Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats

• Published in: Journal of bone and mineral research 2010-12, Vol.25 (12), p.2647-2656
• Main Authors: Li, Xiaodong, Warmington, Kelly S, Niu, Qing‐Tian, Asuncion, Franklin J, Barrero, Mauricio, Grisanti, Mario, Dwyer, Denise, Stouch, Brian, Thway, Theingi M, Stolina, Marina, Ominsky, Michael S, Kostenuik, Paul J, Simonet, William S, Paszty, Chris, Ke, Hua Zhu
• Format: Article
• Language: English
• Subjects: Absorptiometry, Photon; AGING; Aging - metabolism; Animals; Antibodies, Monoclonal - immunology; Biological and medical sciences; BIOMECHANICS; Bone and Bones - anatomy & histology; Bone and Bones - cytology; Bone and Bones - diagnostic imaging; Bone and Bones - metabolism; Bone Density - physiology; Bone Morphogenetic Proteins - antagonists & inhibitors; Bone Morphogenetic Proteins - metabolism; Collagen Type I - metabolism; Fundamental and applied biological sciences. Psychology; Genetic Markers; HISTOMORPHOMETRY; Male; MALE OSTEOPOROSIS; Organ Size; Osteocalcin - blood; Osteogenesis; Rats; Rats, Sprague-Dawley; SCLEROSTIN ANTIBODY; Serotonin - blood; Skeleton and joints; Tomography, X-Ray Computed; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.182

The purpose of this study was to evaluate the effects of sclerostin inhibition by treatment with a sclerostin antibody (Scl‐AbII) on bone formation, bone mass, and bone strength in an aged, gonad‐intact male rat model. Sixteen‐month‐old male Sprague‐Dawley rats were injected subcutaneously with vehicle or Scl‐AbII at 5 or 25 mg/kg twice per week for 5 weeks (9–10/group). In vivo dual‐energy X‐ray absorptiometry (DXA) analysis showed that there was a marked increase in areal bone mineral density of the lumbar vertebrae (L1 to L5) and long bones (femur and tibia) in both the 5 and 25 mg/kg Scl‐AbII‐treated groups compared with baseline or vehicle controls at 3 and 5 weeks after treatment. Ex vivo micro–computed tomographic (µCT) analysis demonstrated improved trabecular and cortical architecture at the fifth lumbar vertebral body (L5), femoral diaphysis (FD), and femoral neck (FN) in both Scl‐AbII dose groups compared with vehicle controls. The increased cortical and trabecular bone mass was associated with a significantly higher maximal load of L5, FD, and FN in the high‐dose group. Bone‐formation parameters (ie, mineralizing surface, mineral apposition rate, and bone‐formation rate) at the proximal tibial metaphysis and tibial shaft were markedly greater on trabecular, periosteal, and endocortical surfaces in both Scl‐AbII dose groups compared with controls. These results indicate that sclerostin inhibition by treatment with a sclerostin antibody increased bone formation, bone mass, and bone strength in aged male rats and, furthermore, suggest that pharmacologic inhibition of sclerostin may represent a promising anabolic therapy for low bone mass in aged men. © 2010 American Society for Bone and Mineral Research.