Inhibition ofin VitroBone Resorption by a Parathyroid Hormone Receptor Antagonist in the Canine Adenocarcinoma Model of Humoral Hypercalcemia of Malignancy*

In vitro bone resorption induced by tumor extract derived from a hypercalcemic canine adenocarcinoma was significantly inhibited by the PTH receptor antagonist, [Nle8,18,Tyr34]bovine (b) PTH-(3-34) amide. Dose-response curves were prepared for in vitro bone resorption induced in neonatal mouse calvaria by tumor extract, bPTH-(1-34), and prostaglandin E2. A 1:2000-fold ratio of bPTH-(1-34) to [Nle8,18,Tyr34]bPTH-(3-34) amide significantly inhibited bone resorption induced by bPTH-(1-34); however, a 1:10,000 ratio completely antagonized bone resorption. At equivalent potency (1.80-fold stimulation of in vitro bone resorption) of tumor extract compared to bPTH-(1-34), [Nle8,18,Tyr34]bPTH-(3-34) amide (5.0 microM) was capable of significantly reducing in vitro bone resorption. Bone resorption induced by tumor extract (1.35-fold stimulation) was inhibited by [Nle8,18,Tyr34]bPTH-(3-34) amide at concentrations of 5.0 and 1.0 microM. Bone resorption induced by prostaglandin E2 (300 nM) was not inhibited by [Nle8,18,Tyr34]bPTH-(3-34) amide (5.0 microM). These data indicate that [Nle8,18,Tyr34]bPTH-(3-34) amide antagonizes in vitro bone resorption induced by bPTH-(1-34) in a dose-dependent manner and significantly inhibits bone resorption induced by the canine adenocarcinoma model of humoral hypercalcemia of malignancy.