RANKL inhibition for the management of patients with benign metabolic bone disorders

Expert Opinion on Investigational Drugs

Volumn 18, Issue 8, 2009, Pages 1085-1102

  Anastasilakis, Athanasios D ^b   Toulis, Konstantinos A ^b   Polyzos, Stergios A ^c   Terpos, Evangelos ^a  

^a UNIVERSITY OF ATHENS MEDICAL SCHOOL   (Greece)

^b 424 General Army Hospital   (Greece)

^c ARISTOTLE UNIVERSITY OF THESSALONIKI   (Greece)

Author keywords

Bone mineral density; Denosumab; Fracture; Osteoporosis; Osteoprotegerin; RANKL; Rheumatoid arthritis

Indexed keywords

ALENDRONIC ACID; BISPHOSPHONIC ACID DERIVATIVE; CORTICOSTEROID; DENOSUMAB; ESTROGEN; ETIDRONIC ACID; GLUCOCORTICOID; HYBRID PROTEIN; IMMUNOGLOBULIN FC FRAGMENT; IMMUNOGLOBULIN G1; IMMUNOGLOBULIN G1 FC FRAGMENT OSTEOPROTEGERIN; METHOTREXATE; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOCLAST DIFFERENTIATION FACTOR IMMUNOGLOBULIN G1 FC FRAGMENT; OSTEOPROTEGERIN; PAMIDRONIC ACID; PARATHYROID HORMONE[1-34]; RALOXIFENE; RECOMBINANT OSTEOPROTEGERIN; RISEDRONIC ACID; STRONTIUM RANELATE; TILUDRONIC ACID; UNCLASSIFIED DRUG; ZOLEDRONIC ACID;

BONE DENSITY; BONE METASTASIS; BONE TURNOVER; BREAST CANCER; CORTICOSTEROID INDUCED OSTEOPOROSIS; CROHN DISEASE; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG SPECIFICITY; DRUG WITHDRAWAL; ESTROGEN THERAPY; FRACTURE; FRACTURE HEALING; FRAGILITY FRACTURE; GENE THERAPY; HUMAN; HYPERTHYROIDISM; IMMUNE DEFICIENCY; JAW OSTEONECROSIS; LIVER DISEASE; METABOLIC BONE DISEASE; NONHUMAN; ORGAN TRANSPLANTATION; OSTEOARTHRITIS; OSTEOLYSIS; OSTEOPENIA; OSTEOPOROSIS; PAGET BONE DISEASE; PATHOPHYSIOLOGY; PERTHES DISEASE; POSTMENOPAUSE OSTEOPOROSIS; PRIMARY HYPERPARATHYROIDISM; PROTEIN BLOOD LEVEL; PROTEIN FUNCTION; PSORIATIC ARTHRITIS; RENAL OSTEODYSTROPHY; REVIEW; RHEUMATOID ARTHRITIS; RISK REDUCTION; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; THALASSEMIA; ULCERATIVE COLITIS; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION;

ANTIBODIES, MONOCLONAL; BONE DENSITY; BONE DENSITY CONSERVATION AGENTS; BONE DISEASES, METABOLIC; BONE REMODELING; HUMANS; OSTEOPROTEGERIN; RANK LIGAND; RECOMBINANT PROTEINS;

EID: 68049142558     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543780903048929     Document Type: Review

References (205)

