Sclerostin: how human mutations have helped reveal a new target for the treatment of osteoporosis

•Sclerosteosis is a rare human high bone mass condition.•Characterisation of sclerosteosis helped identify a new bone regulatory pathway.•Rare monogenic conditions can preview the effects of drugs.•Technological advances will allow more use of human phenotypes in target discovery.•A key challenge is identifying informative new phenotypes. In the 1990s there was a tremendous mood of optimism among pharmaceutical scientists that identification of disease-associated variations in the human genome would result in a surge of new drug targets (the ‘gene-to-drug’ mantra). To date the expected deluge of new drugs has not arrived. However, a small number of drugs arising directly from the study of rare human disorders showing Mendelian inheritance are now entering late stage clinical trials. Here we describe the advantages of this approach and discuss the background and early clinical trial findings with antibodies directed at a target identified in this way.