Curr Osteoporos Rep (2010) 8:23–27 DOI 10.1007/s11914-010-0005-4 Anabolic Therapies Nancy E. Lane & Stuart L. Silverman Published online: 19 February 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract The striking clinical benefits of intermittent parathyroid hormone in osteoporosis have begun a new era of skeletal anabolic agents. Recombinant human parathyroid hormone (rhPTH) (1–34) is the first US Food and Drug Administration–approved anabolic therapy. Its use has been limited by the need for subcutaneous injection. Newer delivery systems include transdermal and oral preparations. Newer anabolic therapies include monoclonal antibody to sclerostin, a potent inhibitor of osteoblasto- genesis; and use of bone morphogenetic proteins and parathyroid hormone–related protein PTHrP, a calcium- regulating hormone similar to PTH. Keywords Wnt . Sclerostin . BMP. PTH . BMD . Osteoporosis Introduction The Wnt signaling pathway demonstrates a complex network of proteins well known for their roles in embryogenesis but also involving normal physiologic processes of bone formation in response to loading and unloading. The interaction between Wnt proteins and cell surface receptors can result in a variety of intracellular responses [1]. Studies have revealed the existence of S. L. Silverman (*) Clinical Professor of Medicine Cedars-Sinai/UCLA, OMC Clinical Research Center, 8641 Wilshire Boulevard, Suite 301, Beverly Hills, CA 90211, USA e-mail: stuarts@omcresearch.org N. E. Lane Aging Center, Medicine and Rheumatology, University of California at Davis Medical Center, 4800 2nd Avenue, Suite 2600, Sacramento, CA 95817, USA e-mail: nancy.lane@ucdmc.ucdavis.edu extensive crosstalk between numerous ligands, receptors, and coreceptors, as well as between downstream intracel- lular messengers [1]. The Wnt pathway involves a large network of proteins that can regulate the production of Wnt signaling molecules and interaction with receptors and target cells, and the physiologic response of target cells that result in exposure of cells to the extracellular Wnt ligands. The canonical Wnt pathway describes events when Wnt proteins bind to cell surface receptors in the Frizzled family, causing the receptors to activate disheveled family proteins and ultimately result in the change in the amount of β- catenin that reaches the nucleus [1]. Several proteins have been described that inhibit Wnt signaling [2]. One such protein is sclerostin, which binds low-density lipoprotein receptor-related protein (LRP) and inhibits Wnt signaling. Antibodies to dickkopf and secreted frizzled-related protein produce similar outcomes in animal models to sclerostin [2]. This article discusses several anabolic agents, including sclerostin, bone morphogenetic protein (BMP), and para- thyroid hormone (PTH), and new delivery systems for PTH. Sclerostin Sclerostin, a glycoprotein secreted by osteocytes and to a lesser extent other cell types (vascular, kidney), is a potent inhibitor of osteoblastogenesis. Sclerostin is secreted from osteocytes and travels through the canaliculi to the bone surface where it binds to coreceptors LRP5 and LRP6 and prevents colocalization with frizzled protein and Wnt signaling, thereby reducing osteoblastogenesis and bone formation [3]. Loss-of-function mutations in SOST are associated with an autosomal-recessive disorder, sclero- steosis, which causes progressive bone overgrowth [4]. A deletion downstream of the SOST gene, which results in reduced sclerostin expression, is associated with a milder form of the disease called van Buchem disease [5].