The antiresorptive activity of bisphosphonates such as zoledronic acid (ZOL) has been shown in vitro to be because of their effect on osteoclasts and osteoblasts. However, whether the effect of ZOL on monocultures might be reproducible on cocultures and whether cell interactions might influence this effect has not been described. The aim of the study was to investigate the effect of ZOL on cocultures of osteoblasts and osteoclasts in vitro. ZOL was incorporated in an implant coating based on poly(D,L-lactide) in different concentrations (10-50 microM). Cell number was measured, and procollagen I synthesis, osteoprotegerin (OPG) secretion and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) were analyzed. Moreover, TRAP-positive cells and resorption lacunas on dentin chips were counted. Results showed that cell viability was not affected when treated with doses equivalent up to 50-microM ZOL-coated implants (ZOL-CI). Procollagen I and OPG synthesis was highest when treated with 10 microM ZOL-CI, whereas sRANKL showed no significant decrease when treated with the investigated concentrations of ZOL-CI. TRAP-positive cells were decreased when treated with ZOL-CI in a dose-dependent manner. Resorption activity of osteoclasts was not significantly decreased when treated with investigated concentrations of ZOL-CI. Exposure to specific concentrations of ZOL-CI showed a beneficial effect on osteoblast differentiation and protein synthesis. Formation of osteoclast was decreased, whereas a significant decrease in sRANKL secretion and resorption activity of osteoclasts could not be shown. The investigated effect on cocultures might be clinically useful to support fracture healing and to reduce orthopedic implant loosening.