Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength in a Rat Model of Postmenopausal Osteoporosis

作者：Xiaodong Li, Michael S. Ominsky, Kelly S. Warmington, Sean Morony, Jianhua Gong, Jin Cao, Yongming Gao, Victoria Shalhoub, Barbara Tipton, Raj Haldankar, Qing Chen, Aaron G. Winters, T. Boone, Zhaopo Geng, Qing‐Tian Niu, Hua Zhu Ke, Paul J. Kostenuik, W. Scott Simonet, David L. Lacey, Chris Pászty · 发表于：Journal of Bone and Mineral Research · 年份：2008 · DOI：10.1359/jbmr.081206 · 被引用次数：791 · 研究领域：Bone health and osteoporosis research、Bone Metabolism and Diseases、Growth Hormone and Insulin-like Growth Factors

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, fu...