Summary
Dose-related effects of APD on bone metabolism and Ca homeostasis were studied in rats. The experimental approach consisted of longitudinal and cross-sectional observations, aiming at a kinetic interpretation. Bone and cartilage resorption was inhibited within 2–8 days at doses between 0.16 and 16 µmol/kg body weight/day. This was followed by changes in bone apposition that needed at least 23 days for a maximal effect. The time lag created a transient dissociation between resorption and apposition resulting in excess Ca and P retention, adding to increased metaphyseal bone mass. At high doses of APD (≥40 µmol/kg/day) the mineral content of new matrix decreased, associated with impairment of longitudinal growth of long bones. It is concluded that the lower doses of APD inhibited resorption of bone and cartilage, possibly by physicochemical stabilization of bone mineral, whereas the effect on bone apposition was due to a cellular homeostatic mechanism. Inhibition of growth and of matrix calcification, requiring much higher doses, may be due to a direct, toxic effect on bone cells. The modes of action of APD are discussed in relation to EHDP and Cl2MDP.
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References
Francis, M.D.: The inhibition of calcium hydroxyapatite growth by polyphosphonates and polyphosphates, Calcif. Tissue Res.3:151–162, 1969
Fleisch, H., Russell, R.G.G., Francis, M.D.: Diphosphonates inhibit hydroxyapatite dissolutionin vitro and bone resorption in tissue culture andin vivo, Science165:1262–1264, 1969
Gasser, A.B., Morgan, D.B., Fleisch, H.A., Richelle, L.J.: The influence of two diphosphonates on calcium metabolism in the rat, Clin. Sci.43:31–45, 1972
Russell, R.G.G., Kislig, A.-M., Casey, P.A., Fleisch, H., Thornton, J., Schenk, R., Williams, D.A.: Effect of diphosphonates and calcitonin on the chemistry and quantitative histology of rat bone, Calcif. Tissue Res.11:179–195, 1973
Schenk, R., Merz, W.A., Mühlbauer, R., Russell, R.G.G., Fleisch, H.: Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats, Calcif. Tissue Res.11:196–214, 1973
Smith, R., Russell, R.G.G., Woods, C.G., Bishop, M.: Paget's disease of bone: experience with a diphosphonate (disodium etidronate) in treatment, Q. J. Med., New SeriesXVII:235–256, 1973
Altman, R.D., Johnston, C.C., Khairi, M.R.A., Wellman, H., Serafim, A.N., Sankey, R.R.: Influence of disodium etidronate on clinical and laboratory manifestations of Paget's disease of bone (osteitis deformans), N. Engl. J. Med.289:1379–1384, 1973
Jowsey, J., Holley, K.E., Linman, J.W.: The effect of sodium etidronate in adult cats, J. Lab. Clin. Med.76:126–133, 1970
King, W.R., Francis, M.D., Michael, W.R.: Effect of disodium ethane-1-hydroxy-1,1-diphosphonate on bone formation. Clin. Orthop.78:251–270, 1970
Russell R.G.G., Smith, R., Preston, C., Walton, R.J., Woods, C.G.: Diphosphonates in Paget's disease, Lanceti:894–898, 1974
Guncaga, J., Lauffenburger, Th., Lentner, Ch., Dambacher, M.A., Haas, H.G.: Diphosphonate treatment of Paget's disease of bone, Horm. Metab. Res.6:62–69, 1974
DeVries, H.R., Bijvoet, O.L.M.: Results of prolonged treatment of Paget's disease of bone with disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP), Neth. J. Med.17:281–298, 1974
Miller, S.C., Jee, W.S.S.: The comparative effects of dichloromethylene diphosphonate (Cl2MDP) and ethane-1-hydroxy-1,1-diphosphonate (EHDP) on growth and modeling of the rat tibia, Calcif. Tissue Res.23:207–214, 1977
Lemkes, H.H.P.J., Reitsma, P.H., Frijlink, W.B., Verlinden-Ooms, H., Bijvoet, O.L.M.: A new diphosphonate: dissociation between effects on cells and mineral in rats and a preliminary trial in Paget's disease. In S.G. Massry, E. Ritz, A. Rapado (eds.): Homeostasis of Phosphate and Other Minerals. pp. 459–469. Plenum Press, New York, 1978
Johnson, L.C.: Morphologic analysis of pathology: the kinetics of disease and general biology of bone. In H.M. Frost (ed): Bone Biodynamics, pp. 543–654. J. & A. Churchill, London 1964
Frost, H.M.: Dynamics of bone remodeling. In H.M. Frost (ed.): Bone Biodynamics, pp. 315–333. J & A. Churchill, London, 1964
Rasmussen, H., Bordier, P.: The Physiological and Cellular Basis of Metabolic Bone Disease. Williams & Wilkins, Baltimore, 1974
Prockop, D.J., Udenfriend, S.: A specific method for the analysis of hydroxyproline in tissues and urine, Anal. Biochem.1:228–239, 1960
Grogan, C.H., Cahmann, H.J., Lehco, E.: Micro-determination of chromium in small samples of various biological media. Anal. Chem.27:983–986, 1955
