New insights into the mechanisms of bisphosphonates action
Efstathia TSETSENEKOU, Dimos KALYVAS
Oral & Maxillofacial Surgery Clinic. Dental School, University of Athens (Head: Professor C. Αlexandridis)
Hellenic Archives of Oral & Maxillofacial Surgery (2010) 3, 157-166
SUMMARY: Bisphosphonates are nowadays the most common class of drugs used to prevent and treat skeletal disorders related to diseases resulting from increased osteoclastic activity, such as multiple myeloma, metastatic cancer, Paget’s disease, as well as for management of osteoporosis. The use of bisphosphonates as promoters of osseointegration for dental implants is currently being investigated. Their application in joint arthroplasty for optimizing long-term success has also produced promising results. However, the knowledge of their mechanisms of action is constantly being enriched or modified. Each bisphosphonate has its own unique profile regarding its binding affinity with bone mineral and intracellular biochemical activities. The supposed relation between their pharmacological differences and clinical effectiveness has not yet been confirmed. It appears that the major difference between bisphosphonates arises from their biochemical targets (after their cellular uptake). The aim of this study is to report new insights into the mechanisms of action of bisphosphonates.
KEY WORDS: Βisphosphonates, osteoclastic activity, osteoporosis
REFERENCES
Bisaz S, Jung A, Fleisch H: Uptake by bone of pyrophosphate, diphosphonates and their technetium derivatives. Clin Sci Mol Med 54: 265-268, 1978 Boonekamp PM, Van Der Wee-Pals LJA, Van Wijk –Van Lennep MLL et al: Two models of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner 1: 27-39, 1986
David P, Baron R: The vacuolar H1- ATPase: a potential target for drug development in bone diseases. Expert Opin Investig Drugs 4: 725-739, 1995
Deutsch E, Barnett BL: Synthetic and structural aspects of technetium chemistry as related to nuclear medicine. In: Inorganic chemistry in biology and medicine. American Chemistry Society, Washin - gton, DC, 1980, pp 103-119
Dunford JE, Roger MJ, Edetino FH et al: Inhibition of protein prenylation by bisphosphonates causes sustained activation of Rac, Cdc42 and Rho GTPases. J Bone Miner Res 21:684-694, 2006
Ebetino FH, Francis MD, Rogers JM et al: Mechanisms of action of etidronate and other bisphosphonates. Rev Contemp Pharma - cother 9: 233- 243, 1998 Ebetino FH, Barnet BL, Russel RGG: A computational model delineates differences in hydroxyapatite binding affinities of bisphosphonates[abstract]. J Bone Miner Res 20 [Suppl 1]:S259, 2005
Ebrahimpour A, Francis MD: Bisphosphonate therapy in acute and chronic bone loss Physical and chemical considerations in bisphosphonate- related therapies. In: OLM Bijvoet , HA Fleisch, RE Canfield, RGG Russell, eds Bisphosphonates on Bones. Amste - rdam, Holland: Elsevier Science; 1995, pp.125-136
Ferrara N, Houck K, Jakeman L, Leung: Molecular and biological properties of the vascular endothelial growth-factor family of proteins. Endocr Rev 13: 18-32, 1992
Ferretti G, Fabi A, Carlini P, Papaldo P, Cordiali Fei P, Di Cosimo S et al: Zoledronic-Acid-Induced Circulating Level Modifications of Angiogenic Factors, Metalloproteinases and Proinflammatory Cytokines in Metastatic Breast Cancer Patients. Oncology 69(1): 35-43, 2005
Fisher, J.E., M.J. Rogers, J.M. Halasy, et al: Alendronate mechanism of action: genarylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci. USA 96: 133-138, 1999
Fleisch H, Russell RGG, Francis MD: Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 165:1262-1264, 1969
Follet H, Li J, Phipps RJ, Hui S et al: Risedronate and alendronate suppress asteocyte apoptosis following cyclic fatigue loading. Bone 40(4):1172-1177, 2007 Frith JC, Monkkonen J, Auriola S et al: The molecular mechanism of action of antiresorptive and anti-inflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 44: 2201-2210, 2001 Kogianni G, Mann V, Ebetino F et al: Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis. Life Sci 75(24): 2879- 2895, 2004
Lawson MA, Triffin JT, Ebetino FH: Potential bone mineral binding differences among bisphosphonates can be demonstrated by the use of hydroxyapatite column chromatography. J Bone Miner Res 20: 396- 398, 2005 Liberman UA, Weis SR, Broll J et al: Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl j med 333 (22):1437-1443, 1995 Luckman SP, Hughes DE, Coxon FP et al: NBPs inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13: 581- 589, 1998 Marshall MJ, Wilson AS, Davie MW: Effects of (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate on mouse osteoclasts. J Bone Miner Res 5: 955- 962, 1990
