title: Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats.
abstract: 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 (L(1) to L(5) ) 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 (L(5) ), 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 L(5) , 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.
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, USA. xli@amgen.com
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Warmington
authors.forename: Qing-Tian
authors.initials: QT
authors.lastname: Niu
authors.forename: Franklin J
authors.initials: FJ
authors.lastname: Asuncion
authors.forename: Mauricio
authors.initials: M
authors.lastname: Barrero
authors.forename: Mario
authors.initials: M
authors.lastname: Grisanti
authors.forename: Denise
authors.initials: D
authors.lastname: Dwyer
authors.forename: Brian
authors.initials: B
authors.lastname: Stouch
authors.forename: Theingi M
authors.initials: TM
authors.lastname: Thway
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: William S
authors.initials: WS
authors.lastname: Simonet
authors.forename: Chris
authors.initials: C
authors.lastname: Paszty
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
mesh_terms: D015502:Absorptiometry, Photon; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015519:Bone Density / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D005819:Genetic Markers; D008297:Male; D009929:Organ Size; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000097:blood; D014057:Tomography, X-Ray Computed
chemical_list: D000911:Antibodies, Monoclonal; D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; D005819:Genetic Markers; C486031:Sost protein, rat; D015675:Osteocalcin; D012701:Serotonin