Reynolds, J.J.: Skeletal tissue in culture. In G.H. Bourne (ed).: The Biochemistry and Physiology of Bone, Vol. I, pp. 69–126. Academic Press, New York, 1972
Juva, K., Prockop, D.J.: Modified procedure for the assay of3H-or14C-labeled hydroxyproline, Anal. Biochem.15:77–83, 1966
Wöltgens, J.H.M., Bonting, S.L., Bijvoet, O.L.M.: Relationship of inorganic pyrophosphatase and alkaline phosphatase activities in hamster molars, Calcif. Tissue Res.5:333–343, 1970
Fishman, W.H.: The influence of steroids onβ-glucuronidase of mouse kidneys. In R.I. Dorfman (ed): Methods in Hormone Research, Vol. IV, pp. 273–326. Academic Press, New York, 1965
Fiske, C.H., Subbarow, Y.: The colorimetric determination of phosphorus, J. Biol. Chem.66:375–400, 1925
TeVelde, J., Burckhardt, R., Kleiverda, K., Leenheers-Binmendijk, L., Sommerfelt, W.: Methylmethacrylate in histopathology, Histopathology1:319–330, 1977
Goldner, J.A.: A modification of the Masson trichrome technique for routine laboratory purpose, Am. J. Pathol.14:237–243, 1938
Vaes, G.: La Résorption Osseuse et l'Hormone Parathyroidienne. De Visscher, Bruxelles, 1967
Fleisch, H., Russell, R.G.G., Bisaz, S., Mühlbauer, R.C., Williams, D.A.: The inhibitory effect of phosphonates on the formation of calcium phosphate crystalsin vitro and on aortic and kidney calcificationin vivo, Eur. J. Clin. Invest.1:12–18, 1970
Potokar, M., Schmidt-Dunker, M.: The inhibitory effect of new diphosphonic acids on aortic and kidney calcificationin vivo, Atherosclerosis30:313–320, 1978
Larsson, A., Larsson, S.-E.: Light microscopic and ultrastructural observations on the short-term effects of ethylene-1-hydroxy-1,1-diphosphonate (EHDP) on rat tibia epiphysis, Acta Pathol. Microbiol. Scand. [A]84:17–27, 1976
Howell, D.S., Pita, J.C., Marquez, J.F., Gatter, R.A.: Demonstration of macromolecular inhibitor(s) of calcification in fluid from calcifying sites in cartilage. J. Clin. Invest.48:630–641, 1969
Fast, D.K., Felix, R., Dowse, C., Neuman, W.F., Fleisch, H.: The effects of diphosphonates on the growth and glycolysis of connective-tissue cells in culture, Biochem. J.172:97–107, 1978
Walker, D.G.: Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Science190:784–785, 1975
Walker, D.G.: Spleen cells transmit osteopetrosis in mice, Science190:785–787, 1975
Mundy, G.R., Varani, J., Orr, W., Gondek, M.D., Ward, P.A.: Resorbing bone is chemotactic for monocytes, Nature275:132–135, 1978
Marks, S.C.: Pathogenesis of osteopetrosis in theia rat: reduced resorption due to reduced osteoclast function, Am. J. Anat.138:165–190, 1973
Parfitt, A.M.: The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. Part I: Mechanisms of calcium transfer between blood and bone and their cellular basis: Morphological and kinetic approaches to bone turnover, Metabolism25:809–844, 1976
Morgan, D.B., Gasser, A., Largiadèr, U., Jung, A., Fleisch, H.: Effects of a diphosphonate on calcium metabolism in calcium-deprived rats, Am. J. Physiol.228:1750–1756, 1975
Frijlink, W.B., Bijvoet, O.L.M., TeVelde, J., Heynen, G.: Treatment of Paget's disease with (3-amino-1-hydroxy-propylidene)-1,1-biphosphonate (APD), Lanceti:799–803, 1979
Wuthier, R.E.: A zonal analysis of inorganic and organic constituents of the epiphysis during enchondral calcification, Calcif. Tissue Res.4:20–38, 1969
Reitsma, P.H., Bijvoet, O.L.M., Frijlink, W.B., Vismans, F.J.F.E., Van Breukelen, F.J.M.: Pharmacology of disodium (3-amino-1-hydroxypropylidene)-1,1-biphosphonate. In S.G. Massry (ed): Proceedings of the Fourth International Workshop on Phosphate and Other Minerals, 1979. Plenum Press, New York (in press)
Bijvoet, O.L.M., Hosking, D.J., Lemkes, H.H.P.J., Reitsma, P.H., Frijlink, W.B.: Development in the treatment of Paget's disease. In: Exerpta Med. Int. Congr. Ser. No. 421: Endocrinology of Calcium Metabolism, pp. 48–54. Excerpta Medica, Amsterdam, 1977
Van Breukelen, F.J.M., Bijvoet, O.L.M., Van Oosterom, A.T.: Inhibition of osteolytic bone lesions by (3-amino-1-hydroxypropylidene)-1,1-biphosphonate (APD), Lanceti:803–805, 1979
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Reitsma, P.H., Bijvoet, O.L.M., Verlinden-Ooms, H. et al. Kinetic studies of bone and mineral metabolism during treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in rats. Calcif Tissue Int 32, 145–157 (1980). https://doi.org/10.1007/BF02408534
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DOI: https://doi.org/10.1007/BF02408534