title: Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.
abstract: The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.
authors.affiliation: Department of Metabolic Disorders, Amgen, Thousand Oaks, California 91320-1799, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Warmington
authors.forename: Sean
authors.initials: S
authors.lastname: Morony
authors.forename: Jianhua
authors.initials: J
authors.lastname: Gong
authors.forename: Jin
authors.initials: J
authors.lastname: Cao
authors.forename: Yongming
authors.initials: Y
authors.lastname: Gao
authors.forename: Victoria
authors.initials: V
authors.lastname: Shalhoub
authors.forename: Barbara
authors.initials: B
authors.lastname: Tipton
authors.forename: Raj
authors.initials: R
authors.lastname: Haldankar
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Aaron
authors.initials: A
authors.lastname: Winters
authors.forename: Tom
authors.initials: T
authors.lastname: Boone
authors.forename: Zhaopo
authors.initials: Z
authors.lastname: Geng
authors.forename: Qing-Tian
authors.initials: QT
authors.lastname: Niu
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: W Scott
authors.initials: WS
authors.lastname: Simonet
authors.forename: David L
authors.initials: DL
authors.lastname: Lacey
authors.forename: Chris
authors.initials: C
authors.lastname: Paszty
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use*; D001681:Biological Assay; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D019070:Cell Lineage / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D005819:Genetic Markers / Q000276:immunology*; D006801:Humans; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology; D051379:Mice; D009500:Neutralization Tests; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects*; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D014057:Tomography, X-Ray Computed
chemical_list: D000911:Antibodies, Monoclonal; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat; D015675:Osteocalcin