Bisphosphonate Mechanisms of Action (original) (raw)

References

1. Jensen GF, Christiansen C Boesen J Hegedus V Transbol I. Epidemiology of postmenopausal spinal and long bone fractures. A unifying approach to postmenopausal osteoporosis. Clin Orthop 1982;166:75–81.
   PubMed Google Scholar
2. Melton LJ III. Epidemiology of fractures. In:Riggs BL, Melton LJ III, eds. Osteoporosis: etiology, diagnosis, and management. New York: Raven Press, 1988:133–154.
   Google Scholar
3. Hochberg MC, Ross PD, Black D, Cummings SR, Genant HK, Nevitt MC, Barrett Connor E, Musliner T, Thompson D. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. Arthritis Rheum 1999;42(6):1246–1254.
   Article PubMed CAS Google Scholar
4. Nevitt MC, Ross PD, Palermo L, Musliner T, Genant HK, Thompson DE. Association of prevalent vertebral fractures, bone density, and alendronate treatment with incident vertebral fractures: effect of number and spinal location of fractures. The Fracture Intervention Trial Research Group. Bone 1999;25(5):613–619.
   Article PubMed CAS Google Scholar
5. Adachi JD. The correlation of bone mineral density and biochemical markers to fracture risk. Calcif Tissue Int 1996;59(Suppl 1):16–19.
   Article PubMed Google Scholar
6. Ravn P, Rix M, Andreassen H, Clemmesen B, Bidstrup M, Gunnes M. High bone turnover is associated with low bone mass and spinal fracture in postmenopausal women. Calcif Tissue Int 1997;60(3):255–260.
   Article PubMed CAS Google Scholar
7. Hochberg MC, Greenspan S, Wasnich RD, Miller P, Thompson DE, Ross PD. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 2002;87(4):1586–1592.
   Article PubMed CAS Google Scholar
8. Cocquyt V, Kline WF, Gertz BJ, Van Belle SJ, Holland SD, DeSmet M, Quan H, Vyas KP, Zhang KE, De Greve J, Porras AG. Pharmacokinetics of intravenous alendronate. J Clin Pharmacol 1999;39(4):385–393.
   Article PubMed CAS Google Scholar
9. Porras AG, Holland SD, Gertz BJ. Pharmacokinetics of alendronate. Clin Pharmacokinet 1999;36(5):315–328.
   Article PubMed CAS Google Scholar
10. Leu CT, Luegmayr E, Freedman LP, Rodan GA, Reszka AA. Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy. Bone 2006;38(5):628–636.
    Article PubMed CAS Google Scholar
11. van Beek E, Hoekstra M, van de Ruit M, Lowik C, Papapoulos S. Structural requirements for bisphosphonate actions in vitro. J Bone Miner Res 1994;9(12):1875–1882.
    Article PubMed CAS Google Scholar
12. van Beek E, Lowik C, Que I, Papapoulos S. Dissociation of binding and antiresorptive properties of hydroxybisphosphonates by substitution of the hydroxyl with an amino group. J Bone Miner Res 1996;11(10):1492–1497.
    Article PubMed Google Scholar
13. van Beek ER, Lowik CW, Ebetino FH, Papapoulos SE. Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: structure-activity relationships. Bone 1998;23(5):437–442.
    Article PubMed Google Scholar
14. Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 2006;38(5):617–627.
    Article PubMed CAS Google Scholar
15. Otter M, Goheen S, Williams WS. Streaming potentials in chemically modified bone. J Orthop Res 1988;6(3):346–359.
    Article PubMed CAS Google Scholar
16. Kowalchuk RM, Corcoran TA, Pollack SR, Steinberg ME. Effects of etidronate and oophorectomy on the zeta potential of rat bone. Clin Orthop Relat Res 1996;328:241–249.
    Article PubMed Google Scholar
17. Reginster JY, Wilson KM, Dumont E, Bonvoisin B, Barrett J. Monthly oral ibandronate is well tolerated and efficacious in postmenopausal women: results from the monthly oral pilot study. J Clin Endocrinol Metab 2005;90(9):5018–5024.
    Article PubMed CAS Google Scholar
18. Mitchell DY, Eusebio RA, Sacco-Gibson NA, Pallone KA, Kelly SC, Nesbitt JD, Brezovic CP, Thompson GA, Powell JH. Dose-proportional pharmacokinetics of risedronate on single-dose oral administration to healthy volunteers. J Clin Pharmacol 2000;40(3):258–265.
