Objective: The aim of this study is to investigate the clinical efficacy of percutaneous kyphoplasty (PKP) combined with zoledronic acid (aclasta) in the treatment and prevention of osteoporotic vertebral compression fractures (OVCF). Method: A total of 104 patients with OVCF were treated with PKP from February 15, 2014 to January 17, 2016. All patients were randomly assigned to control and experimental groups, each group having 52 patients. All patients in the control group were treated with PKP. On the other hand, all patients in the experimental group were treated with PKP combined with aclasta. To evaluate the clinical efficacy, Visual Analogue Scale (VAS), Oswestry disability index (ODI), bone mineral density (BMD), and bone metabolism (N-MID and -CTX) were evaluated during the follow-up period. Result: One week after operation, the value of VAS and ODI improved in both groups. One year after operation, these worsened rapidly in the control group but not in the experimental group. Six months and one year after operation, the BMD improved significantly but the bone metabolism decreased significantly in the experimental group. In contrast, the BMD and bone metabolism did not change in the control group. Moreover, four patients again suffered from OVCF in the control group, and three patients had fever symptoms in the experimental group during the follow-up period. Conclusions: Results of this study indicate that the clinical efficacy of PKP combined with aclasta in the treatment and prevention of OVCF is significant.