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Effects of Weekly Administrations of Alendronate+Clodronate on Young Mouse Tibia: Localized Action at the Proximal Growth Plate

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Abstract

Alendronate (A), a typical aminobisphosphonate (aminoBP), has a strong bone-resorption-inhibitory activity (BRIA). However, like other aminoBPs it has inflammatory side effects. In contrast, the BRIA of clodronate (C), a non-aminoBP, is much weaker, and in animal experiments it suppresses aminoBP-induced inflammatory reactions. In the present study, we examined the effects of weekly administrations of A (1.6 µmol/kg) + C (160 µmol/kg) on the tibias in young mice and compared them to those induced by A or C alone. Radiophotography showed that A increased bone density at a selective site in the tibia. Indeed, one week after the final injection of A (given alone), clear sclerotic lines (tentatively called BP-lines) were visible at sites corresponding to the location of the growth plate at the time of the each injection. C also produced BP-lines, although they were weaker than those produced by A. Combined administration of A and C produced similar BP-lines as seen in mice given A alone. These results together with other physicochemical effects of A on the tibia suggest that (1) each injection of A and C inhibits bone resorption selectively and transiently at the tibial growth plate in young mice, although minor effects on other sites cannot be excluded, and (2) the combination of A and C keeps still a strong BRIA. Our findings may suggest a strategy for the prevention or reduction of some inflammatory side effects of A or other aminoBPs.

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References

  1. GA Rodan HA Fleisch (1996) ArticleTitleBisphosphonates: mechanism of action. J Clin Invest 97 2692–2696 Occurrence Handle1:CAS:528:DyaK28XjvVWksrw%3D Occurrence Handle8675678

    CAS  PubMed  Google Scholar 

  2. JP Bonjour R Rizzoli P Ammann T Chevalley (1994) Bisphosphonates in clinical medicine. NM Heershe JK Kanis (Eds) Bone and Mineral Research, vol 8. Elsevier Science BV Amsterdam 205–264

    Google Scholar 

  3. AD Geddes SM D’Souza FH Ebentino JI Kenneth (1994) Bisphosphonates: structure-activity relationships and therapeutic implications. NM Heershe JK Kanis (Eds) Bone and Mineral Research, vol 8. Elsevier Science BV Amsterdam 265–306

    Google Scholar 

  4. FH Glorieux NJ Bishop H Plotkin G Chabot G Lanoue R Travers (1998) ArticleTitleCyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 339 947–952

    Google Scholar 

  5. S Adami AK Bhalla R Dorizzi F Montesani S Rosini G Salvagno V Lo Cascio (1987) ArticleTitleThe acute phase response after bisphosphonate administration. Calcif Tissue Int 41 326–331 Occurrence Handle1:STN:280:BieC3srktlM%3D Occurrence Handle3124942

    CAS  PubMed  Google Scholar 

  6. A Sauty M Pecherstorfer I Zimmer-Roth P Fioroni L Juillerat M Markert H Ludwig P Leuenberger P Burckhardt D Thiébaud (1996) ArticleTitleInterleukin-6 and tumor necrosis factor α levels after bisphosphonates treatment in vitro and in patients with malignancy. Bone 18 133–139 Occurrence Handle10.1016/8756-3282(95)00490-4 Occurrence Handle8833207

    Article  PubMed  Google Scholar 

  7. D Thiébaud A Sauty P Burckhardt P Leuenberger L Sitzler JR Green A Kandra J Zieschang P Ibarra de Palacios (1997) ArticleTitleAn in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int 61 386–392 Occurrence Handle10.1007/s002239900353 Occurrence Handle9351880

    Article  PubMed  Google Scholar 

  8. E Siris (1993) ArticleTitleBisphosphonates and iritis. Lancet ii 436–437 Occurrence Handle10.1016/0140-6736(93)93029-Z

    Article  Google Scholar 

  9. V Macarol FT Frauenfelder (1994) ArticleTitlePamidronate disodium and possible ocular adverse drug reactions. Am J Ophthamol 118 220–224 Occurrence Handle1:STN:280:ByuA3s%2FkslM%3D

    CAS  Google Scholar 

  10. HA Fleisch (1997) ArticleTitleBisphosphonates: preclinical aspects and use in osteoporosis. Anal Med 29 56–62

    Google Scholar 

  11. J Mönkkönen HM Koponen P Ylitalo (1989) ArticleTitleComparison of the distribution of three bisphosphonates in mice. Pharmacol Toxicol 65 294–298

