Objective:The study is aimed to examine the effects of zoledronate(ZOL) on gene expression of calmodulin and calcineurin during differentiation of osteoclasts. Methods:RAW264.7 cells were divided into 2 groups,group A and group B. The cells in both groups were induced with 100 ng/ml RANKL(ligand of receptor activator of nuclear factor κB)for 4 d for osteoclast differentiation. At the second day of RANKL induction,cells in group B also treated with 1×10-6 mol/L ZOL for 48 h. Four days later,the cells were harvested and examined for osteoclastogenesis,as well as gene expression of both calmodulin and calcineurin. Results: TRAP positive multinuclear cells,number and size of resorption lacunaes in group B were 8.8 ± 2.3,6.7 ± 1.2 and 997.1 ± 14.8 μm2 respevtively,which were significantly lower than those (19.7 ± 2.9,13.3 ± 1.5 and 1676.9 ± 24.9 μm2)in group A (P < 0.01). mRNA and protein level of calmodulin in group B decreased about 51% and 78.7%,respectively when compared with group A (P < 0.05),and those of calcineurin also decreased about 37% and 69.5%,respectively(P < 0.05). Immunofluorescent cytochemistry showed obvious decrease of fluorescent intensity of calmodulin and calcineurin protein in group B when compared with group A. Conclusion:ZOL significantly inhibits osteoclastogenesis and down-regulates gene expression of calmodulin and calcineurin,which may play a role in ZOL-induced inhibition of osteoclastogenesis.