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Bisphosphonates are in widespread use to prevent bone resorption in a number of metabolic and tumour-induced bone diseases including multiple myeloma. Recent reports suggest that bisphosphonate treatment may be associated with an increase in patient survival, raising the possibility that these compounds may have a direct effect on the tumour cells. We have investigated whether the bisphosphonates clodronate, pamidronate and YM175 can directly affect the human myeloma cell lines U266-B1, JJN-3 and HS-Sultan in vitro. The effect of bisphosphonate treatment on cell number and cell cycle progression was examined using flow cytometry. The ability of bisphosphonates to induce apoptosis in human myeloma cell lines was determined on the basis of changes in nuclear morphology and of DNA fragmentation. Pamidronate and the more potent bisphosphonate, YM175, significantly decreased cell number (P < 0.001) in JJN-3 and HS-Sultan cells. YM175 also caused cells to arrest in the S-phase of the cell cycle in the JJN-3 cell line. Both pamidronate and YM175 also caused an increase in the proportion of cells with altered nuclear morphology (P < 0.05) and fragmented DNA, characteristic of apoptosis, in both JJN-3 and HS-Sultan cells. In contrast, clodronate had little effect on cell number and did not cause apoptosis at the concentrations examined. These data raise the possibility that some bisphosphonates could have direct anti-tumour effects on human myeloma cells in vivo.