A Review of the Physiological and Pharmacological Effects of Pyrophosphate and Diphosphonates on Bones and Teeth

Fleisch, H. , and Neuman, W.F. : Mechanisms of Calcification: Role of Collagen, Polyphosphates, and Phosphatase , Amer J Physiol 200:1296-1300, 1961 .

Fleisch, H. ; Russell, R.G.G. ; Bisaz, S. ; Termine, J.D. ; and Posner, A.S. : Influence of Pyrophosphate on the Transformation of Amorphous to Crystalline Calcium Phosphate, Calc Tiss Res 2 :49-59, 1968.

Termine, J.D. ; Peckauskas, R.A. ; and Posner, A.S. : Calcium Phosphate Formation In Vitro: II. Effects of Environment on Amorphous-Crystalline Transformation , Arch Biochem 140:318-325, 1970.

Francis, M.D. : The Inhibition of Calcium Hydroxyapatite Crystal Growth by Polyphosphonates and Polyphosphates, Calc Tiss Res 3:151-162, 1969.

Termine, J.D. , and Posner, A.S. : Calcium Phosphate Formation In Vitro: I. Factors Affecting Initial Phase Separation, Arch Biochem 140:307-317, 1970.

Jung, A. ; Bisaz, S. ; and Fleisch, H. : The Binding of Pyrophosphate and Diphosphonates to Hydroxyapatite Crystals , submitted for publication.

Krane, S.M. , and Glimcher, M.J. : Trans-phosphorylation From Nucleoside Diand Triphosphates by Apatite Crystals , J Biol Chem 237:2991-2998, 1962 .

Burton, F.G. ; Neuman, M.W. ; and Neuman, W.F. : On the Possible Role of Crystals in the Origins of Life: I. The Adsorption of Nucleosides, Nucleotides, and Pyrophosphate by Apatite Crystals, Curr Mod Biol 3:20-26, 1969.

Fleisch, H. ; Russell, R.G.G. ; and Straumann, F. : Effect of Pyrophosphate on Hydroxyapatite and Its Implications in Calcium Homeostasis, Nature 212 :901-903, 1966.

Fleisch, H. ; Maerki, J. ; and Russell, R.G.G. : Effect of Pyrophosphate on Dissolution of Hydroxyapatite and Its Possible Importance in Calcium Homeostasis, Proc Soc Exp Biol 122:317-320, 1966.

Amdur, B.H. ; Spinelli, M.A. ; Messer, A.C. ; and Brudevold, F. : Some Interactions of Hydroxylapatite with Polymerized Phosphate Compounds, abstracted, IADR Program and Abstracts of Papers, No. 118, 1963.

Napper, D.H. , and Smythe, B.M. : The Dissolution Kinetics of Hydroxyapatite in the Presence of Kink Poisons, J Dent Res 45:1775-1783, 1966.

Buehrer, T. , and Reitemeier, R. : The Inhibiting Action of Minute Amounts of Sodium Hexametaphosphate on the Precipitation of Calcium Carbonate from Ammoniacal Solutions, J Phys Chem 44: 552-574, 1940.

Reitemeier, R. , and Buehrer, T. : The Inhibiting Action of Minute Amounts of Sodium Hexametaphosphate on the Precipitation of Calcium Carbonate from Ammoniacal Solutions, J Phys Chem 44: 535-551, 1940.

Fleisch, H. , and Bisaz, S. : The Inhibitory Effect of Pyrophosphate on Calcium Oxalate Precipitation and Its Relation to Urolithiasis, Experientia 20:276-277, 1964.

Otani, S. : Crystal Habit Modification of Strontium Sulfates: II. Characteristic Effect of Sodium Triphosphate on Crystallization and Mechanism of Spherulite Formation , Bull Chem Soc Jap 33 :1549-1554, 1960.

Sears, G.W. : Dislocation Etchings, J Chem Phys 32:1317-1322, 1960.

Russell, R.G.G. ; Bisaz, S. ; Donath , A. ; Morgan, D.B. ; and Fleisch, H. : Inorganic Pyrophosphate in Plasma in Normal Persons and in Patients With Hypophosphatasia, Osteogenesis Imperfecta and Other Disorders of Bone, J Clin Invest 50:961-969, 1971.

Fleisch, H. , and Bisaz, S. : Isolation From Urine of Pyrophosphate, A Calcification Inhibitor, Amer J Physiol 203: 671-675, 1962.

Fleisch, H. , and Bisaz, S. : Die Pyrophosphatausscheidung im Harn beim gesunden Menschen, Helv Physiol Pharmacol Acta 21:88-94, 1963.

