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OPG and PTH-(1–34) Have Additive Effects on Bone Density and Mechanical Strength in Osteopenic Ovariectomized Rats

Departments of Pharmacology/Pathology (P.J.K., C.C., S.M., S.A., D.L.L.), Process Development (G.S.), and Development (C.R.D.), Amgen, Inc., Thousand Oaks, California 91320; and Skeletech (V.S.), Bothell, Washington 98021

Address all correspondence and requests for reprints to: Dr. Paul J. Kostenuik, Department of Pathology/Pharmacology, One Amgen Center Drive, Thousand Oaks, California 91320. E-mail: paulk{at}amgen.com

PTH is a potent bone anabolic factor, and its combination with antiresorptive agents has been proposed as a therapy for osteoporosis. We tested the effects of PTH, alone and in combination with the novel antiresorptive agent OPG, in a rat model of severe osteopenia. Sprague Dawley rats were sham-operated or ovariectomized at 3 months of age. Rats were untreated for 15 months, at which time ovariectomy had caused significant decreases in bone mineral density in the lumbar vertebrae and femur. Rats were then treated for 5.5 months with vehicle (PBS), human PTH-(1–34) (80 µg/kg), rat OPG (10 mg/kg), or OPG plus PTH (all three times per wk, sc). Treatment of ovariectomized rats with OPG or PTH alone increased bone mineral density in the lumbar vertebrae and femur, whereas PTH plus OPG caused significantly greater and more rapid increases than either therapy alone (P < 0.05). OPG significantly reduced osteoclast surface in the lumbar vertebrae and femur (P < 0.05 vs. sham or ovariectomized), but had no effect on osteoblast surface at either site. Ovariectomy significantly decreased the mechanical strength of the lumbar vertebrae and femur. In the lumbar vertebrae, OPG plus PTH was significantly more effective than PTH alone at reversing ovariectomy-induced deficits in stiffness and elastic modulus. These data suggest that OPG plus PTH represent a potentially useful therapeutic option for patients with severe osteoporosis.

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