Both groups of bisphosphonates (non-nitrogen containing and nitrogen containing) inhibit bone resorption by induction of osteoclast apoptosis. However, at the molecular level the mechanism of action of these molecules differ. Non-nitrogen containing bisphosphonates such as Clodronate are metabolically incorporated into analogues of ATP that are resistant to hydrolysis by ATP-dependent metabolic enzymes. On the other hand, nitrogen containing bisphosphonates such as pamidronate and zoledronate are inhibitors of the mevalonate pathway and thereby they prevent prenylation of small GTPase signaling protein required for osteoclast function.
The table below summarizes the toxicity of free and encapsulated bisphosphonates that were reported in various scientific papers.
Table 1- IC50 values (after 4 hours of incubation) of free and liposomal encapsulated clodronate, pamidronate and zoledronate in human rhabdomyosarcoma (A673), murine teratocarcinoma cells (F9) and human umbilical vein endothelial cells (HUVECs) and non activated and activated mouse peritonial macrophages. (Source: Comparison of cytotoxic properties of free and liposomal bisphosphonates in vitro, Renate Frei, Thesis, Swiss Federal Institute of Technology Zurich, 2005)
** The IC50 unit is mM.