Abstract: Fosamax (FSM) and risedronate (RDT) are a second and a third generation aminobisphosphonate respectively that are approved for the prevention and treatment of osteoporosis in post-menopausal women and elderly men. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that RDT has a much larger LUMO-HOME energy difference than FMX so that it would be more inert kinetically than FMX. The molecular surface of FSM is found to abound more in electron-rich red and yellow regions than that of RDT so that FSM may be subject to electrophilic attack. This means that FSM can compete better than RDT, with phospholipids for the binding sites on the surface of the mucus gel layer, thus causing a much greater reduction in the protective hydrophobic barrier. The lower gastric irritating action of FSM and RDT at low pH may be explained as being due to partial neutralization of surface charge on the molecules as a result of association with readily available hydrogen ions. Also at low pH, hydrogen ion may displace sodium ion from FSM producing the acid form of the molecule that is found to have much lower negative charge on its molecular surface.