Masarachia P, Weinreb M, Balena R et al: Comparison of the distribution of 3-H aledronate and 3-H etidronate in rat and mouse bones. Bone 19: 281-290, 1996
Monkkonen H, Auriola S, Lehenkari P et al: A new endogenous ATP analog (Apppl) inhibits the mitochondrial adenine nucleotide transocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol 147: 437-445, 2006
Murakami H, Takahashi N, Sasaki T et al: A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders. Bone 17: 137-144, 1995
Nancollas GH, Tang R, Phipps RJ et al: Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38(5): 617-627, 2006
Owens JM, Fuller K, Chambers TJ: Osteoclast activation: potent inhibition by the bisphosphonate aledronate through a nonresorptive mechanism. J Cell Physiol 172: 79-86, 1997
Parfitt A.M: The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. Part I of IV parts: mechanisms of calcium transfer between blood and bone and their cellular basis: morphological and kinetic approaches to bone turnover. Metabolism 25: 809-844, 1976
Plotkin LI, Weinstein RS, Parfitt AM, et al: Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104: 1363-1374, 1999
Plotkin LI, Manolagas SC, Bellido T: Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their antiapoptotic effects on osteoblasts/osteocytes with novel analogs. Bone 39(3):443-452, 2006
Plotkin LI, Goellner J, Vyas K et al: bisphosphonate analog that lacks anti-remodeling activity prevents osteocyte and osteoblast apo - ptosis in vivo [abstract]. J Bone Miner Res 22 [Suppl 1]:S4, 2007
Reginster JY, Mine HW, Sorensen OH et al: Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 11:83-91, 2000
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL: Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62: 527-34, 2004
Russell RG, Muhlbauer RC, Bisaz S et al: 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. Calcif Tissue Res 6(3):183-196, 1970
Russell RGG, Xia Z, Dunford JE, Oppermann U, Kwaasi A et al: Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann.N.Y.Acad. Sci. 2007; 1117: 209-257
Russell RGG, Watts NB, Ebetino FH, Rogers MJ: Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos 2008; 19: 733-759
Santini D, Vincenzi B, Avvisati G et al: Pamidronate induces modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 8: 1080–1084, 2002
Sato M, Grasser W: Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res 5: 31- 40, 1990 Selander K, Lehenkari P, Vaananen HK: The effects of bisphosphonates on the resorption cycle of isolated osteoclasts. Calcif Tissue Int 1994; 55: 368- 375, 1994
Suda T, Nakamura I, Jimi E et al: Regulation of osteoclast function. J Bone Miner Res 12: 869-879, 1997
Vitte C, Fleisch H, Guenther HL.: Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology 137: 2324-2333, 1996
Watts NB, Harris ST, Genant HK et al: Intermittent cyclical editronate treatment of postmenopausal osteoporosis N Engl J Med 323(2): 73-79, 1990
Wood J, Bonjean K, Ruetz S et al: Novel Antiangiogenic Effects of the Bisphosphonate Compound Zoledronic Acid. JPET 302: 1055- 1061, 2002
Oral & Maxillofacial Surgery Clinic. Dental School, University of Athens (Head: Professor C. Αlexandridis)
Hellenic Archives of Oral & Maxillofacial Surgery (2010) 3, 157-166
SUMMARY: Bisphosphonates are nowadays the most common class of drugs used to prevent and treat skeletal disorders related to diseases resulting from increased osteoclastic activity, such as multiple myeloma, metastatic cancer, Paget’s disease, as well as for management of osteoporosis. The use of bisphosphonates as promoters of osseointegration for dental implants is currently being investigated. Their application in joint arthroplasty for optimizing long-term success has also produced promising results. However, the knowledge of their mechanisms of action is constantly being enriched or modified. Each bisphosphonate has its own unique profile regarding its binding affinity with bone mineral and intracellular biochemical activities. The supposed relation between their pharmacological differences and clinical effectiveness has not yet been confirmed. It appears that the major difference between bisphosphonates arises from their biochemical targets (after their cellular uptake). The aim of this study is to report new insights into the mechanisms of action of bisphosphonates.