    Article PubMed CAS Google Scholar
19. Schnitzer T, Bone HG, Crepaldi G, Adami S, McClung M, Kiel D, Felsenberg D, Recker RR, Tonino RP, Roux C, Pinchera A, Foldes AJ, Greenspan SL, Levine MA, Emkey R, Santora AC II, Kaur A, Thompson DE, Yates J, Orloff JJ. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging (Milano) 2000;12(1):1–12.
    CAS Google Scholar
20. Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996;18(2):75–85.
    Article PubMed CAS Google Scholar
21. Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, McCloskey EV, Beneton MN, Gertz BJ, Sciberras DG, Holland SD, Orgee J, Coombes GM, Rogers SR, Porras AG. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 1997;12(10):1700–1707.
    Article PubMed CAS Google Scholar
22. Phipps R, Lindsay R, Burgio D, Sun A, Russell D, Kuzmak B, Keck B, Christiansen C. Head-to-head comparison of risedronate and alendronate pharmacokinetics at clinical doses. Bone 2004;34:S81–S82.
    Google Scholar
23. Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD, Golub E, Rodan GA. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 1991;88(6):2095–2105.
    Article PubMed CAS Google Scholar
24. Azuma Y, Sato H, Oue Y, Okabe K, Ohta T, Tsuchimoto M, Kiyoki M. Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models. Bone 1995;16(2):235–245.
    Article PubMed CAS Google Scholar
25. Masarachia P, Weinreb M, Balena R, Rodan GA. Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat and mouse bones. Bone 1996;19(3):281–290.
    Article PubMed CAS Google Scholar
26. Salo J, Lehenkari P, Mulari M, Metsikko K, Vaananen HK. Removal of osteoclast bone resorption products by transcytosis. Science 1997;276(5310):270–273.
    Article PubMed CAS Google Scholar
27. Palokangas H, Mulari M, Vaananen HK. Endocytic pathway from the basal plasma membrane to the ruffled border membrane in bone-resorbing osteoclasts. J Cell Sci 1997;110(Pt 15):1767–1780.
    PubMed CAS Google Scholar
28. Murakami H, Takahashi N, Sasaki T, Udagawa N, Tanaka S, Nakamura I, Zhang D, Barbier A, Suda T. A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders. Bone 1995;17(2):137–144.
    Article PubMed CAS Google Scholar
29. Thompson K, Rogers MJ, Coxon FP, Crockett JC. Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis. Mol Pharmacol 2006;69(5):1624–1632.
    Article PubMed CAS Google Scholar
30. Halasy-Nagy JM, Rodan GA, Reszka AA. Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis. Bone 2001;29(6):553–559.
    Article PubMed CAS Google Scholar
31. Reszka AA, Halasy Nagy JM, Masarachia PJ, Rodan GA, Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem 1999;274(49):34967–34973.
    Article PubMed Google Scholar
32. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354(8):821–831.
    Article PubMed CAS Google Scholar
33. Cremers SC, Lodder MC, Den Hartigh J, Vermeij P, Van Pelt P, Lems WF, Papapoulos SE, Dijkmans BA. Short term whole body retention in relation to rate of bone resorption and cartilage degradation after intravenous bisphosphonate (pamidronate) in rheumatoid arthritis. J Rheumatol 2004;31(9):1732–1737.
    PubMed CAS Google Scholar
34. Cremers SC, Papapoulos SE, Gelderblom H, Seynaeve C, den Hartigh J, Vermeij P, van der Rijt CC, van Zuylen L. Skeletal retention of bisphosphonate (pamidronate) and its relation to the rate of bone resorption in patients with breast cancer and bone metastases. J Bone Miner Res 2005;20(9):1543–1547.
    Article PubMed CAS Google Scholar
35. Cremers S, Sparidans R, Den HJ, Hamdy N, Vermeij P, Papapoulos S. A pharmacokinetic and pharmacodynamic model for intravenous bisphosphonate (pamidronate) in osteoporosis. Eur J Clin Pharmacol 2002;57(12):883–890.
    Article PubMed CAS Google Scholar
36. Rodan G, Reszka A, Golub E, Rizzoli R. Bone safety of long-term bisphosphonate treatment. Curr Med Res Opin 2004;20(8):1291–1300.
