title: A toxicity profile of osteoprotegerin in the cynomolgus monkey.
abstract: Osteoprotegerin (OPG) is a novel secreted glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that acts as an antiresorptive agent inhibiting osteoclast maturation. OPG acts by competitively inhibiting the association of the OPG ligand with the RANK receptor on osteoclasts and osteoclast precursors. This inhibition of osteoclasts can lead to excess accumulation of newly synthesized bone and cartilage in vivo. The purpose of this study was to investigate the potential toxicity of a human recombinant form of OPG in the young cynomolgus monkey. OPG was administered by intravenous (i.v.) or subcutaneous (s.c.) injection three times per week for either 4 or 13 weeks. There were no deaths during the study, no clinical signs related to treatment, no effect on body weight, appetence, or ophthalmology. No toxicologically relevant changes in routine laboratory investigations, organ weights, or gross or histopathological findings were observed. Serum ionized calcium and phosphorus were decreased at all dose levels. Evaluations were performed to monitor biochemical markers of bone resorption (N-telopeptide [NTx], deoxypyridinoline [DPD]), bone formation (skeletal alkaline phosphatase [sALP], osteocalcin [OC]), parathyroid hormone [PTH], and bone density of the proximal tibia and distal radius in vivo. Dose-related decreases in NTx and/or DPD were observed at each dose level, with up to a 90% decrease in NTx noted for animals treated i.v. or s.c. at 15 mg/kg. Similar decreases were observed for sALP and OC. PTH was increased for animals treated at 5 and 15 mg/kg (i.v. or s.c.). Trabecular bone density was increased for the majority of males and females treated i.v. or s.c. at 15 mg/kg and males treated i.v. at 5 mg/kg. Microscopic examination of the sternebrae revealed corresponding increases in bone. Decreases in markers of bone turnover, and corresponding increases in bone density, were consistent with the pharmacological action of OPG as an osteoclast inhibitor. The no-observable-adverse-effect level (NOAEL) of OPG was 15 mg/kg.
authors.affiliation: Amgen, Inc, Thousand Oaks, California 91320, USA. bsmith@amgen.com
authors.forename: Brenda B
authors.initials: BB
authors.lastname: Smith
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cosenza
authors.forename: Audrey
authors.initials: A
authors.lastname: Mancini
authors.forename: Colin
authors.initials: C
authors.lastname: Dunstan
authors.forename: Richard
authors.initials: R
authors.lastname: Gregson
authors.forename: Steven W
authors.initials: SW
authors.lastname: Martin
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.forename: Harold
authors.initials: H
authors.lastname: Davis
mesh_terms: D015502:Absorptiometry, Photon; D000596:Amino Acids / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015519:Bone Density / Q000187:drug effects*; D001862:Bone Resorption / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000378:metabolism; D003094:Collagen / Q000652:urine; D024042:Collagen Type I; D004305:Dose-Response Relationship, Drug; D005260:Female; D006023:Glycoproteins / Q000633:toxicity*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D015675:Osteocalcin / Q000097:blood; D053244:Osteoprotegerin; D010281:Parathyroid Hormone / Q000097:blood; D010455:Peptides / Q000652:urine; D011884:Radius / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000633:toxicity; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D024042:Collagen Type I; D006023:Glycoproteins; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D010455:Peptides; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C506030:TNFRSF11B protein, human; C052929:collagen type I trimeric cross-linked peptide; D015675:Osteocalcin; C036020:deoxypyridinoline; D003094:Collagen