title: OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats.
abstract: 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 microg/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.
authors.affiliation: Department of Pharmacology/Pathology, Amgen, Inc., Thousand Oaks, California 91320, USA. paulk@amgen.com
authors.forename: P J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: C
authors.initials: C
authors.lastname: Capparelli
authors.forename: S
authors.initials: S
authors.lastname: Morony
authors.forename: S
authors.initials: S
authors.lastname: Adamu
authors.forename: G
authors.initials: G
authors.lastname: Shimamoto
authors.forename: V
authors.initials: V
authors.lastname: Shen
authors.forename: D L
authors.initials: DL
authors.lastname: Lacey
authors.forename: C R
authors.initials: CR
authors.lastname: Dunstan
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000503:physiopathology; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology* / Q000627:therapeutic use; D053244:Osteoprotegerin; D010052:Ovariectomy; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor; D019379:Teriparatide / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D006023:Glycoproteins; D053244:Osteoprotegerin; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506032:Tnfrsf11b protein, rat; D019379:Teriparatide; C035748:parathyroid hormone (1-34)amide