The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys
- M. S. OminskyAffiliated withDepartment of Metabolic Disorders, Amgen Inc.
- , P. J. KostenuikAffiliated withDepartment of Metabolic Disorders, Amgen Inc.Metabolic Disorders Research, Amgen Inc. Email author
- , P. CranmerAffiliated withDepartment of Toxicology, Amgen Inc.
- , S. Y. SmithAffiliated withCharles River Laboratories Preclinical Services Montreal, Inc.
- , J. E. AtkinsonAffiliated withDepartment of Toxicology, Amgen Inc.
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Weekly treatment of gonad-intact cynomolgus monkeys (for up to 6 months) with the RANKL inhibitor OPG-Fc reduced bone turnover markers and increased volumetric cortical and trabecular BMD and BMC at radial and tibial metaphyses. OPG-Fc was well tolerated in this study without evidence of change in measured toxicologic parameters vs. control.
RANKL is the primary mediator of osteoclast formation, function, and survival. The catabolic effects of RANKL are inhibited by OPG, a soluble decoy receptor for RANKL. We investigated the safety and pharmacology of OPG-Fc in gonad-intact cynomolgus monkeys.
Males and females were treated weekly with vehicle (n = 5/sex) or OPG-Fc (15 mg/kg) by s.c. (n = 5/sex) or i.v. (n = 3/sex) injection for 6 months.
Routine toxicologic investigations, hematologic parameters, body and organ weights, and ophthalmologic and electrocardiographic findings were not affected by OPG-Fc treatment. Because s.c. and i.v. dosing of OPG-Fc caused similar effects, these groups were combined for analyses. The following endpoints were significantly different in males and/or females treated with OPG-Fc relative to sex-matched vehicle controls after 6 months (p < 0.05). Biochemical markers of bone turnover (urine N-telopeptide and serum osteocalcin) were significantly decreased with OPG-Fc treatment. Cortical and trabecular volumetric BMD and BMC, cortical thickness, and cross-sectional moment of inertia were significantly increased by OPG-Fc treatment at the proximal tibia and distal radius metaphyses. Increases in cortical thickness were associated with significantly greater periosteal circumference.
OPG-Fc increased cortical and trabecular BMD and BMC in young gonad-intact cynomolgus monkeys.
KeywordsBone geometry Bone remodeling Cortical bone OPG Primate RANKL
- The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys
Volume 18, Issue 8 , pp 1073-1082
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- Bone geometry
- Bone remodeling
- Cortical bone
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- Author Affiliations
- 1. Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA
- 4. Metabolic Disorders Research, Amgen Inc., 1 Amgen Center Drive M/S 15-2-B, Thousand Oaks, CA, 91320, USA
- 2. Department of Toxicology, Amgen Inc., Thousand Oaks, CA, USA
- 3. Charles River Laboratories Preclinical Services Montreal, Inc., Senneville, Quebec, Canada