Osteoprotegerin diminishes advanced bone cancer pain

Bone cancer pain most commonly occurs when tumors originating in breast, pr ostate, or lung metastasize to long bones, spinal vertebrae, and/or pelvis. Primary and metastatic cancers involving bone account for approximately 40 0,000 new cancer cases per year in the United States alone, and > 70% of pa tients with advanced breast or prostate cancer have skeletal metastases. Wh ereas pain resulting from bone cancer can dramatically impact an individual 's quality of life, very little is known about the mechanisms that generate and maintain this pain. To begin to define the mechanisms that give rise t o advanced bone cancer pain, osteolytic 2472 sarcoma cells or media were in jected into the intramedullary space of the femur of C3H/HeJ mice, and the injection hole was sealed using dental amalgam, confining the tumor cells t o the bone. Twelve days after injection of 2472 tumor cells, animals showed advanced tumor-induced bone destruction of the injected femur, bone cancer pain, and a stereotypic set of neurochemical changes in the spinal cord do rsal horn that receives sensory inputs from the affected femur. Administrat ion of osteoprotegerin, a naturally secreted decoy receptor that inhibits o steoclast maturation and activity and induces osteoclast apoptosis, or vehi cle was begun at 12 days, when significant bone destruction had already occ urred, and administration was continued daily until day 21. Ongoing pain be haviors, movement-evoked pain behaviors, and bone destruction were assessed on days 10, 12, 14, 17, and 21. The neurochemistry of the spinal cord was evaluated at days 12 and 21. Results indicated that osteoprotegerin treatme nt halted further bone destruction, reduced ongoing and movement-evoked pai n, and reversed several aspects of the neurochemical reorganization of the spinal cord. Thus, even in advanced stages of bone cancer, ongoing osteocla st activity appears to be involved in the generation and maintenance of ong oing and movement-evoked pain. Blockade of ongoing osteoclast activity appe ars to have the potential to reduce bone cancer pain in patients with advan ced tumor-induced bone destruction.