Bone signaling pathways and treatment of osteoporosis

Osteoporotic fractures are a major healthcare burden costing over US$50 billion/per year. Bone turnover is a continuous process regulated by the coupled activities of osteocytes, osteoclasts and osteoblasts that maintain bone mass and strength. Osteoclastic bone resorption is regulated by the RANKL/osteoprotegerin/RANK pathway, while osteoblastic bone formation is controlled by canonical Wnt signaling. Antiresorptive bisphosphonates remain the mainstay of treatment but recombinant parathyroid hormone is increasingly being used as an anabolic agent. Nevertheless, these drugs are limited by patient compliance, efficacy and cost. Cathepsin K inhibitors and RANKL antibodies have been developed as new antiresorptive drugs, while short-acting calcilytics and antibodies to Dickkopf-1 and sclerostin are promising anabolics. The recent identification of adipocytes and duodenal enterochromaffin cells as novel regulators of bone mass represent exciting opportunities for future drug development.