1. Sambrook P, Cooper C. Osteoporosis. Lancet 2006;367:2010-8
2. Melton L Jr. Adverse outcomes of osteoporotic fractures in the general population. J Bone Miner Res 2003;18:1139-41
3. Cohen A, Shane E. Treatment of premenopausal women with low bone mineral density. Curr Osteoporos Rep 2008;6:39-46
4. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998;19:80-100
5. Roodman GD. Advances in bone biology: the osteoclast. Endocr Rev 1996;17:308-32
6. Itoh K, Udagawa N, Matsuzaki K, et al. Importance of membrane- or matrix-associated forms of M-CSF and RANKL/ODF in osteoclastogenesis supported by SaOS-4/3 cells expressing recombinant PTH/PTHrP receptors. J Bone Miner Res 2000;15:1766-75
7. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999;397:315-23
8. Hofbauer L, Schoppet M. Clinical implications of the osteoprotegerin/ RANKL/RANK system for bone and vascular diseases. JAMA 2004;292:490-5
9. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-19
10. Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13:2412-24
11. Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998;12:1260-8
12. Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997;390:175-9
13. Wong B, Josien R, Lee SY, et al. TRANCE (tumor necrosis factor [TNF]-related activation induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med 1997;186:2075-80
14. Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999;402:304-9
15. Yun TJ, Chaudhary PM, Shu GL, et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol 1998;161:6113-21
16. Bachmann MF, Wong BR, Josien R, et al. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J Exp Med 1999;189:1025-31
17. Collin-Osdoby P, Rothe L, Anderson F, et al. Receptor activator of NF-κB and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem 2001;276:20659-72
18. Olesen P, Ledet T, Rasmussen LM. Arterial osteoprotegerin: increased amounts in diabetes and modifiable synthesis from vascular smooth muscle cells by insulin and TNF-α. Diabetologia 2005;48:561-8
19. Schoppet M, Al-Fakhri N, Franke FE, et al. Localization of osteoprotegerin, tumor necrosis factorrelated apoptosis-inducing ligand, and receptor activator of nuclear factor-κB ligand in Monckeberg's sclerosis and atherosclerosis. J Clin Endocrinol Metab 2004;89:4104-12
20. Dhore CR, Cleutjens JP, Lutgens E, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2001;21:1998-2003
21. Min H, Morony S, Sarosi I, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 2000;192:463-74
22. Price PA, June HH, Buckley JR, et al. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol 2001;21:1610-6
23. Malyankar UM, Scatena M, Suchland KL, et al. Osteoprotegerin is an αvβ3-induced, NF-κBdependent survival factor for endothelial cells. J Biol Chem 2000;275:20959-62
24. Rogers A, Eastell R. Circulating osteoprotegerin and receptor activator for nuclear factor κB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 2005;90:6323-31
25. Chen D, Sarikaya NA, Gunn H, et al. ELISA methodology for detection of modified osteoprotegerin in clinical studies. Clin Chem 2001;47:747-9
26. Eghbali-Fatourechi G, Khosla S, Sanyal A, et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003;111:1221-30
27. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995;332:305-11
28. Miyazaki T, Matsunaga T, Miyazaki S, et al. Changes in receptor activator of nuclear factor-κB, and its ligand, osteoprotegerin, bone-type alkaline phosphatase, and tartrate-resistant acid phosphatase in ovariectomized rats. J Cell Biochem 2004;93:503-12
29. Yoneda T, Ishimaru N, Arakaki R, et al. Estrogen deficiency accelerates murine autoimmune arthritis asociated with receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis. Endocrinology 2004;145:2384-91
30. Yano K, Tsuda E, Washida N, et al. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 1999;14:518-27
31. Riggs BL, Khosla S, Atkinson EJ, et al. Evidence that type I osteoporosis results from enhanced responsiveness of bone to estrogen deficiency. Osteoporos Int 2003;14:728-33
32. Rogers A, Saleh G, Hannon RA, et al. Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. J Clin Endocrinol Metab 2002;87:4470-5
33. Mezquita-Raya P, de la Higuera M, Garcia DF, et al. The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women. Osteoporos Int 2005;16:1368-74
34. Kudlacek S, Schneider B, Woloszczuk W, et al. Serum levels of osteoprotegerin increase with age in a healthy adult population. Bone 2003;32:681-6
35. Jorgensen HL, Kusk P, Madsen B, et al. Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios. J Bone Miner Res 2004;22:132-8
36. Indridason OS, Franzson L, Sigurdsson G. Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover. Osteoporos Int 2005;16:417-23
37. Khosla S, Arrighi HM, Melton LJ, et al. Correlates of osteoprotegerin levels in women and men. Osteoporos Int 2002;13:394-9
38. Han KO, Choi JT, Choi HA, et al. The changes in circulating osteoprotegerin after hormone therapy in postmenopausal women and their relationship with oestrogen responsiveness on bone. Clin Endocrinol (Oxf ) 2005;62:349-53
39. Schett G, Kiechl S, Redlich K, et al. Soluble RANKL and risk of nontraumatic fracture. JAMA 2004;291:1108-13
40. Liu JM, Zhao HY, Ning G, et al. Relationships between the changes of serum levels of OPG and RANKL with age, menopause, bone biochemical markers and bone mineral density in Chinese women aged 20-75. Calcif Tissue Int 2005;76:1-6
41. Oh KW, Rhee EJ, Lee WY, et al. Circulating osteoprotegerin and receptor activator of NF-kappaB ligand system are associated with bone metabolism in middle-aged males. Clin Endocrinol (Oxf ) 2005;62:92-8
42. Gannage-Yared MH, Fares F, Semaan M, et al. Circulating osteoprotegerin is correlated with lipid profile, insulin sensitivity, adiponectin and sex steroids in an ageing male population. Clin Endocrinol (Oxf ) 2006;64:652-8
