Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.
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.
Li
Xiaodong
X
Department of Metabolic Disorders, Amgen, Thousand Oaks, California 91320-1799, USA.
Ominsky
Michael S
MS
Warmington
Kelly S
KS
Morony
Sean
S
Gong
Jianhua
J
Cao
Jin
J
Gao
Yongming
Y
Shalhoub
Victoria
V
Tipton
Barbara
B
Haldankar
Raj
R
Chen
Qing
Q
Winters
Aaron
A
Boone
Tom
T
Geng
Zhaopo
Z
Niu
Qing-Tian
QT
Ke
Hua Zhu
HZ
Kostenuik
Paul J
PJ
Simonet
W Scott
WS
Lacey
David L
DL
Paszty
Chris
C
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
D000911:Antibodies, Monoclonal; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat; D015675:Osteocalcin