Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength.
The development of bone-rebuilding anabolic agents for treating bone-related conditions 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. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis.
Ominsky
Michael S
MS
Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA 91320-1799, USA.
Vlasseros
Fay
F
Jolette
Jacquelin
J
Smith
Susan Y
SY
Stouch
Brian
B
Doellgast
George
G
Gong
Jianhua
J
Gao
Yongming
Y
Cao
Jin
J
Graham
Kevin
K
Tipton
Barbara
B
Cai
Jill
J
Deshpande
Rohini
R
Zhou
Lei
L
Hale
Michael D
MD
Lightwood
Daniel J
DJ
Henry
Alistair J
AJ
Popplewell
Andrew G
AG
Moore
Adrian R
AR
Robinson
Martyn K
MK
Lacey
David L
DL
Simonet
W Scott
WS
Paszty
Chris
C
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects*; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005819:Genetic Markers / Q000276:immunology*; D008252:Macaca fascicularis; D010012:Osteogenesis
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human