The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys

• Published in: Osteoporosis international Vol. 18; no. 8; pp. 1073 - 1082
• Main Authors: OMINSKY, M. S, KOSTENUIK, P. J, CRANMER, P, SMITH, S. Y, ATKINSON, J. E
• Format: Journal Article
• Language: English
• Published: London Springer 01.08.2007; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - pathology; Bone density; Bone Density - drug effects; Bone Remodeling - drug effects; Diseases of the osteoarticular system; Drug Administration Schedule; Drug therapy; Female; Fundamental and applied biological sciences. Psychology; Gonads - physiology; Macaca fascicularis; Male; Medical sciences; Monkeys & apes; Osteoporosis. Osteomalacia. Paget disease; Osteoprotegerin - administration & dosage; Osteoprotegerin - adverse effects; Parathyroid Hormone - blood; Pharmacology; Radius - drug effects; Radius - pathology; RANK Ligand - antagonists & inhibitors; Receptors, IgG - administration & dosage; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Sex Factors; Skeleton and joints; Tibia - drug effects; Tibia - pathology; Vertebrates: osteoarticular system, musculoskeletal system; RANKL; Receptor activator Nfkb ligand; Diseases of the osteoarticular system; Monkey; OPG; Bone geometry Bone remodeling Cortical bone; Bone remodeling; Geometry; Osteoporosis; Vertebrata; Mammalia; Bone mass; Gonad; Animal; Primates; Bone trabeculae; Primate; Cortical bone
• ISSN: 0937-941X; 1433-2965
• DOI: 10.1007/s00198-007-0363-7

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.