    Google Scholar 

  12. Y Endo N Nakamura T Kikuchi H Shinoda K Takeda Y Nitta K Kumagai (1993) ArticleTitleAminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo. Calcif Tissue Int 52 248–254 Occurrence Handle1:CAS:528:DyaK3sXktVSksr4%3D Occurrence Handle8481841

    CAS  PubMed  Google Scholar 

  13. M Nakamura T Ando A Masataka K Kumagai Y Endo (1996) ArticleTitleContrast between effects of aminobisphosphonates and non-aminobisphosphonates on collagen-induced arthritis in mice. Br J Pharmacol 119 205–212 Occurrence Handle1:CAS:528:DyaK28XmtFSju7g%3D Occurrence Handle8886399

    CAS  PubMed  Google Scholar 

  14. S Sugawara M Shibazaki H Takada K Kosugi Y Endo (1998) ArticleTitleContrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide-induced production of interleukin-1 and tumour necrosis factor α in mice. Br J Pharmacol 125 735–740 Occurrence Handle1:CAS:528:DyaK1cXnsVaqt7o%3D Occurrence Handle9831909

    CAS  PubMed  Google Scholar 

  15. H Funayama H Mayanagi H Takada Y Endo (2000) ArticleTitleElevation of histidine decarboxylase activity in the mandible of mice by Prevotella intermedia lipopolysaccharide and its augmentation by an aminobisphosphonate. Arch Oral Biol 45 787–795 Occurrence Handle10.1016/S0003-9969(00)00039-X Occurrence Handle1:CAS:528:DC%2BD3cXktlKnsrw%3D Occurrence Handle10869492

    Article  CAS  PubMed  Google Scholar 

  16. K Yamaguchi K Motegi Y Iwakura Y Endo (2000) ArticleTitleInvolvement of interleukin-1 in the inflammatory actions of aminobisphosphonates in mice. Br J Pharmacol 130 1646–1654 Occurrence Handle1:CAS:528:DC%2BD3cXlslygs74%3D Occurrence Handle10928970

    CAS  PubMed  Google Scholar 

  17. Y Endo M Shibazaki M Nakamura H Kosugi (1999) ArticleTitleInhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non-aminobisphosphonate. Br J Pharmacol 126 903–910 Occurrence Handle1:CAS:528:DyaK1MXhvVymsL4%3D Occurrence Handle10193770

    CAS  PubMed  Google Scholar 

  18. GB Kasting MD Francis (1992) ArticleTitleRetention of etidronate in human, dog, and rat. J Bone Miner Res 7 513–522

    Google Scholar 

  19. JP Devogelaer J Malghem B Maldague D Nagant de Deuxchaisnes (1987) ArticleTitleRadiological manifestation of bisphosphonate treatment with APD in a child suffering from osteogenesis imperfecta. Skeletal Radiol 16 360–363 Occurrence Handle1:STN:280:BiiA3MbnsVc%3D Occurrence Handle3629280

    CAS  PubMed  Google Scholar 

  20. M Sato W Grasser N Endo R Akins H Simmons DD Thompson E Golub GA Rodan (1991) ArticleTitleBisphosphonate action: alendronate localization in rat bone and effects on osteoclast ultrastructure. J din Invest 88 2095–2105 Occurrence Handle1:CAS:528:DyaK38XjsVGgtA%3D%3D

    CAS  Google Scholar 

  21. D Amin SA Cornell SK Gustafson SJ Needle JW Ullrich GE Bilder MH Perrone (1992) ArticleTitleBisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res 33 1657–1663 Occurrence Handle1:CAS:528:DyaK3sXntlCktA%3D%3D Occurrence Handle1464749

    CAS  PubMed  Google Scholar 

  22. D Amin SA Cornell MH Perrone GE Bilder (1996) ArticleTitle1-Hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase. Drug Res 46 759–762 Occurrence Handle1:CAS:528:DyaK28XltVyrt70%3D

    CAS  Google Scholar 

  23. JE Fisher MJ Rogers JM Halasy et al. (1999) ArticleTitleAlendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclasts formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA 96 133–138 Occurrence Handle10.1073/pnas.96.1.133 Occurrence Handle1:CAS:528:DyaK1MXjvV2isA%3D%3D Occurrence Handle9874784

    Article  CAS  PubMed  Google Scholar 

  24. E Van Beek C Löwik G Van Der Pluijm S Papapoulos (1999) ArticleTitleThe role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: a clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 14 722–729

