Sclerostin and Wnt Antagonists: Implications for Osteoporosis Therapies

Abstract

The connection between Wnt signaling and bone formation was established through studying the high bone mass phenotypes of patients with LRP5 gain-of-function mutations. Sclerostin, a protein discovered through the genetic mapping study of sclerosteosis patients, is a key secreted Wnt antagonist that inhibits bone formation. It is now recognized that high bone mass phenotype associated with sclerostin deficiency in sclerosteosis patients was the result of activated Wnt signaling in osteoblast lineage cells. Inhibition of sclerostin leads to higher bone formation, bone mass and bone strength with normal bone quality. Efforts in the discovery and development of sclerostin inhibitors lead to the approval of romosozumab, a humanized sclerostin monoclonal antibody (Scl-Ab), for the treatment of postmenopausal women with osteoporosis at high risk for fracture in 2019. Unlike existing antiresorptive and anabolic therapies, romosozumab has dual action of increasing bone formation and decreasing bone resorption. This article summarizes the molecular and cellular mechanisms of sclerostin and other Wnt antagonists on bone, tissue-level mechanism and in vivo pharmacology of sclerostin monoclonal antibodies, and implications of the discovery of sclerostin monoclonal antibodies for the treatment of osteoporosis and other bone disorders.