Russell, R.G.G. , and Hodgkinson, A. : The Urinary Excretion of Inorganic Pyrophosphate by Normal Subjects and Patients with Renal Calculus, Clin Sci 31: 51-62, 1966.

Hausmann, E. ; Bisaz, S. ; Russell, R.G.G. ; and Fleisch , H. : The Concentration of Inorganic Pyrophosphate in Human Saliva and Dental Calculus , Arch Oral Biol 15:1389-1392, 1970 .

Schibler, D. ; Russell, R.G.G. ; and Fleisch , H. : Inhibition by Pyrophosphate and Polyphosphate of Aortic Calcification Induced by Vitamin D3 in Rats, Clin Sci 35:363-372, 1968.

Schibler, D. , and Fleisch, H. : Inhibition of Skin Calcification (Calciphylaxis) by Polyphosphates, Experientia 22:367, 1966.

Gabbiani, G. : Effect of Phosphates Upon Experimental Skin Calcinosis, Canad J Physiol Pharmacol 44:320-327, 1966.

Fleisch, H. , and Russell, R.G.G. : Pyrophosphate and Polyphosphate. International Encyclopedia of Pharmacology and Therapeutics, Oxford: Pergamon Press, 1970, pp 61-100.

Alcock, N.W. , and Shils, M.E. : Association of Inorganic Pyrophosphatase Activity with Normal Calcification of Rat Costal Cartilage In Vivo, Biochem J 112:505-510, 1969.

Fernley, H.N. , and Bisaz, S. : Studies on Alkaline Phosphatase. Phosphorylation of Calf-Intestinal Alkaline Phosphatase by 32P-labelled Pyrophosphate , Biochem J 107:279-283, 1968.

Fernley, H.N. , and Walker, P.G. : Studies on Alkaline Phosphatases: Inhibition by Phosphate Derivates and the Substrate Specificity, Biochem J 104: 1011-1018, 1967.

Russell, R.G.G. ; Bisaz, S. ; Casey, P. ; and Fleisch, H. : Further Studies on the Role of Pyrophosphate in Mineralised Tissues and on the Function of Phosphatases, in Proceedings of the 5th European Symposium on Calcified Tissues, Paris : SEDES, 1968, pp 65-69.

Eaton, R.H. , and Moss, D.W. : Partial Purification and Some Properties of Human Bone Alkaline Phosphatase, Enzymologia 35:31-39, 1968.

Robison, R. : The Significance of Phosphoric Esters in Metabolism, New York: New York University Press, 1932.

Ali, S.Y. ; Sajdera, S.W. ; and Anderson , H.C. : Isolation and Characterization of Calcifying Matrix Vesicles From Epiphyseal Cartilage , Proc Nat Acad Sci (USA) 67:1513-1520, 1970.

Hekkelman, J.W. : Studies on the Alkaline Phosphatase Activity of the Surface of Living Bone Cells, Calc Tiss Res 4(suppl):73-74, 1970.

Göthlin, G. , and Ericsson, J.L.E. : Fine Structural Localization of Alkaline Phosphomonoesterase in the Fracture Callus of the Rat, Israel J Med Sci 7: 488-490, 1971.

Cartier, P. : La mineralisation du cartilage ossifiable. VIII. Les pyrophosphates du tissu osseux, Bull Soc Chim Biol (Paris) 41:573-583, 1959.

Perkins, H.R. , and Walker, P.G. : The Occurrence of Pyrophosphate in Bone , J Bone Joint Surg 40-B:333-339, 1958.

Bisaz, S. ; Russell, R.G.G. ; and Fleisch, H. : Isolation of Inorganic Pyrophosphate From Bovine and Human Teeth, Arch Oral Biol 13:683-696, 1968.

Soodsma, J. , and Nordlie, R.C. : Rat Heart Pyrophosphate Phosphohydrolase Activities: Sub-cellular Distribution, Catalytic Properties, and Hormonal Responses, Biochim Biophys Acta 122:510-519, 1966.

Nayudu, P.R.V. , and Miles, P.L. : Inhibition of Pyrophosphatase Activity of Mouse Duodenal Alkaline Phosphatase by Magnesium Ions, Biochem J 115:29-35, 1969.

Vaes, G. , and Vreven, J. : Acid Pyrophosphatase, Phosphoproteinphosphatase and Phosphomonoesterase Activities in Bone Tissue, Israel J Med Sci 7:401-402, 1971.

