Aseptic loosening and osteolysis are currently the most common causes of failure of total joint replacements. Osteolysis is initiated by a macrophage response to wear debris, resulting in localized, osteoclastic peri-implant bone loss. We have previously inhibited osteoclast-mediated bone resorption in a canine total hip arthroplasty model using oral bisphosphonate therapy. Based on serendipitous observations from our canine study, we hypothesized that bisphosphonates have an anabolic effect on osteoblasts, in a manner distinct from their inhibitory effect on osteoclastic bone resorption. We studied the anabolic effects of two FDA-approved bisphosphonates (alendronate and risedronate) on two in vitro models: a primary human trabecular bone cell culture and the MG-63 osteoblast-like cell line. Following treatment with bisphosphonates at varying concentrations and time periods, cells were assayed for proliferation effects and results were quantified using the methods of direct cell count, and the colorimetric MTT (3-dimethylthiazol-2,5-diphenyltetrazolium bromide) assay at 24, 48, and 72 h. The effect of bisphosphonates on the maturation of osteoblasts were tested with alkaline phosphatase bioassay and reverse transcription-polymerase chain reaction for markers of osteoblast differentiation. Results from both the primary human trabecular bone cell culture and the MG-63 osteoblast-like cell line showed that both bisphosphonates significantly increased the cell number over controls, attaining peak levels at a concentration of 10(-8)M. Alkaline phosphatase activity was also increased, representing earlier commitment of osteoprogenitor cells towards the osteoblastic phenotype. Bisphosphonates also enhanced gene expression of BMP-2, Type I collagen and osteocalcin. In summary, bisphosphonates, aside from their role as inhibitors of osteoclastic bone resorption, are promoters of osteoblast proliferation and maturation.