    Google Scholar 

  25. E Van Beek E Pieterman L Cohen C Löwik S Papapoulos (1999) ArticleTitleNitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo. Biochem Biophys Res Commun 255 491–494 Occurrence Handle10049736

    PubMed  Google Scholar 

  26. E Van Beek E Pieterman L Cohen C Löwik S Papapoulos (1999) ArticleTitleFarnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 264 108–111 Occurrence Handle10.1006/bbrc.1999.1499 Occurrence Handle1:CAS:528:DyaK1MXms1ynu74%3D Occurrence Handle10527849

    Article  CAS  PubMed  Google Scholar 

  27. MB Martin W Arnold HT Heath JA Urbina E Oldfield (1999) ArticleTitleNitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis. Biochem Biophys Res Commun 263 754–758 Occurrence Handle10.1006/bbrc.1999.1404 Occurrence Handle1:CAS:528:DyaK1MXmtlCrtrg%3D Occurrence Handle10512752

    Article  CAS  PubMed  Google Scholar 

  28. K Keller SJ Fliesler (1999) ArticleTitleMechanism of aminobisphosphonate action: characterization of alendronate inhibition of isoprenoid pathway. Biochem Biophys Res Commun 266 560–563 Occurrence Handle10.1006/bbrc.1999.1849 Occurrence Handle1:CAS:528:DyaK1MXnvFersbg%3D Occurrence Handle10600541

    Article  CAS  PubMed  Google Scholar 

  29. JC Frith J Mönkkönen GM Blackburn RG Russel MJ Rogers (1997) ArticleTitleClodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res 12 1358–1367

    Google Scholar 

  30. S Auriola JC Frith MJ Rogers A Koivuniemi J Mönkkönen (1997) ArticleTitleIdentification of adenine nucleotide-containing metabolites of bisphosphonate drugs using ion-pair liquid chromatography-electrospray mass spectrometry. J Chromatogr B 704 187–195 Occurrence Handle10.1016/S0378-4347(97)00490-8 Occurrence Handle1:CAS:528:DyaK1cXjslGrug%3D%3D

    Article  CAS  Google Scholar 

  31. JM Halasy-Nagy GA Rodan AA Reszka (2001) ArticleTitleInhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis. Bone 29 553–559 Occurrence Handle10.1016/S8756-3282(01)00615-9 Occurrence Handle1:CAS:528:DC%2BD3MXos1Knt70%3D Occurrence Handle11728926

    Article  CAS  PubMed  Google Scholar 

  32. S Suri J Mönkkönen M Taskinen J Pesonen MA Blank RJ Phipps MJ Rogers (2001) ArticleTitleNitrogen-containing bisphosphonates induce apoptosis of Cao-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. Bone 29 336–343 Occurrence Handle10.1016/S8756-3282(01)00589-0 Occurrence Handle1:CAS:528:DC%2BD3MXnsVSlsLY%3D Occurrence Handle11595616

    Article  CAS  PubMed  Google Scholar 

  33. AA Reszka J Halasy-Nagy GA Rodan (2001) ArticleTitleNitrogen-bisphosphonate block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in keratinocyte model for esophageal irritation. Mol Pharmacol 59 193–202 Occurrence Handle1:CAS:528:DC%2BD3MXnsl2isg%3D%3D Occurrence Handle11160853

    CAS  PubMed  Google Scholar 

  34. K Ayada S Oguri K Yamaguchi K Kumagai Y Endo (2003) ArticleTitleElevation of histidine decarboxylase activity in the stomach of mice by ulcerogenic drugs. Eur J Pharmacol 460 63–69 Occurrence Handle10.1016/S0014-2999(02)02878-9 Occurrence Handle1:CAS:528:DC%2BD3sXivVOltA%3D%3D Occurrence Handle12535861

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Dentistry, Graduate School of Dentistry, Tohoku University, Seiryo-machi, Aoba-ku Sendai 980, Japan

    Y. Monma, H. Funayama & H. Mayanagi

  2. Department of Immunology, Graduate School of Dentistry, Tohoku University, Seiryo-machi, Aoba-ku Sendai 980, Japan

    Y. Monma, H. Funayama & Y. Endo

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  1. Y. Monma
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Correspondence to Y. Endo.

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Monma, Y., Funayama, H., Mayanagi, H. et al. Effects of Weekly Administrations of Alendronate+Clodronate on Young Mouse Tibia: Localized Action at the Proximal Growth Plate . Calcif Tissue Int 74, 115–121 (2004). https://doi.org/10.1007/s00223-002-2156-5

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