Changes in NAD+ and its metabolites contribute to longevity and age-associated diseases. The role of NAD+ metabolism in bone diseases has however not been investigated, despite the fact that osteoporosis is a leading cause of morbidity in old age. TRAP(+) osteoclast formation from C57 Bl/6J mice was assessed after the addition of varying concentrations of NAD+ metabolites or exogenous ADPribosyl cyclase and NADase enzymes. The NAD+ metabolite cyclic ADPribose (cADPr) or exogenous addition of the enzyme ADPribosyl cyclase stimulated osteoclast formation. Blocking cADPr action with the antagonist 8-Br-cADPr potently inhibited osteoclast formation. In contrast to cADPr, its noncyclized derivative ADPribose (ADPr) or the exogenous addition of NADase both inhibited osteoclastogenesis. As CD38 is the major NAD+ -degrading enzyme present in the bone marrow, these results suggest that CD38-mediated inhibition of osteoclastogenesis is related to its NADase activity, not its ADPribosyl cyclase activity.