    Article PubMed CAS Google Scholar
37. Schmidt A, Rutledge SJ, Endo N, Opas EE, Tanaka H, Wesolowski G, Leu CT, Huang Z, Ramachandaran C, Rodan SB, Rodan GA. Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate. Proc Natl Acad Sci USA 1996;93(7):3068–3073.
    Article PubMed CAS Google Scholar
38. Endo N, Rutledge SJ, Opas EE, Vogel R, Rodan GA, Schmidt A. Human protein tyrosine phosphatase-sigma: alternative splicing and inhibition by bisphosphonates. J Bone Miner Res 1996;11(4):535–543.
    Article PubMed CAS Google Scholar
39. Opas EE, Rutledge SJ, Golub E, Stern A, Zimolo Z, Rodan GA, Schmidt A. Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Biochem Pharmacol 1997;54(6):721–727.
    Article PubMed CAS Google Scholar
40. Murakami H, Takahashi N, Tanaka S, Nakamura I, Udagawa N, Nakajo S, Nakaya K, Abe M, Yuda Y, Konno F, Barbier A, Suda T. Tiludronate inhibits protein tyrosine phosphatase activity in osteoclasts. Bone 1997;20(5):399–404.
    Article PubMed CAS Google Scholar
41. Skorey K, Ly HD, Kelly J, Hammond M, Ramachandran C, Huang Z, Gresser MJ, Wang Q. How does alendronate inhibit protein-tyrosine phosphatases? J Biol Chem 1997;272(36):22472–22480.
    Article PubMed CAS Google Scholar
42. Biller SA, Forster C, Gordon EM, Harrity T, Scott WA, Ciosek CP Jr. Isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthetase. J Med Chem 1988;31(10):1869–1871.
    Article PubMed CAS Google Scholar
43. Amin D, Cornell SA, Gustafson SK, Needle SJ, Ullrich JW, Bilder GE, Perrone MH. Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res 1992;33(11):1657–1663.
    PubMed CAS Google Scholar
44. Ciosek CP Jr, Magnin DR, Harrity TW, Logan JV, Dickson JK Jr, Gordon EM, Hamilton KA, Jolibois KG, Kunselman LK, Lawrence RM. Lipophilic 1,1-bisphosphonates are potent squalene synthase inhibitors and orally active cholesterol lowering agents in vivo. J Biol Chem 1993;268(33):24832–24837.
    PubMed CAS Google Scholar
45. Magnin DR, Biller SA, Dickson JK Jr, Logan JV, Lawrence RM, Chen Y, Sulsky RB, Ciosek CP Jr, Harrity TW, Jolibois KG, Kunselman LK, Rich LC, Slusarchyk DA. 1,1-Bisphosphonate squalene synthase inhibitors: interplay between the isoprenoid subunit and the diphosphate surrogate. J Med Chem 1995;38(14):2596–2605.
    Article PubMed CAS Google Scholar
46. Amin D, Cornell SA, Perrone MH, Bilder GE. 1-Hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase. Arzneimittelforschung 1996;46(8):759–762.
    PubMed CAS Google Scholar
47. Berkhout TA, Simon HM, Patel DD, Bentzen C, Niesor E, Jackson B, Suckling KE. The novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 1996;271(24):14376–14382.
    Article PubMed CAS Google Scholar
48. Berkhout TA, Simon HM, Jackson B, Yates J, Pearce N, Groot PH, Bentzen C, Niesor E, Kerns WD, Suckling KE. SR-12813 lowers plasma cholesterol in beagle dogs by decreasing cholesterol biosynthesis. Atherosclerosis 1997;133(2):203–212.
    Article PubMed CAS Google Scholar
49. Jackson B, Gee AN, Guyon-Gellin Y, Niesor E, Bentzen CL, Kerns WD, Suckling KE. Hypocholesterolaemic and antiatherosclerotic effects of tetra-iso-propyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl-1,1-diphosphonate (SR-9223i). Arzneimittelforschung 2000;50(4):380–386.
    PubMed CAS Google Scholar
50. Risser F, Pfister CU, Degen PH. An enzyme inhibition assay for the quantitative determination of the new bisphosphonate zoledronate in plasma. J Pharm Biomed Anal 1997;15(12):1877–1880.
    Article PubMed CAS Google Scholar
51. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G. Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys 2000;373(1):231–241.
    Article PubMed CAS Google Scholar
52. Luegmayr E, Glantschnig H, Wesolowski GA, Gentile MA, Fisher JE, Rodan GA, Reszka AA. Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins. Cell Death Differ 2004;11(Suppl 1):S108–S118.