Russell, R.G.G. ; Mühlbauer, R. ; Williams , D.A. ; Reynolds, J. ; Morgan, B. ; Copp, H. ; and Fleisch, H. : Differences Between the Effects of Calcitonin and Diphosphonates on Bone Resorption Induced by Parathyroid Hormone in Tissue Culture and on the Osteoporosis of Immobilisation in Rats, 4th Parathyroid Conference, Chapel Hill, North Carolina, March, 1971. Excerpta Medica, Congress Series, in press.

Morgan, D.B. ; Monod, A. ; Russell, R.G.G. ; and Fleisch , H. : Effect of Diphosphonates on Enzyme Changes Induced by Parathyroid Hormone in Tissue Culture, in preparation.

Tenenhouse, A. , and Rasmussen , H. : Parathyroid Hormone, Thyrocalcitonin and Ascites Tumor Cells, in Talmage, E.V., and Bélanger, L.F. (eds): Parathyroid Hormone and Thyrocalcitonin (Calcitonin), Proceedings of the 3rd Parathyroid Conference, Montreal: Excerpta Medica Foundation, 1968, pp 392-400.

Jung, A. ; Russell, R.G.G. ; Bisaz, S. ; Morgan, D.B. ; and Fleisch, H. : Fate of Intravenously Injected Pyrophosphate-32P in Dogs, Amer J Physiol 218 :1757-1764, 1970 .

Borle, A. : Les hormones et le calcium, Paris: Expansion Scientifique Française, 1971, pp 138-154.

Rasmussen, H. ; Feinblatt, J. ; Nagata, N. ; and Delong, A. : Regulation of Bone Cell Function, in Barzel, U.S. (ed): Osteoporosis, New York: Grune and Stratton, 1970, pp 187-198.

Fraser, D. : Hypophosphatasia, Amer J Med 22:730-746, 1957.

Russell, R.G.G. : Excretion of Inorganic Pyrophosphate in Hypophosphatasia , Lancet II:461-464, 1965.

Russell, R.G.G. ; Bisaz, S. ; and Fleisch, H. : Pyrophosphate and Diphosphonates in Calcium Metabolism and Their Possible Role in Renal Failure, Arch Int Med 124: 571-577, 1969.

Solomons, C.C. , and Styner, J. : Osteogenesis Imperfecta: Effect of Magnesium Administration on Pyrophosphate Metabolism, Calc Tiss Res 3:318-326, 1969.

Howard, J.E. : Urinary Stone, Canad Med Assn J 86:1001-1007, 1962.

Thomas, W.C. , and Miller, G.H. : Inorganic Phosphates in the Treatment of Renal Calculi, Modern Treatment 4 :494-504, 1967.

Fleisch, H. ; Bisaz, S. ; and Care, A.D. : Effect of Orthophosphate on Urinary Pyrophosphate Excretion and the Prevention of Urolithiasis, Lancet 1:1065-1067, 1964.

Russell, R.G.G. ; Edwards, N.A. ; and Hodgkinson , A. : Urinary Pyrophosphate and Urolithiasis, Lancet 1:1446, 1964.

Russell, R.G.G. , and Fleisch, H. : Pyrophosphate and Stone Formation, in Hodgkinson, A., and Nordin, B.E.C. (eds): Renal Stone Research Symposium, London : J.&A. Churchill Ltd., 1969, pp 165-180.

Thielmann, K. ; Schulze, M. ; Siegmund , S. ; and Hoeppener, H. : Biochemische und klinische Aspekte des Pyrophosphatstoffwechsels II, Acta Biol Med German 22:687-698, 1969.

Fleisch, H. ; Bisaz, S. ; and Russell, R.G.G. : Influence of Pyrophosphate on the Crystallisation of Uric Acid and Magnesium Ammonium Phosphate and Its Implications in Phosphate Therapy for Urolithiasis, Urol Int 22:483-491, 1967.

McCarty, D. : Pseudogout: Articular Chondrocalcinosis, in Hollander, J.L. (ed): Arthritis and Allied Conditions, 6th ed, Philadelphia: W.B. Saunders, 1966.

Russell, R.G.G. ; Bisaz, S. ; Fleisch , H. ; Currey, H.L.F. ; Rubinstein , H.M. ; Dietz, A.A. ; Boussine, I. ; Gabay, R. ; Micheli, A. ; and Fallet, G. : Inorganic Pyrophosphate in the Plasma, Urine and Synovial Fluid of Patients With Pyrophosphate Arthropathy (Chondrocalcinosis or Pseudogout), Lancet 11:899-902, 1970.

Vogel, J.J. , and Amdur, B.H. : Inorganic Pyrophosphate in Parotid Saliva and Its Relation to Calculus Formation, Arch Oral Biol 12:159-163, 1967.

