The mechanisms of action of bisphosphonates (BP) are poorly determined. Besides their actions on osteoclasts, these agents exhibit gastrointestinal complications. They have also been recently described to affect various preparations which express an epithelial Na⁺ channel. To understand the effects of BP's on ion channels and the epithelial Na⁺ channel (ENaC) in particular, we utilized the Xenopus oocyte expression system. Alendronate, and similarly risedronate, two amino-bisphosphonates, caused a large stimulation of an endogenous non-selective cation conductance (NSCC). This stimulation averaged 63 ± 12 µS (n=18) 60 min after the addition of 2 mM alendronate. The effects on the endogenous NSCC were blocked by extracellular acidification to pH 6.4. On the other hand, alendronate caused a small inhibition of ENaC conductance at both pH 7.4 and 6.4, but the effects at pH 6.4 were more readily observed in the absence of changes of the endogenous conductance. The effects on membrane capacitance (C_m) were also markedly different with a clear decrease at pH 6.4, and no consistent changes at pH 7.4. The effects on the endogenous channel were further augmented by genistein, and inhibited by a tyrosine phosphatase inhibitor, indicating the involvement of the tyrosine kinase pathway. Stimulation of NSCC with BP's is expected to cause membrane depolarization, and may explain, in part, its mechanisms of action in inhibiting osteoclasts.