title: Progressive increases in bone mass and bone strength in an ovariectomized rat model of osteoporosis after 26 weeks of treatment with a sclerostin antibody.
abstract: The effects of up to 26 weeks of sclerostin antibody (Scl-Ab) treatment were investigated in ovariectomized (OVX) rats. Two months after surgery, 6-month-old osteopenic OVX rats were treated with vehicle or Scl-Ab (25 mg/kg, sc, one time per week) for 6, 12, or 26 weeks. In vivo dual-energy x-ray absorptiometry analysis demonstrated that the bone mineral density of lumbar vertebrae and femur-tibia increased progressively through 26 weeks of Scl-Ab treatment along with progressive increases in trabecular and cortical bone mass and bone strength at multiple sites. There was a strong correlation between bone mass and maximum load at lumbar vertebra, femoral neck, and diaphysis at weeks 6 and 26. Dynamic histomorphometric analysis showed that lumbar trabecular and tibial shaft endocortical and periosteal bone formation rates (BFR/BS) increased and peaked at week 6 with Scl-Ab-treatment; thereafter trabecular and endocortical BFR/BS gradually declined but remained significantly greater than OVX controls at week 26, whereas periosteal BFR/BS returned to OVX control levels at week 26. In the tibia metaphysis, trabecular BFR/BS in the Scl-Ab treated group remained elevated from week 6 to week 26. The osteoclast surface and eroded surface were significantly lower in Scl-Ab-treated rats than in OVX controls at all times. In summary, bone mass and strength increased progressively over 26 weeks of Scl-Ab treatment in adult OVX rats. The early gains were accompanied by increased cortical and trabecular bone formation and reduced osteoclast activity, whereas later gains were attributed to residual endocortical and trabecular osteoblast stimulation and persistently low osteoclast activity.
authors.affiliation: Departments of Metabolic Disorders (X.L., Q.-T.N., K.S.W., F.J.A., D.D., M.G., C.-Y.H., M.S., P.J.K., W.S.S., M.S.O., H.Z.K.) and Biostatistics (M.J.E.), Amgen Inc, Thousand Oaks, California 91320.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Qing-Tian
authors.initials: QT
authors.lastname: Niu
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Warmington
authors.forename: Franklin J
authors.initials: FJ
authors.lastname: Asuncion
authors.forename: Denise
authors.initials: D
authors.lastname: Dwyer
authors.forename: Mario
authors.initials: M
authors.lastname: Grisanti
authors.forename: Chun-Ya
authors.initials: CY
authors.lastname: Han
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eschenberg
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: William S
authors.initials: WS
authors.lastname: Simonet
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005819:Genetic Markers; D010024:Osteoporosis / Q000188:drug therapy*; D010052:Ovariectomy; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D055114:X-Ray Microtomography
chemical_list: D000911:Antibodies, Monoclonal; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat