid arthritis patient.
Let us look forward to more studies with denosumab. Perhaps there will be a time in the future when patients and doctors can use this new drug, and the two birds of rheumatoid arthritis and osteoporosis will be effectively killed with the one stone, denosumab.