The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy.
Humoral hypercalcemia of malignancy (HHM) is mediated primarily by skeletal and renal responses to tumor-derived PTHrP. PTHrP mobilizes calcium from bone by inducing the expression of receptor activator for nuclear factor-kappaB ligand (RANKL), a protein that is essential for osteoclast formation, activation, and survival. RANKL does not influence renal calcium reabsorption, so RANKL inhibition is a rational approach to selectively block, and thereby reveal, the relative contribution of bone calcium to HHM. We used the RANKL inhibitor osteoprotegerin (OPG) to evaluate the role of osteoclast-mediated hypercalcemia in two murine models of HHM. Hypercalcemia was induced either by sc inoculation of syngeneic colon (C-26) adenocarcinoma cells or by sc injection of high-dose recombinant PTHrP (0.5 mg/kg, s.c., twice per day). In both models, OPG (0.2-5 mg/kg) caused rapid reversal of established hypercalcemia, and the speed and duration of hypercalcemia suppression were significantly greater with OPG (5 mg/kg) than with high-dose bisphosphonates (pamidronate or zoledronic acid, 5 mg/kg). OPG also caused greater reductions in osteoclast surface and biochemical markers of bone resorption compared with either bisphosphonate. In both models, hypercalcemia gradually returned despite clear evidence of ongoing suppression of bone resorption by OPG. These data demonstrate that osteoclasts and RANKL are important mediators of HHM, particularly in the early stages of the condition. Aggressive antiresorptive therapy with a RANKL inhibitor therefore might be a rational approach to controlling HHM.
Morony
Sean
S
Metabolic Disorders Research, Amgen, Inc., Thousand Oaks, California 91320-1789, USA.
Warmington
Kelly
K
Adamu
Stephen
S
Asuncion
Frank
F
Geng
Zhaopo
Z
Grisanti
Mario
M
Tan
Hong Lin
HL
Capparelli
Casey
C
Starnes
Charlie
C
Weimann
Bernadette
B
Dunstan
Colin R
CR
Kostenuik
Paul J
PJ
D000230:Adenocarcinoma / Q000097:blood / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001862:Bone Resorption / Q000517:prevention & control*; D002118:Calcium / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000097:blood / Q000517:prevention & control*; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology / Q000517:prevention & control*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D053244:Osteoprotegerin; D000077268:Pamidronate; D044162:Parathyroid Hormone-Related Protein / Q000502:physiology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004164:Diphosphonates; D006023:Glycoproteins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D000077268:Pamidronate; D002118:Calcium