Effects of the RANKL inhibitor, osteoprotegerin, on the pain and histopathology of bone cancer in rats.
BACKGROUND
This study investigated the effects of the receptor activator for nuclear factor kappaB ligand (RANKL) inhibitor, osteoprotegerin (OPG), on tumor-induced allodynia, osteolysis, and bone histology in the mammary tumor (MRMT-1) rat model for bone cancer pain.


METHODS
Rats (n = 8/group) were inoculated with MRMT-1 or culture medium in the proximal right tibia, injected with OPG or vehicle subcutaneously 2-3 times weekly, evaluated for mechanical allodynia with von Frey paw stimulation, and euthanized on Day 20 for necropsy. Three groups were evaluated starting on Day 5 and received the following interventions beginning on Day 1: tumor and OPG, tumor and vehicle, or culture medium and vehicle. Three additional groups received the same interventions but were evaluated starting on Day 3. A seventh group started OPG on Day 8 after tumor inoculation.


RESULTS
Starting OPG on Day 1 reduced allodynia significantly compared with vehicle injections; pain relief was observed within 5-6 days after tumor inoculation and lasted throughout follow-up. Starting OPG on Day 8 did not reverse allodynia significantly compared with the tumor control group. Regardless of treatment start time, OPG treatment reduced osteoclast number and tartrate-resistant acid phosphatase levels, increased bone mineral density, preserved normal bone volume and integrity on micro-computed tomography, reduced relative tumor volume in the bone, and reduced staining for glial fibrillary acidic protein in the spinal cord.


CONCLUSIONS
RANKL inhibition with OPG reduced bone resorption and bone pain in rats with malignant bone disease; further study is warranted to determine if RANKL inhibition has similar benefits in humans.
Roudier
Martine P
MP
SkeleTech, Inc., Bothell, WA, USA. mroudier@amgen.com
Bain
Steven D
SD
Dougall
William C
WC
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001862:Bone Resorption / Q000188:drug therapy; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D009368:Neoplasm Transplantation; D053244:Osteoprotegerin / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D053244:Osteoprotegerin; D053245:RANK Ligand