More on monoclonal antibody to RANKL
Inhibition of RANKL by denosumab to treat osteoporosis. There is a previous update on this topic that involved the initial phase 1 dose escalation clinical trials of this method of treating osteoporosis. This initial study was very promising showing that biochemical markers of bone breakdown were affected very rapidly, positively and long term by this potential medication. Now there is a further study by McClung, MR and others, N Engl J Med. 2006 Feb 23;354(8):821-31, PMID: 16495394. This is a rather complex topic that I'll let you read if you want. I'll try to simplify the bottom-line details in a nonscientific way to describe how important this concept could be in the fight against osteoporosis. First some background information. Osteoclasts are the cells that break down bone, generally overdoing their work in the case of osteoporosis by breaking down more bone that gets formed. So, if you can shut these cells down while still allowing osteoblasts (the cells that form bone) to work, you could have an excellent way to treat osteoporosis. In fact, this is basically how the bisphosphonates such as Fosamax or Actonel work—they block osteoclasts. Now think of RANKL as a critical on switch needed for the development of osteoclasts. Then think of denosumab (the fully human monoclonal antibody used in this study), as the off switch for RANKL. If you switch off RANKL, you stop osteoclasts from doing their job, which should mean a net gain in bone mineral density (BMD). This study showed that is exactly what happened and determined that, in a one-year period, women gained 6.7% BMD in the lumbar spine and 3.6% BMD in the total hip. It was also determined that the ideal dose appears to be a single 60 mg subcutaneous injection ONCE EVERY SIX MONTHS. Editor's comments: Obviously the exciting aspect of denosumab is the very long-acting effect it has on blocking osteoclasts with a single injection. One of the items mentioned by the authors that make this method of treating osteoporosis so interesting is that one recent study found for all osteoporosis therapies examined, there was a reported one-year adherence rate of less than 25%. PMID: 15207894. A subcutaneous injection only twice yearly should improve this compliance rate tremendously. We are a few years away from an FDA approval on this, but it appears to be something to look forward to that could be a very significant advance in the treatment of osteoporosis. For an overview of the inhibition of RANKL concept by the lead author of the above article, see Current Osteoporosis Reports: 2006, 4:28-33. PMID: 16527005. One interesting comment he makes is, “Additionally, because of the antibodies extracellular mechanism of action, the possibility exists of using denosumab to enhance the effect of other antiresorptive agents or, more interestingly, potent anabolic agents.” Thus there could be an even greater increase in BMD if denosumab is, e.g., combined with teriparatide or one of the bisphosphonates. So this is an exciting area of osteoporosis research.
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