KEY WORDS: Βisphosphonates, osteoclastic activity, osteoporosis
REFERENCES
Bisaz S, Jung A, Fleisch H: Uptake by bone of pyrophosphate, diphosphonates and their technetium derivatives. Clin Sci Mol Med 54: 265-268, 1978 Boonekamp PM, Van Der Wee-Pals LJA, Van Wijk –Van Lennep MLL et al: Two models of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner 1: 27-39, 1986
David P, Baron R: The vacuolar H1- ATPase: a potential target for drug development in bone diseases. Expert Opin Investig Drugs 4: 725-739, 1995
Deutsch E, Barnett BL: Synthetic and structural aspects of technetium chemistry as related to nuclear medicine. In: Inorganic chemistry in biology and medicine. American Chemistry Society, Washin - gton, DC, 1980, pp 103-119
Dunford JE, Roger MJ, Edetino FH et al: Inhibition of protein prenylation by bisphosphonates causes sustained activation of Rac, Cdc42 and Rho GTPases. J Bone Miner Res 21:684-694, 2006
Ebetino FH, Francis MD, Rogers JM et al: Mechanisms of action of etidronate and other bisphosphonates. Rev Contemp Pharma - cother 9: 233- 243, 1998 Ebetino FH, Barnet BL, Russel RGG: A computational model delineates differences in hydroxyapatite binding affinities of bisphosphonates[abstract]. J Bone Miner Res 20 [Suppl 1]:S259, 2005
Ebrahimpour A, Francis MD: Bisphosphonate therapy in acute and chronic bone loss Physical and chemical considerations in bisphosphonate- related therapies. In: OLM Bijvoet , HA Fleisch, RE Canfield, RGG Russell, eds Bisphosphonates on Bones. Amste - rdam, Holland: Elsevier Science; 1995, pp.125-136
Ferrara N, Houck K, Jakeman L, Leung: Molecular and biological properties of the vascular endothelial growth-factor family of proteins. Endocr Rev 13: 18-32, 1992
Ferretti G, Fabi A, Carlini P, Papaldo P, Cordiali Fei P, Di Cosimo S et al: Zoledronic-Acid-Induced Circulating Level Modifications of Angiogenic Factors, Metalloproteinases and Proinflammatory Cytokines in Metastatic Breast Cancer Patients. Oncology 69(1): 35-43, 2005
Fisher, J.E., M.J. Rogers, J.M. Halasy, et al: Alendronate mechanism of action: genarylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci. USA 96: 133-138, 1999
Fleisch H, Russell RGG, Francis MD: Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 165:1262-1264, 1969
Follet H, Li J, Phipps RJ, Hui S et al: Risedronate and alendronate suppress asteocyte apoptosis following cyclic fatigue loading. Bone 40(4):1172-1177, 2007 Frith JC, Monkkonen J, Auriola S et al: The molecular mechanism of action of antiresorptive and anti-inflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 44: 2201-2210, 2001 Kogianni G, Mann V, Ebetino F et al: Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis. Life Sci 75(24): 2879- 2895, 2004
Lawson MA, Triffin JT, Ebetino FH: Potential bone mineral binding differences among bisphosphonates can be demonstrated by the use of hydroxyapatite column chromatography. J Bone Miner Res 20: 396- 398, 2005 Liberman UA, Weis SR, Broll J et al: Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl j med 333 (22):1437-1443, 1995 Luckman SP, Hughes DE, Coxon FP et al: NBPs inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13: 581- 589, 1998 Marshall MJ, Wilson AS, Davie MW: Effects of (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate on mouse osteoclasts. J Bone Miner Res 5: 955- 962, 1990
