Bone cancer pain: From mechanism to model to therapy

Although bone cancer pain can be severe and is relatively common, very little is known about the basic mechanisms that generate and maintain this debilitating pain. To begin to define the mechanisms that give rise to bone cancer pain, a mouse model was developed using the intramedullary injection and containment of osteolytic sarcoma cells in the mouse femur. These tumor cells induced bone destruction as well as ongoing and movement-evoked pain behaviors similar to that found in patients with bone cancer pain. In addition, there was a significant reorganization of the spinal cord that received sensory input from the cancerous bone, and this reorganization was significantly different from that observed in mouse models of chronic neuropathic or inflammatory pain. To determine whether this mouse model of bone cancer could be used to define the basic mechanisms giving rise to bone cancer pain, we targeted excessive osteoclast activity using osteoprotegerin, a secreted decoy receptor that inhibits osteoclast activity. Osteoprotegerin blocked excessive tumor-induced, osteoclast-mediated bone destruction, and significantly reduced ongoing and movement-evoked pain, and the neurochemical reorganization of the spinal cord. These data suggest that this model can provide insight into the mechanisms that generate bone cancer pain and provide a platform for developing and testing novel analgesics to block bone cancer pain.