Both the intracellular compartment and bone mineral are supposed to play a role in acid-base balance by contributing to the extrarenal acid buffering capacity. Bisphosphonates could affect extrarenal acid buffering capacity by interfering with the formation and/or dissolution of bone mineral. In the present study, rats were pretreated with either 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP, 10 mg/kg.day sc), with prevailing inhibitory action on bone mineral formation, or dichloromethylene bisphosphonate (Cl2MBP, 10 mg p/kg.day sc) with prevailing action on bone resorption, or NaCl injections (controls) for 7 days. In intact rats, blood acid-base variables were influenced by neither HEBP, nor Cl2MBP. Two hours after nephrectomy and before acute acid loading, HEBP-but not Cl2MBP-pretreated rats displayed a significant increase in both blood HCO3- and PCO2. After HCl infusion (2.5 mEq/kg), the relative decrement in blood HCO3- (difference in blood HCO3- before and after acid loading) was transiently more important in the two bisphosphonate pretreated groups than in controls. After a 24 hour fasting period, nephrectomized animals pretreated with Cl2MBP displayed significantly lower blood HCO3- and pH values than controls or HEBP-pretreated rats. These results suggest that bisphosphonates influence extrarenal buffering capacity according to their prevailing inhibitory action on either bone mineral formation and/or dissolution. These compounds could interfere with the release rate of bone proton buffers. However, in the presence of normal renal function, this effect does not disturb the blood acid-base equilibrium.