Novel potential drug targets for the antiresorptive treatment of osteoporosis

Osteoclasts are bone resorbing cells. The increased formation and activation of osteoclasts underlies many common bone lytic disorders such as osteoporosis, Paget’s disease, bone metastatic diseases, arthritis, and aseptic bone loosening. Currently, drugs used in management of osteoporosis are limited to bisphosphonates, calcium and vitamin D. Although there is evidence that hormone replacement therapy prevents bone loss in postmenopausal women, its beneficial effect on bone is overshadowed by its association with increased risks in breast cancer and cardiovascular disease. Unravelling the genetic regulation of osteoclastogenesis and osteoclast activation and discovering therapeutic agents to control these processes are critical for the development of effective treatment for osteoporosis. This chapter reviews novel potential targets for anti-resorptive drugs and determines the viability of these targets, giving special consideration to specificity to bone and any side effects. Several groups of targets have been identified as being promising: including the RANKL/RANK/OPG axis; intracellular signalling molecules, such as c-Src; integrins, especially the avp3 integrin, and enzymes, such as cathepsins and vacuolar H+ATPase. A significant amount of in vitro data concerning many of these targets have been generated, yet there is still little research investigating the capacity for drugs to manipulate these targets and to provide beneficial and non-toxic therapy in a clinical setting. It is clear that some targets are more promising than others, namely RANKL/RANK/OPG axis, cathepsin K and c-Src tyrosine kinase. However, additional research is required before any one target or therapy can be pursued clinically.