Using Bone Cells to Target Pain

Harnessing the remodelling processes in bone is a target for treating pain related to cancer that has spread to the bone. Remodelling is the natural process by which bone recycles and regenerates. Two major cell types drive the remodelling of bone – osteoblasts and osteoclasts.

Osteoclasts recycle bone by creating an acidic environment to dissolve bone, which is a process that can trigger bone pain. In the presence of tumour cells, the number and size of osteoclasts increases in bone tissue. Larger osteoclasts are better at doing their job at forming an acid environment and dissolving bone.

When RANK binds to its receptor (RANK ligand) it activates NF-kB, which promotes the formation of osteoclasts in bone and increases bone resorption, so inhibiting this activation will help preserve bone health. This feature has been exploited in the treatment of osteoporosis.

Osteoprotonegrin acts a decoy receptor for RANK and prevents bone resorption. A monoclonal antibody, denosumab has been developed that mimics this decoy receptor action. In animal models, denosumab reduced pain in half plus preserved bone mass by interfering with osteoclast demineralisation. Bone cancer pain is reduced when the bone is less fragile and the bone is much less likely to fracture, which is a major problem. The drug reduces the pain that bone cancer patients have when they move. It also may slow down the spread of the cancer as weaker bone is more vulnerable to cancer spread.

Cancers that promote bone formation when they spread also cause bone pain. For example, prostate cancer when infiltrates bone causes this type of pain. The nerve growth factor neurotrophin regulates the growth of nerves and what we perceive as painful. Normal activity or movement is often perceived as painful when cancer is causing the pain. TrkA is the receptor for neurotrophin and it switches on and off what we consider painful. The antibody tanezumab binds TrkA and reduces the bone pain associated with types of cancer that increase bone formation.

The influence of hormones on bone cancer pain is unclear, but testosterone clearly could have a role. After castration, bone density decreases. Also in animals lowering testosterone lowers pain thresholds and animals perceive pain at a lower level.

Research into new pain medicines for bone cancers is limited by the risk of reducing pain at the cost of enhancing cancer growth. For example, using VEGF will improve pain of constricted blood impeded by a bone cancer. However, cancers grow using VEGF to promote blood vessel growth and anti-VEGF is a drug to treat cancer.



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