Therapeutics: Receptor activator of NF-κB ligand (RANKL; TNFSF11); macrophage colony-stimulating factor 1 (CSF1; M-CSF)

Cell culture and rodent studies suggest indazole-based inhibitors of RANKL signaling could help treat osteoporosis. Chemical synthesis and in vitro testing of indazole carboxylic acid analogs identified a compound that inhibited RANKL-induced NF-κB signaling in mouse macrophages and decreased RANKL- and CSF1-induced osteoclastogenesis in rat osteoclast progenitors by 90% compared with vehicle. In a mouse model of osteoporosis, the compound increased trabecular bone volume, bone thickness and trabecular bone number - a measure of bone density and structure - compared with vehicle. Next steps could include optimizing the compound and confirming its molecular target.

Amgen Inc., Daiichi Sankyo Co. Ltd. and GlaxoSmithKline plc market the anti-RANKL mAb Prolia denosumab to treat osteoporosis. Amgen and Daiichi Sankyo also market the mAb for bone repair and bone cancer and have it approved for musculoskeletal indications...