    Article PubMed CAS Google Scholar
53. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA 1999;96(1):133–138.
    Article PubMed CAS Google Scholar
54. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 1998;13(4):581–589.
    Article PubMed CAS Google Scholar
55. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001;296(2):235–242.
    PubMed CAS Google Scholar
56. van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S. Nitrogen-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 1999;255(2):491–494.
    Article PubMed Google Scholar
57. Coxon FP, Helfrich MH, Larijani B, Muzylak M, Dunford JE, Marshall D, McKinnon AD, Nesbitt SA, Horton MA, Seabra MC, Ebetino FH, Rogers MJ. Identification of a novel phosphonocarboxylate inhibitor of Rab geranylgeranyl transferase that specifically prevents Rab prenylation in osteoclasts and macrophages. J Biol Chem 2001;276(51):48213–48222.
    PubMed CAS Google Scholar
58. Thompson K, Dunford JE, Ebetino FH, Rogers MJ. Identification of a bisphosphonate that inhibits isopentenyl diphosphate isomerase and farnesyl diphosphate synthase. Biochem Biophys Res Commun 2002;290(2):869–873.
    Article PubMed CAS Google Scholar
59. Wiemer AJ, Tong H, Swanson KM, Hohl RJ. Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. Biochem Biophys Res Commun 2007;353(4):921–925.
    Article PubMed CAS Google Scholar
60. Martin MB, Arnold W, Heath HT III; Urbina JA, Oldfield E. Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis. Biochem Biophys Res Commun 1999;263(3):754–758.
    Article PubMed CAS Google Scholar
61. Dunford JE, Ebetino FH, Rogers MJ. The mechanism of inhibition of farnesyl diphosphate synthase by nitrogen-containing bisphosphonates. Bone 2002;30(3):40S.
    Google Scholar
62. Hosfield DJ, Zhang Y, Dougan DR, Broun A, Tari LW, Swanson RV, Finn J. Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis. J Biol Chem 2004;279(10):8526–8529.
    Article PubMed CAS Google Scholar
63. Rondeau JM, Bitsch F, Bourgier E, Geiser M, Hemmig R, Kroemer M, Lehmann S, Ramage P, Rieffel S, Strauss A, Green JR, Jahnke W. Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs. ChemMedChem 2006;1(2):267–273.
    Article PubMed CAS Google Scholar
64. Reszka AA, Halasy-Nagy JM, Masarachia PJ, Rodan GA. Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem 1999;274(49):34967–34973.
    Article PubMed CAS Google Scholar
65. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 1996;65:241–269.
    Article PubMed CAS Google Scholar
66. Sinensky M. Recent advances in the study of prenylated proteins. Biochim Biophys Acta 2000;1484(2–3):93–106.
    PubMed CAS Google Scholar
67. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 1992;70(3):401–410.
    Article PubMed CAS Google Scholar
68. Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 1992;70(3):389–399.
    Article PubMed CAS Google Scholar
69. Zhang D, Udagawa N, Nakamura I, Murakami H, Saito S, Yamasaki K, Shibasaki Y, Morii N, Narumiya S, Takahashi N, Suda T. The small GTP-binding protein, rho p21, is involved in bone resorption by regulating cytoskeletal organization in osteoclasts. J Cell Sci 1995;108(Pt 6):2285–2292.
    PubMed CAS Google Scholar
70. Clark EA, King WG, Brugge JS, Symons M, Hynes RO. Integrin-mediated signals regulated by members of the rho family of GTPases. J Cell Biol 1998;142(2):573–586.
    Article PubMed CAS Google Scholar
71. Dunford JE, Rogers MJ, Ebetino FH, Phipps RJ, Coxon FP. Inhibition of protein prenylation by bisphosphonates causes sustained activation of Rac, Cdc42, and Rho GTPases. J Bone Miner Res 2006;21(5):684–694.
    Article PubMed Google Scholar
72. Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000;15(8):1467–1476.
    Article PubMed CAS Google Scholar
73. Fisher JE, Rodan GA, Reszka AA. In vivo effects of bisphosphonates on the osteoclast mevalonate pathway. Endocrinology 2000;141(12):4793–4796.
    Article PubMed CAS Google Scholar
74. Frith JC, Monkkonen J, Auriola S, Monkkonen H, Rogers MJ. The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 2001;44(9):2201–2210.
