Osteoporosis and several other bone disorders occur when there is an imbalance 
between the resorption and formation components of bone remodeling activity. 
Therapies available for some of these conditions modulate the activity of 
osteoclasts and/or osteoblasts. The recent discoveries of receptor activator of 
NF-kappaB ligand (RANKL), an endogenous activator of osteoclastogenenesis and 
osteoclast activity and its inhibitor, osteoprotegerin (OPG) as pivotal 
regulatory factors in the pathogenesis of bone diseases like osteoporosis 
provide unique targets for therapeutic agents. In laboratory animals and now in 
humans, administering forms of OPG markedly inhibits osteoclast activity and 
improves bone strength, documenting that the strategy of inhibiting RANKL 
activity has therapeutic promise. A highly specific, fully human antibody 
against RANKL has been produced (denosumab) that in early studies in humans 
reduces bone turnover and improves bone density. Attributes of denosumab in 
these clinical studies include a very rapid onset of action, sustained effects 
for several months after a single injection, and good tolerability. These 
results provide the basis for studies evaluating the effectiveness of denosumab 
in several clinical conditions characterized by increased osteoclastic activity.