RANKL, the primary mediator of osteoclast formation, function and survival, is implicated in bone loss across a broad range of conditions. RANK and RANKL are expressed by cells involved in bone remodeling, by cells of the immune system, and by cells in other tissues. Preclinical and clinical data support the following conclusions: (1) The immune and skeletal phenotypes associated with RANKL inhibition differ in important ways from those associated with the complete absence or ablation of RANK or RANKL. (2) Immune challenge performed in animals in the presence of RANKL inhibition demonstrates normal immune function, consistent with the interpretation that RANKL inhibition does not impair the ability of animals to mount an effective immune response. (3) In animal models of inflammatory disease, inhibition of RANKL prevents bone loss but does not show a detectable effect on immune mediators or inflammation. (4) A phase 2 study in postmenopausal women with low BMD using the RANKL inhibitor denosumab showed an increase in BMD with an incidence of adverse events that was similar to placebo and to open-label alendronate. In addition, in a subset of patients tested for immunological markers, there were no clinically meaningful differences in T, B, or NK cell numbers or in immunoglobulin levels across dose or treatment groups.