    Article PubMed CAS Google Scholar
75. Ortiz-Gomez A, Jimenez C, Estevez AM, Carrero-Lerida J, Ruiz-Perez LM, Gonzalez-Pacanowska D. Farnesyl diphosphate synthase is a cytosolic enzyme in Leishmania major promastigotes and its overexpression confers resistance to risedronate. Eukaryot Cell 2006;5(7):1057–1064.
    Article PubMed CAS Google Scholar
76. Frith JC, Monkkonen J, Blackburn GM, Russell RG, Rogers MJ. Clodronate 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 1997;12(9):1358–1367.
    Article PubMed CAS Google Scholar
77. Rogers HL, Marshall D, Rogers MJ. Effects of bisphosphonates on osteoclasts in vitro, studies by scanning electron microscopy. Bone 2002;30(3):43S.
    Google Scholar
78. Alakangas A, Selander K, Mulari M, Halleen J, Lehenkari P, Monkkonen J, Salo J, Vaananen K. Alendronate disturbs vesicular trafficking in osteoclasts. Calcif Tissue Int 2002;70(1):40–47.
    Article PubMed CAS Google Scholar
79. Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, Mundy GR, Boyce BF. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995;10(10):1478–1487.
    Article PubMed CAS Google Scholar
80. Luckman SP, Coxon FP, Ebetino FH, Russell RG, Rogers MJ. Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: evidence from structure-activity relationships in J774 macrophages. J Bone Miner Res 1998;13(11):1668–1678.
    Article PubMed CAS Google Scholar
81. Shipman CM, Croucher PI, Russell RG, Helfrich MH, Rogers MJ. The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Res 1998;58(23):5294–5297.
    PubMed CAS Google Scholar
82. Benford HL, Frith JC, Auriola S, Monkkonen J, Rogers MJ. Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol 1999;56(1):131–140.
    PubMed CAS Google Scholar
83. Glantschnig H, Rodan GA, Reszka AA. Alendronate mechanism of action: the role of geranylgeranylation in p70S6 kinase-dependent osteoclast survival. Bone 2002;30(3):41S.
    Google Scholar
84. Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA. M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ 2003;10(10):1165–1177.
    Article PubMed CAS Google Scholar
85. Sugatani T, Hruska KA. Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem 2005;280(5):3583–3589.
    Article PubMed CAS Google Scholar
86. Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M, Chernoff J, Clark EA, Krebs EG. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J 1998;17(8):2224–2234.
    Article PubMed CAS Google Scholar
87. Graves JD, Draves KE, Gotoh Y, Krebs EG, Clark EA. Both phosphorylation and caspase-mediated cleavage contribute to regulation of the Ste20-like protein kinase Mst1 during CD95/Fas-induced apoptosis. J Biol Chem 2001;276(18):14909–14915.
    Article PubMed CAS Google Scholar
88. Lee KK, Ohyama T, Yajima N, Tsubuki S, Yonehara S. MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J Biol Chem 2001;276(22):19276–19285.
    Article PubMed CAS Google Scholar
89. Seedor JG, Quartuccio HA, Thompson DD. The bisphosphonate alendronate (MK-217) inhibits bone loss due to ovariectomy in rats. J Bone Miner Res 1991;6(4):339–346.
    Article PubMed CAS Google Scholar
90. Bikle DD, Morey Holton ER, Doty SB, Currier PA, Tanner SJ, Halloran BP. Alendronate increases skeletal mass of growing rats during unloading by inhibiting resorption of calcified cartilage. J Bone Miner Res 1994;9(11):1777–1787.
    Article PubMed CAS Google Scholar
91. Fisher JE, Reszka A. Evidence that High-Dose, Intermittent Ibandronate and Zoledronate Inhibit Osteoclastic Bone Resorption through a Mechanism Independent of the Mevalonate Pathway. J Bone Miner Res 2006;21(Suppl. 1):S414.
    Google Scholar
92. Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009;(1):53–62.
    Google Scholar
93. Schenk R, Merz WA, Muhlbauer R, Russell RG, Fleisch H. Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif Tissue Res 1973;11(3):196–214.
    Article PubMed CAS Google Scholar
94. Sato M, Grasser W. Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res 1990;5(1):31–40.
    Article PubMed CAS Google Scholar
95. Selander K, Lehenkari P, Vaananen HK. The effects of bisphosphonates on the resorption cycle of isolated osteoclasts. Calcif Tissue Int 1994;55(5):368–375.
