BACKGROUND: Osteoporotic vertebral compression fracture (OVCF) is usually treated by percutaneous kyphoplasty (PKP) which has limitations. We aimed to evaluate the effects of PKP combined with zoledronic acid (ZOL) injection on OVCF and bone metabolism indices. METHODS: A total of 600 OVCF patients admitted from June 2015 to June 2020 were randomly divided into group A (PKP alone), group B (PKP combined with ZOL 1 month later) and group C (PKP concurrently combined with ZOL) (N.=200). Before as well as 1 month (before ZOL treatment in group B) and 1 year after PKP, the pain degree, physical function and self-care ability in daily life were assessed, the height and kyphosis Cobb angle of vertebral body with compression fracture and bone mineral densities (BMDs) at different parts were measured, the clinical efficacy, adverse reactions and recurrence of vertebral fractures during 3 years of follow-up were observed, and the serum levels of BAP, BGP, p-CTx and TP1NP were detected. RESULTS: Compared with groups A and B, group C had significantly reduced visual analogue scale (VAS) and Oswestry disability index (ODI) scores and raised activity of daily living (ADL) score 1 month after PKP (P<0.05). Groups A-C had successively lowered VAS and ODI scores and elevated ADL Score 1 year after PKP (P<0.05). Compared with before PKP, the height of vertebral body with compression fracture significantly increased, and the kyphosis Cobb angle decreased in the three groups 1 month and 1 year after PKP (P<0.05). In group A, the height was lower whereas the angle was larger 1 year after PKP than those 1 month after PKP (P<0.05). One month after PKP, the height was significantly higher and the angle was smaller in group C than those of groups A and B (P<0.05). One year after PKP, the height significantly increased and the angle decreased successively in groups A-C (P<0.05). BMDs at different parts were significantly higher in group C than those of groups A and B 1 month after PKP (P<0.05). One year after PKP, BMDs were highest in group C and lowest in group A (P<0.05). The overall response rate was significantly higher in group C than that in group A (P<0.05). The recurrence rate of fractures was significantly higher in group A than those of groups B and C (P<0.05). The BAP, BGP, p-CTx and TP1NP levels were significantly lower in group C than those of groups A and B 1 month after PKP (P<0.05), and declined successively in groups A-C 1 year after PKP (P<0.05). CONCLUSIONS: PKP concurrently combined with ZOL exert the most significant therapeutic effects on OVCF, with the lowest recurrence rate of fractures. It relieves pain and improves the physical function and self-care ability in daily life probably by reducing bone metabolism indices, increasing BMD, and maintaining the height and kyphosis Cobb angle of recovered vertebral body.