Sclerostin: a novel target for intervention in the treatment of osteoporosis

Bone remodeling is the process by which the adult skeleton is continually renewed through the highly coordinated activity of three types of cells - osteoclasts, osteoblasts, and osteocytes. Disruptions in signaling among these cells and alterations in their activity have been associated with skeletal diseases. In a rare accident of nature, some families have been found to have dense and strong bones due to a recessive loss of function mutation in the SOST gene that encodes for sclerostin, a protein expressed by osteocytes that downregulates osteoblastic bone formation. Individuals who are homozygous for this mutation have sclerosteosis, a disease with no detectable circulating sclerostin, resulting in generalized osteosclerosis with skeletal deformities, cranial nerve compression, and increased intracranial pressure due to boney overgrowth in the skull, and premature death. However, family members who are heterozygous carriers for the mutation have normal phenotype and normal lifespan, with dense bones and low risk of fracture. This observation has led to the concept that compounds that reduce sclerostin levels might mimic the heterozygous carrier state and be effective in the treatment of osteoporosis. To this end, monoclonal antibodies to sclerostin have been developed. Preclinical and early clinical studies of sclerostin inhibitors have shown robust stimulation of osteoblastic bone formation. The investigational compound that has advanced the furthest in development is AMG 785 (CDP7851), a humanized monoclonal antibody to sclerostin. Monoclonal antibodies to sclerostin represent a class of compounds with potential benefit in the treatment of osteoporosis and other skeletal disorders.