Modification by clodronate and fluoride of hydroxyapatite-induced neutrophil chemiluminescence in vitro

In the light of previous studies demonstrating an inhibition of oxidative metabolism in human neutrophil granulocytes by the bisphosphonate, clodronate, and considerable evidence of oxidative pathway stimulation by fluoride, the aim of this study was to determine the combined effect of these two agents. A luminol-dependent, fMLP stimulated chemiluminescence system was used and showed that 10(-3) M fluoride significantly increased the inhibitory effect of clodronate (3 ug/ml and 10 ug/ml) when bound to particulate hydroxyapatite (HA), phagocytosed by the neutrophils. By contrast, 10(-4) M fluoride appeared to counteract this inhibition and was subsequently shown, following more prolonged incubation within the cell model system, to significantly enhance cellular oxidative activity by 25% compared to the HA/clodronate control. It is likely that the kinetics of clodronate and fluoride follow a different time course and their intracellular target receptors differ, but the cellular model employed may help to elucidate more precisely the basis of their therapeutic use in bone diseases.