Sawinski, V.J. , and Cole, D.F. : Phosphate Concentrations of Sterile Human Parotid Saliva and Its Relationship to Dental Disorders, J Dent Res 44:827, 1965.

Kinoshita, S. , and Muehlemann , H.R. : Effect of Sodium Ortho- and Pyrophosphate on Supragingival Calculus, Helv Odont Acta 10:46-48, 1966.

Muehlemann, H.R. ; Bowles, D. ; Schatt , A. ; and Bernimoulin , J.P. : Effect of Diphosphonates on Human Supragingival Calculus, Helv Odont Acta 14:31-33, 1970.

Francis, M.D. , and Briner, W.W. : The Effect of Phosphonates on Dental Enamel In Vitro and on Calculus Formation In Vivo, in press.

Sturzenberger, O.P. ; Swancar, J.R. ; and Reiter, G. : Reduction of Dental Calculus in Humans Through the Use of a Dentifrice Containing a Crystal Growth Inhibitor, J Periodont 42:416-418, 1971.

McCune, H.W. , and Tucker, N.B. : US Patent No. 3,488,419, January 6, 1970.

Harris, R.S. ; Das, S.K. ; and Nizel, A.E. : Cariostatic Effect of Three Types of Phosphates When Fed Singly or in Combinations in the Diets of Rats, J Dent Res 44:549-553, 1965.

Koenig, K.G. ; Marthaler, Th. M. ; and Muehlemann , H.R. : Effects of Some Phosphates in a Short-Period Rat Caries Experiment, Arch Oral Biol 3:258-270, 1961.

Feagin, F.F. ; Walker, A.A. ; and Pigman, W. : Evaluation of the Calcifying Characteristics of Biological Fluids and Inhibitors of Calcification , Calc Tiss Res 4:231-244, 1969.

Regolati, B. , and Muehlemann, H.R. : Effect of Diphosphonate and Fluoride on Caries, Fluorine Content and Dissolution of Rat Molars, Helv Odont Acta 14 :37-42, 1970.

Fleisch, H. ; Russell, R.G.G. ; Bisaz, S. ; Casey, P.A. ; and Mühlbauer , R.C. : The Influence of Pyrophosphate Analogues (Diphosphonates) on the Precipitation and Dissolution of Calcium Phosphate In Vitro and In Vivo, Calc Tiss Res 2 (suppl):10-10A, 1968.

Francis, M.D. ; Russell, R.G.G. ; and Fleisch , H. : Diphosphonates Inhibit Formation of Calcium Phosphate Crystals In Vitro and Pathological Calcification In Vivo, Science 165:1264-1266, 1969 .

Fleisch, H. ; Russell, R.G.G. ; Bisaz, S. ; Mühlbauer, R.C. ; and Williams, D.A. : The Inhibitory Effect of Phosphonates on the Formation of Calcium Phosphate Crystals In Vitro and on Aortic and Kidney Calcification In Vivo , Europ J Clin Invest 1:12-18, 1970.

Jung, A. ; Bisaz, S. ; and Fleisch, H. : Influence of Pyrophosphate on the Exchange of 45Ca and 32P-phosphate with Hydroxyapatite Crystals, submitted for publication.

Fleisch, H. ; Russell, R.G.G. ; and Francis, M.D. : Diphosphonates Inhibit Hydroxyapatite Dissolution In Vitro and Bone Resorption in Tissue Culture and In Vivo, Science 165:1262-1264, 1969.

Russell, R.G.G. ; Mühlbauer, R.C. ; Bisaz , S. ; Williams, D.A. ; and Fleisch, H. : The Influence of Pyrophosphate, Condensed Phosphates, Phosphonates and Other Phosphate Compounds on the Dissolution of Hydroxyapatite In Vitro and on Bone Resorption Induced by Parathyroid Hormone in Tissue Culture and in Thyroparathyroidectomised Rats, Calc Tiss Res 6:183-196, 1970.

Fraser, D. ; Russell, R.G.G. ; Pohler, O. ; Robertson, W.G. ; and Fleisch, H. : The Influence of Ethane-1-hydroxy- 1, 1-diphosphonate (EHDP) on the Development of Urinary Stones in Rats, Clin Sci, in press.

Russell, R.G.G. ; Preston, C. ; and Fleisch, H. : Effects of Phosphonates on Phosphatases and Pyrophosphatases, in preparation.

La Nauze, J.M. ; Rosenberg, H. ; and Shaw, D.C. : The Enzymatic Cleavage of the Carbon-Phosphorus Bond: Purification and Properties of Phosphonatase , Biochim Biophys Acta 212:332-350, 1970.