Masarachia P, Weinreb M, Balena R et al: Comparison of the distribution of 3-H aledronate and 3-H etidronate in rat and mouse bones. Bone 19: 281-290, 1996
Monkkonen H, Auriola S, Lehenkari P et al: A new endogenous ATP analog (Apppl) inhibits the mitochondrial adenine nucleotide transocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol 147: 437-445, 2006
Murakami H, Takahashi N, Sasaki T et al: A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders. Bone 17: 137-144, 1995
Nancollas GH, Tang R, Phipps RJ et al: Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38(5): 617-627, 2006
Owens JM, Fuller K, Chambers TJ: Osteoclast activation: potent inhibition by the bisphosphonate aledronate through a nonresorptive mechanism. J Cell Physiol 172: 79-86, 1997
Parfitt A.M: The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. Part I of IV parts: mechanisms of calcium transfer between blood and bone and their cellular basis: morphological and kinetic approaches to bone turnover. Metabolism 25: 809-844, 1976
Plotkin LI, Weinstein RS, Parfitt AM, et al: Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104: 1363-1374, 1999
Plotkin LI, Manolagas SC, Bellido T: Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their antiapoptotic effects on osteoblasts/osteocytes with novel analogs. Bone 39(3):443-452, 2006
Plotkin LI, Goellner J, Vyas K et al: bisphosphonate analog that lacks anti-remodeling activity prevents osteocyte and osteoblast apo - ptosis in vivo [abstract]. J Bone Miner Res 22 [Suppl 1]:S4, 2007
Reginster JY, Mine HW, Sorensen OH et al: Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 11:83-91, 2000
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL: Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62: 527-34, 2004
Russell RG, Muhlbauer RC, Bisaz S et al: 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. Calcif Tissue Res 6(3):183-196, 1970
Russell RGG, Xia Z, Dunford JE, Oppermann U, Kwaasi A et al: Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann.N.Y.Acad. Sci. 2007; 1117: 209-257
Russell RGG, Watts NB, Ebetino FH, Rogers MJ: Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos 2008; 19: 733-759
Santini D, Vincenzi B, Avvisati G et al: Pamidronate induces modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 8: 1080–1084, 2002
Sato M, Grasser W: Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res 5: 31- 40, 1990 Selander K, Lehenkari P, Vaananen HK: The effects of bisphosphonates on the resorption cycle of isolated osteoclasts. Calcif Tissue Int 1994; 55: 368- 375, 1994
Suda T, Nakamura I, Jimi E et al: Regulation of osteoclast function. J Bone Miner Res 12: 869-879, 1997
Vitte C, Fleisch H, Guenther HL.: Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology 137: 2324-2333, 1996
Watts NB, Harris ST, Genant HK et al: Intermittent cyclical editronate treatment of postmenopausal osteoporosis N Engl J Med 323(2): 73-79, 1990
Wood J, Bonjean K, Ruetz S et al: Novel Antiangiogenic Effects of the Bisphosphonate Compound Zoledronic Acid. JPET 302: 1055- 1061, 2002
How to cite this article:
|
View the full-text PDF:
|
| ||