The definitive proof-of-concept for this working hypothesis has been the development of antibodies to sclerostin, a protein only identified through analysis of HBM families with sclerosteosis and van Buchem’s disease (110–112), with completion of phase 3 clinical trials (147, 277) and the first-in-class agent (romosozumab) approved for clinical use by the US Food and Drugs Administration. This evidence concerns the gene SOST and sclerosteosis.