    Article PubMed CAS Google Scholar
96. Kim TW, Yoshida Y, Yokoya K, Sasaki T. An ultrastructural study of the effects of bisphosphonate administration on osteoclastic bone resorption during relapse of experimentally moved rat molars. Am J Orthod Dentofacial Orthop 1999;115(6):645–653.
    Article PubMed CAS Google Scholar
97. Zimolo Z, Wesolowski G, Rodan GA. Acid extrusion is induced by osteoclast attachment to bone. Inhibition by alendronate and calcitonin. J Clin Invest 1995;96(5):2277–2283.
    Article PubMed CAS Google Scholar
98. Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350(12):1189–1199.
    Article PubMed CAS Google Scholar
99. Meunier PJ, Boivin G. Bone mineral density reflects bone mass but also the degree of mineralization of bone: therapeutic implications. Bone 1997;21(5):373–377.
    Article PubMed CAS Google Scholar
100. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 2000;27(5):687–694.
     Article PubMed CAS Google Scholar
101. Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K. Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 2001;29(2):185–191.
     Article PubMed CAS Google Scholar
102. Durchschlag E, Paschalis EP, Zoehrer R, Roschger P, Fratzl P, Recker R, Phipps R, Klaushofer K. Bone material properties in trabecular bone from human iliac crest biopsies after 3- and 5-year treatment with risedronate. J Bone Miner Res 2006;21(10):1581–1590.
     Article PubMed CAS Google Scholar
103. Zoehrer R, Roschger P, Paschalis EP, Hofstaetter JG, Durchschlag E, Fratzl P, Phipps R, Klaushofer K. Effects of 3- and 5-year treatment with risedronate on bone mineralization density distribution in triple biopsies of the iliac crest in postmenopausal women. J Bone Miner Res 2006;21(7):1106–1112.
     Article PubMed CAS Google Scholar
104. Boyce RW, Wronski TJ, Ebert DC, Stevens ML, Paddock CL, Youngs TA, Gundersen HJ. Direct stereological estimation of three-dimensional connectivity in rat vertebrae: effect of estrogen, etidronate and risedronate following ovariectomy. Bone 1995;16(2):209–213.
     Article PubMed CAS Google Scholar
105. Ste-Marie LG, Sod E, Johnson T, Chines A. Five years of treatment with risedronate and its effects on bone safety in women with postmenopausal osteoporosis. Calcif Tissue Int 2004;75(6):469–476.
     Article PubMed CAS Google Scholar
106. Balena R, Toolan BC, Shea M, Markatos A, Myers ER, Lee SC, Opas EE, Seedor JG, Klein H, Frankenfield D, Quartuccio H, Fioravanti C, Brown JCE, Hayes WC, Rodan GA. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest 1993;92(6):2577–2586.
     Article PubMed CAS Google Scholar
107. Guy JA, Shea M, Peter CP, Morrissey R, Hayes WC. Continuous alendronate treatment throughout growth, maturation, and aging in the rat results in increases in bone mass and mechanical properties. Calcif Tissue Int 1993;53(4):283–288.
     Article PubMed CAS Google Scholar
108. Lafage MH, Balena R, Battle MA, Shea M, Seedor JG, Klein H, Hayes WC, Rodan GA. Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study. J Clin Invest 1995;95(5):2127–2133.
     Article PubMed CAS Google Scholar
109. Mosekilde L, Thomsen JS, Mackey MS, Phipps RJ. Treatment with risedronate or alendronate prevents hind-limb immobilization-induced loss of bone density and strength in adult female rats. Bone 2000;27(5):639–645.
     Article PubMed CAS Google Scholar
110. Toolan BC, Shea M, Myers ER, Borchers RE, Seedor JG, Quartuccio H, Rodan G, Hayes WC. Effects of 4-amino-1-hydroxybutylidene bisphosphonate on bone biomechanics in rats. J Bone Miner Res 1992;7(12):1399–1406.
     Article PubMed CAS Google Scholar
111. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 2001;28(5):524–531.
     Article PubMed CAS Google Scholar
112. Mori S, Harruff R, Ambrosius W, Burr DB. Trabecular bone volume and microdamage accumulation in the femoral heads of women with and without femoral neck fractures. Bone 1997;21(6):521–526.
     Article PubMed CAS Google Scholar

Download references