Casey, P.A. ; Russell, R.G.G. ; and Fleisch , H. : Effect of Sodium Etidronate, Polyphloretin Phosphate, and Polyoestradiol Phosphate on Soft Tissue Calcification , Experientia, in press.

King, W.R. ; Francis, M.D. ; and Michael, W.R. : Effect of Disodium Ethane- 1 -hydroxy- 1 , 1 -diphosphonate on Bone Formation in Animals, Clin Orthop 78:251-270, 1971.

Jowsey, J. ; Holley, K.E. ; and Linman, J.W. : The Effect of Sodium Etidronate in Adult Cats, J Lab Clin Med 76 :126-133, 1970.

Gasser, A.B. ; Morgan, D.B. ; Fleisch , H. ; and Richelle, L.J. : The Influence of Two Diphosphonates on Calcium Metabolism in the Rat, Clin Sci, in press.

Russell, R.G.G. ; Thornton, T. ; Casey, P.A. ; Mühlbauer, R.C. ; Kislig, A. ; Fleisch, H. ; Williams, D.A. ; and Schenk, R. : Effect of Diphosphonates and Calcitonin on the Chemistry and Quantitative Histology of Rat Bone, in preparation.

Morgan, D.B. ; Bonjour, J.-Ph. ; Gasser, A.B. ; O'Brien , K. ; and Fleisch, H.A. : The Influence of a Diphosphonate on the Intestinal Absorption of Calcium, Israel J Med Sci 7:384-386, 1971.

Bassett, C.A.L. ; Donath, A. ; Macagno , F. ; Preisig, R. ; Fleisch, H. ; and Francis, M.D. : Diphosphonates in the Treatment of Myositis Ossificans, Lancet II:845, 1969.

Weiss, I.W. ; Fisher, L. ; and Phang, J.M. : Diphosphonate Therapy in a patient with Myositis Ossificans Progressiva, Ann Int Med 74:933-936, 1971.

Russell, R.G.G. ; Smith, R. ; Bishop , M. ; Price, D. ; and Squire, C.M. : Myositis Ossificans Progressiva Treated With a Diphosphonate, in press.

Donath, A. , and Fleisch, H. : Unpublished results.

Reynolds, J.J. ; Minkin, C. ; Spycher , D. ; Morgan, D.B. ; and Fleisch, H. : Effects of Diphosphonates on Bone Resorption in Tissue Culture, in preparation.

Reynolds, J.J. ; Murphy, H. ; Mühlbauer , R.C. ; Morgan, D.B. ; and Fleisch, H. : Production of Experimental Osteopetrosis in Mice Treated With Dichloromethylene-Diphosphonate , in preparation.

Schenk, R. ; Russell, R.G.G. ; and Fleisch, H. : The Effect of Diphosphonates on Metaphysical Remodelling in Rats, in preparation.

Fleisch, H. ; Russell, R.G.G. ; Simpson, B. ; and Mühlbauer, R.C. : Prevention by a Diphosphonate of Immobilisation "Osteoporosis" in Rats, Nature 223:211-212, 1969.

Mohlbauer, R.C. ; Russell, R.G.G. ; Williams, D.A. ; and Fleisch, H. : The Effects of Diphosphonates on "Immobilisation Osteoporosis" in Rats, Europ J Clin Invest 1:336-344, 1971.

Michael, W.R. ; King, W.R. ; and Francis, M.D. : Effectiveness of Diphosphonates in Preventing Osteoporosis of Disuse in the Rat, Clin Orthop 78:271-276, 1971.

Smith, R. ; Bishop, M. ; and Russell, R.G.G. : Diphosphonates and Paget's Disease of Bone, Lancet 1:945-947, 1971.

Michael, W.R. , and King, W.R. : Metabolism of Disodium Ethane-1-hydroxyl-1, 1-diphosphonate in the Rat, Rabbit, Dog and Monkey, in press.

Sallis, J. ; Cumming, D. ; and Fleisch, H. : The Effect of Diphosphonates on Mitochondrial Transport of Calcium , in preparation.

Wöltgens, J.H.M. ; Bonting, S.L. ; and Bijvoet, O.L.M. : Influence of Sodium Ethane- 1 -hydroxy- 1 , 1-diphosphonate and Mg2+ on the Inorganic Pyrophosphatase in Calcifying Hamster Molars, Israel J Med Sci 7:406, 1971.

Francis, M.D. , and Flora, L. : The Effects of Disodium Ethane-1-hydroxy-1, 1-diphosphonate on Adjuvant-Induced Arthritis in Rats, Israel J Med Sci 7 :502-503, 1971.