IN-VITRO AND IN-VIVO EFFECTS OF TETRAKISPHOSPHONATES ON BONE-RESORPTION, TUMOR OSTEOLYSIS, ECTOPIC CALCIFICATION, AND MACROPHAGES

The biological effects of bisphosphonates in calcium-related disorders are attributed to the incorporation of the bisphosphonates in bone, e nabling direct interaction with osteoclasts and/or osteoblasts. The hi gh accumulation of bisphosphonates in bone, due to their high affinity to hydroxyapatite (HAP), is essential for mediating in vitro and in v ivo activity. In this study we examined the activity of tetrakisphosph onates, molecules containing two P-C-P type bisphosphonate moieties co nnected by a carbon chain. The novel compounds were examined in a batt ery of in vitro and in vivo models including HAP formation and dissolu tion, ectopic calcification, bone resorption, tumor osteolysis, and of macrophage-like cells (anti- or pro-inflammatory properties). The inh ibition of ectopic calcification was ranked as follows: geminal bispho sphonates > bisacylphosphonates > tetrakisphosphonates. Pamidronate, b ut not the tetrakisphosphonates, was an effective antiosteolytic agent . Neither DNTP (tetrasodium 1,9-dihydroxynonane,1,1,9,9-tetrakisphosph onate) nor the bisacylphosphonate, PiBP (pimeloylbisphosphonate) seem to possess strong macrophage suppressive or inductive effects and can be considered to be relatively inactive in terms of anti- or pro-infla mmatory action. A significant anticalcification effect was caused by v arious phosphonates, such as the tetrakisphosphonates, but DNTP, a tet rakisphosphonate, was found toxic as it impeded somatic growth and bon e development.