Bone cancer pain most commonly occurs when
tumors originating in breast, prostate, or lung metastasize to long bones, spinal vertebrae, and/or pelvis. Primary and metastatic
cancers involving bone account for approximately 400,000 new
cancer cases per year in the United States alone, and >70% of patients with advanced breast or
prostate cancer have skeletal
metastases. Whereas
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 to advanced
bone cancer pain, osteolytic 2472
sarcoma cells or media were injected into the intramedullary space of the femur of C3H/HeJ mice, and the injection hole was sealed using
dental amalgam, confining the
tumor cells to 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 dorsal horn that receives sensory inputs from the affected femur. Administration of
osteoprotegerin, a naturally secreted decoy receptor that inhibits osteoclast maturation and activity and induces osteoclast apoptosis, or vehicle was begun at 12 days, when significant bone destruction had already occurred, and administration was continued daily until day 21. Ongoing
pain behaviors, 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 treatment halted further bone destruction, reduced ongoing and movement-evoked
pain, and reversed several aspects of the neurochemical reorganization of the spinal cord. Thus, even in advanced stages of
bone cancer, ongoing osteoclast activity appears to be involved in the generation and maintenance of ongoing and movement-evoked
pain. Blockade of ongoing osteoclast activity appears to have the potential to reduce
bone cancer pain in patients with advanced
tumor-induced bone destruction.