Genetic Approaches To Identifying Novel Osteoporosis Drug Targets

ABSTRACTDuring the past two decades effective drugs for treating osteoporosis have been developed, including anti‐resorptives inhibiting bone resorption (estrogens, the SERM raloxifene, four bisphosphonates, RANKL inhibitor denosumab) and the anabolic bone forming daily injectable peptide teriparatide. Two potential drugs (odanacatib and romosozumab) are in late stage clinical development. The most pressing unmet need is for orally active anabolic drugs. This review describes the basic biological studies involved in developing these drugs, including the animal models employed for osteoporosis drug development. The genomics revolution continues to identify potential novel osteoporosis drug targets. Studies include human GWAS studies and identification of mutant genes in subjects having abnormal bone mass, mouse QTL and gene knockouts, and gene expression studies. Multiple lines of evidence indicate that Wnt signaling plays a major role in regulating bone formation and continued study of this complex pathway is likely to lead to key discoveries. In addition to the classic Wnt signaling targets DKK1 and sclerostin, LRP4, LRP5/LRP6, SFRP4, WNT16, and NOTUM can potentially be targeted t