title: Romosozumab Improves Bone Mass and Strength While Maintaining Bone Quality in Ovariectomized Cynomolgus Monkeys.
abstract: Romosozumab (Romo), a humanized sclerostin antibody, is a bone-forming agent under development for treatment of osteoporosis. To examine the effects of Romo on bone quality, mature cynomolgus monkeys (cynos) were treated 4 months post- ovariectomy (OVX) with vehicle, 3 mg/kg, or 30 mg/kg Romo for 12 months, or with 30 mg/kg Romo for 6 months followed by vehicle for 6 months (30/0). Serum bone formation markers were increased by Romo during the first 6 months, corresponding to increased cancellous, endocortical, and periosteal bone formation in rib and iliac biopsies at months 3 and 6. Dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD) was increased by 14% to 26% at the lumbar spine and proximal femur at month 12, corresponding to significant increases in bone strength at 3 and 30 mg/kg in lumbar vertebral bodies and cancellous cores, and at 30 mg/kg in the femur diaphysis and neck. Bone mass remained positively correlated with strength at these sites, with no changes in calculated material properties at cortical sites. These bone-quality measures were also maintained in the 30/0 group, despite a gradual loss of accrued bone mass. Normal bone mineralization was confirmed by histomorphometry and ash analyses. At the radial diaphysis, a transient, reversible 2% reduction in cortical BMD was observed with Romo at month 6, despite relative improvements in bone mineral content (BMC). High-resolution pQCT confirmed this decline in cortical BMD at the radial diaphysis and metaphysis in a second set of OVX cynos administered 3 mg/kg Romo for 6 months. Radial diaphyseal strength was maintained and metaphyseal strength improved with Romo as estimated by finite element modeling. Decreased radial cortical BMD was a consequence of increased intracortical remodeling, with no increase in cortical porosity. Romo resulted in marked improvements in bone mass, architecture, and bone strength, while maintaining bone quality in OVX cynos, supporting its bone efficacy and safety profile. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Discovery Research, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.affiliation: Department of Radiology and McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Canada.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Boyd
authors.affiliation: Charles River Laboratories Preclinical Services, Montreal, Canada.
authors.forename: Aurore
authors.initials: A
authors.lastname: Varela
authors.affiliation: Charles River Laboratories Preclinical Services, Montreal, Canada.
authors.forename: Jacquelin
authors.initials: J
authors.lastname: Jolette
authors.affiliation: Charles River Laboratories Preclinical Services, Montreal, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Felx
authors.affiliation: Charles River Laboratories Preclinical Services, Montreal, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Doyle
authors.affiliation: Charles River Laboratories Preclinical Services, Montreal, Canada.
authors.forename: Nacera
authors.initials: N
authors.lastname: Mellal
authors.affiliation: Charles River Laboratories Preclinical Services, Montreal, Canada.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.affiliation: Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Locher
authors.affiliation: Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Buntich
authors.affiliation: Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Pyrah
authors.affiliation: Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Rogely W
authors.initials: RW
authors.lastname: Boyce
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015519:Bone Density / Q000187:drug effects*; D018483:Diaphyses / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D005272:Femur Neck / Q000000981:diagnostic imaging / Q000378:metabolism; D008252:Macaca fascicularis; D010052:Ovariectomy; D011884:Radius / Q000000981:diagnostic imaging / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C557282:romosozumab
keywords: BIOMECHANICS; BONE HISTOMORPHOMETRY; Bone QCT/microCT; OSTEOPOROSIS; THERAPEUTICS-ANABOLICS