Bisphosphonates and tetracycline: experimental models for their evaluation in calcium-related disorders

Pharm Res. 1998 Apr;15(4):606-13. doi: 10.1023/a:1011990129437.


Purpose: This work was aimed at synthesizing novel bisphosphonates (BPs) and examining them in comparison to clinically used BPs such as pamidronate and alendronate, and to tetracycline, in order to evaluate their potential as anticalcification and antiresorption agents. The correlation between the various models was examined in order to establish facile experimental models for pre-screening of potential compounds.

Methods: Nitrogen-containing heterocyclic, novel BPs such as 2-(3-methylimidazolio) ethylidene-1,1-bisphosphonic acid betaine (VS-5b), 2-(2-dimethylamino-4-pyrazinio)ethylidene-1,1-bisphosphonic acid betaine (VS-6b), and 2-(2-alpha-pyridylethylthio) ethylidene-1,1-bisphosphonic acid (ISA-225), were synthesized and evaluated in comparison to clinically used BPs, in various experimental models of resorption and calcification.

Results: The physicochemical properties of the novel compounds are slightly different than the BPs in clinical use: the pKa values are lower, the affinity for hydroxyapatite is lower and the solubilities of the calcium salts are higher. The anticalcification potencies of the novel compounds were high and ranked as follows: alendronate = pamidronate > VS-6b = VS-5b = ISA-225 > tetracycline. The in vivo antiresorption activity of VS-5b and VS-6b in comparison to that of the clinically employed, pamidronate, was shown to be similar and higher, respectively.

Conclusions: The anticalcification activity of the novel compounds as well as that of tetracycline was lower than that of alendronate. The antiresorption activity of VS-6b was similar to that of pamidronate. A good correlation between the different models was found, enabling the facile screening of novel compounds. The activities of tetracycline and EDTA highlight the distinct behavior of BPs as "crystal poison." In addition, tetracycline was found to be a potent anticalcification agent in the ectopic calcification model.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alendronate / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Betaine / analogs & derivatives
  • Betaine / chemical synthesis
  • Betaine / therapeutic use
  • Bone Resorption / drug therapy*
  • Bone and Bones / chemistry
  • Bone and Bones / drug effects*
  • Calcinosis / drug therapy*
  • Chelating Agents / therapeutic use
  • Diphosphonates / chemical synthesis*
  • Diphosphonates / therapeutic use*
  • Edetic Acid / therapeutic use
  • Hindlimb
  • Hydroxyapatites / chemistry
  • Male
  • Pamidronate
  • Protein Synthesis Inhibitors / therapeutic use*
  • Rats
  • Structure-Activity Relationship
  • Tetracycline / therapeutic use*


  • 2-(3'-dimethylaminopyrazinio)ethylidene-1,1-bisphosphonic acid betaine
  • Anti-Inflammatory Agents
  • Chelating Agents
  • Diphosphonates
  • Hydroxyapatites
  • Protein Synthesis Inhibitors
  • Betaine
  • Edetic Acid
  • Tetracycline
  • Pamidronate
  • Alendronate