The Inhibitory Effect of Phosphonates on the Formation of Calcium Phosphate Crystals in vitro and on Aortic and Kidney Calcification in vivo

Abstract

1. Various phosphonates, which are compounds containing C‐P bonds, have been studied to see whether they are able to inhibit, in a manner similar to that of pyrophosphate and the condensed phosphates, the crystallization of calcium phosphate in vitro and the pathological calcification of the aorta and the kidneys of rats given large amounts of vitamin D3. 2. Six of the ten compounds studied markedly increased the minimum product, [Ca] × [P], required to induce the precipitation of calcium phosphate in vitro under physiological conditions of pH, ionic strength and temperature. Inhibition was observed at concentrations as low as 10‐7—106M. 3. Most of the diphosphonates, particularly those possessing P‐C‐P bonds, showed some ability to inhibit the calcification of the aortas and kidneys of rats treated with large amounts of vitamin D3. The most effective inhibitors were methylene diphosphonate (MDP), ethane‐1‐hydroxy‐1: I‐diphosphonate (EHDP) and diehloromethylene diphosphonate (Cl2MDP). 4. The phosphonates that possess P‐C‐P bonds thus appear to have effects on the deposition of calcium phosphate in vitro and in vivo similar to those of inorganic pyrophosphate and the condensed phosphates, which possess P‐O‐P bonds. These phosphonates differ from the condensed phosphates in that they inhibit kidney calcification as well as aortic calcification and are active by mouth as well as parenterally. The wider spectrum of activity of the phosphonates in vivo may be due to the fact that they are more resistant to chemical and enzymic breakdown. 5. Phosphonates might be used therapeutically in man against diseases in which calcium salts deposit in soft tissues.

Bisphosphonates in Chronic Kidney Disease; Balancing Potential Benefits and Adverse Effects on Bone and Soft Tissue

“…The first report of the effects of bisphosphonates on vascular calcification was in the 1970s, with experiments showing inhibition of soft tissue calcification in both animals and humans (100,101). These data have been confirmed by more recent animal studies using a number of bisphosphonates at varying doses ( Table 2).…”

Supragingival Calculus: Formation and Control

“…At a level that does not alter calcium binding by C. matruchotii proteolipid, Mg blocks apatite crystallization and stabilizes calcium phosphate as amorphous mineral (Ennever and Vogel, 1981). Diphosphonates, such as ethane-1-hydroxy-1, 1-Diphosphonate (EHDP), inhibit both apatite nucleation (Fleisch et al, 1970) and crystal growth (Francis, 1969). Importantly, nucleation inhibitors should not be used clinically, because they have been found to interfere with normal mineralization of hard tissues (Schenk et al, 1973).…”

Bisphosphonates: Mode of Action and Pharmacology

“…[11][12][13] Like pyrophosphate, bisphosphonates had high affinity for bone mineral 14 and were found to prevent calcification both in vitro and in vivo but, unlike pyrophosphate, were also able to prevent experimentally induced pathologic calcification when given orally to rats in vivo. 15 This property of being active by mouth was key to their future use in humans.…”