Abstract: Objective To investigate the effect of zoledronate on osteoclastogenesis and theexpression of Capthsin K,Receptor activator of nuclear factor kappa-B(RANK) which related with Osteoclast differentiation,and explore the mechanism of action of zoledronate on osteoclastogenesis. Methods The receptor activator of nuclear factor kappa-B ligand(RANKL) was used to induce differentiation of RAW264.7 cells into osteoclasts in vitro.The cells were divided into two groups at the beginning of the induction:Group one(G1) were induced by 50 ng/ml RANKL as the control group;Group two(G2) were treated with 1×10^-6 mol/L zoledronate simultaneously with the osteoclast induction.The cells were acquired after four days induction.The cells were stained with tartrate resistant acid phosphatase(TRAP) and the osteoclastswere counted.Activity of alkaline phosphatase was detected.The expression of Cathepsin K and RANK were detected by Real-time PCR and western blot,respectively. Results The osteoclastogenesis was decreased by the addition of zoledronate.The number of TRAP+ cells in G2 was decreased(62.0±10.2)% as compared to G1(P<0.05).TRAP activity in G2 was declined as (31.0±4.1)% as compared to G1(P<0.05);the expression of Cathepsin K and RANK in G2 were significant declined by (78.0±4.2)% and (49.0±1.9)% when compared to G1(P<0.05). Conclusion Zoledronate can decrease osteoclastogenesis by inhibiting the expression of RANK in osteoclast precursors.