Effects of the RANKL Inhibitor, Osteoprotegerin, on the Pain and Histopathology of Bone Cancer in Rats

Clin Exp Metastasis. 2006;23(3-4):167-75. doi: 10.1007/s10585-006-9026-x. Epub 2006 Aug 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / secondary*
  • Bone Resorption / drug therapy
  • Female
  • Mammary Neoplasms, Experimental / pathology
  • Neoplasm Transplantation
  • Osteoprotegerin / administration & dosage
  • Osteoprotegerin / pharmacology*
  • Pain / drug therapy*
  • RANK Ligand / antagonists & inhibitors*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors

Substances

  • Osteoprotegerin
  • RANK Ligand