Equilibrium-dependent bisphosphonate interaction with crystalline bone mineral explains anti-resorptive pharmacokinetics and prevalence of osteonecrosis of the jaw in rats

► Repeated applications of fluorescent-labeled BPs to CaP substrate demonstrated the removal of pre-adsorbed BP in an equilibrium-dependent manner. ► Single bolus and repeated fractional doses of ZOL demonstrated different pharmacological effects in vivo despite the equivalent cumulative dose. ► The prevalence of ONJ-like lesion in a vitamin D deficient rat model was dependent on the initial ZOL dose. ► The equilibrium-dependent BP-bone interaction model suggests the possibility of removing pre-adsorbed BP from skeletal tissues by displacement.