43. Fahrleitner-Pammer A, Dobnig H, Piswanger-Soelkner C, et al. Osteoprotegerin serum levels in women: correlation with age, bone mass, bone turnover and fracture status. Wien Klin Wochenschr 2003;115:291-7
44. Browner WS, Lui LY, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 2001;86:613-37
45. Weinstein RS, Jilka RL, Parfitt AM, et al. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 1998;102:274-82
46. Hofbauer LC, Gori F, Riggs BL, et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999;140:4382-9
47. Sasaki N, Kusano E, Ando Y, et al. Changes in osteoprotegerin and markers of bone metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis. Bone 2002;30:853-8
48. von Tirpitz C, Epp S, Klaus J, et al. Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn's disease. Eur J Gastroenterol Hepatol 2003;15:1165-70
49. Kon T, Cho TJ, Aizawa T, et al. Expression of osteoprotegerin, receptor activator of NF-?B ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 2001;16:1004-14
50. Rogers A, Beaumont R, Veitch S, et al. Change in serum OPG after tibial shaft fracture in adults. J Bone Miner Res 2003;18:S280
51. Ulrich-Vinther M, Andreassen TT. Osteoprotegerin treatment impairs remodeling and apparent material properties of callus tissue without influencing structural fracture strength. Calcif Tissue Int 2005;76:280-6
52. Huang JC, Sakata T, Pfleger LL, et al. PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res 2004;19:235-44
53. Lee SK, Lorenzo JA. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 1999;140:3552-61
54. Kondo H, Guo J, Bringhurst FR. Cyclic adenosine monophosphate/protein kinase A mediates parathyroid hormone/parathyroid hormone-related protein receptor regulation of osteoclastogenesis and expression of RANKL and osteoprotegerin mRNAs by marrow stromal cells. J Bone Miner Res 2002;17:1667-79
55. Coetzee M, Haag M, Kruger MC. Effects of arachidonic acid, docosahexaenoic acid, prostaglandin E(2) and parathyroid hormone on osteoprotegerin and RANKL secretion by MC3T3-E1 osteoblast-like cells. J Nutr Biochem 2007;18:54-63
56. Ma YL, Cain RL, Halladay DL, et al. Catabolic effects of continuous human PTH (1-38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology 2001;142:4047-54
57. Ueno Y, Shinki T, Nagai Y, et al. In vivo administration of 1,25-dihydroxyvitamin D3 suppresses the expression of RANKL mRNA in bone of thyroparathyroidectomized rats constantly infused with PTH. J Cell Biochem 2003;90:267-77
58. Stilgren LS, Rettmer E, Eriksen EF, et al. Skeletal changes in osteoprotegerin and receptor activator of nuclear factor-kappab ligand mRNA levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism. Bone 2004;35:256-65
59. Stilgren LS, Hegedüs LM, Beck-Nielsen H, et al. Osteoprotegerin levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism. Calcif Tissue Int 2003;73:210-6
60. Seck T, Diel I, Bismar H, et al. Serum parathyroid hormone, but not menopausal status, is associated with the expression of osteoprotegerin and RANKL mRNA in human bone samples. Eur J Endocrinol 2001;145:199-205
61. Nakchbandi IA, Lang R, Kinder B, et al. The role of the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin cytokine system in primary hyperparathyroidism. J Clin Endocrinol Metab 2008;93:967-73
62. Mochizuki Y, Banba N, Hattori Y, et al. Correlation between serum osteoprotegerin and biomarkers of bone metabolism during anti-thyroid treatment in patients with Graves' disease. Horm Res 2006;66:236-9
63. Amato G, Mazziotti G, Sorvillo F, et al. High serum osteoprotegerin levels in patients with hyperthyroidism: effect of medical treatment. Bone 2004;35:785-91
64. Martini G, Gennari L, De Paola V, et al. The effects of recombinant TSH on bone turnover markers and serum osteoprotegerin and RANKL levels. Thyroid 2008;18:455-60
65. Shigeyama Y, Pap T, Kunzler P, et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum 2000;43:2523-30
66. Haynes DR, Crotti TN, Loric M, et al. Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology 2001;40:623-30
67. Itonaga I, Fujikawa Y, Sabokbar A, et al. Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent. J Pathol 2000;192:97-104
68. Romas E, Bakharevski O, Hards D, et al. Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis. Arthritis Rheum 2000;43:821-6
69. Stolina M, Dwyer D, Middleton S, et al. Progression of inflammatory arthritis is associated with decreased OPG protein, increased RANKL protein and a greater RANKL:OPG ratio. Ann Rheum Dis 2006;65:139
70. Stolina M, Adamu S, Ominsky MS, et al. RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis. J Bone Miner Res 2005;20:1756-65
71. Skoumal M, Kolarz G, Haberhauer G, et al. Osteoprotegerin and the receptor activator of NF-kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding rheumatoid arthritis and osteoarthritis. Rheumatol Int 2005;26:63-9
72. Geusens P, Landewe R, Chen D, et al. Receptor activator of the nuclear factor κ-B ligand (RANKL) in serum is related to bone density, cartilage breakdown and inflammation in early active rheumatoid arthritis. J Bone Miner Res 2002;17:S386
73. Geusens PP, Landewé RB, Garnero P, et al. The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction. Arthritis Rheum 2006;54:1772-7
74. Ziolkowska M, Kurowska M, Radzikowska A, et al. High levels of osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in serum of rheumatoid arthritis patients and their normalization after antitumor necrosis factor α treatment. Arthritis Rheum 2002;46:1744-53
75. Kim HR, Kim HY, Lee SH. Elevated serum levels of soluble receptor activator of nuclear factors-kappaB ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS). Rheumatology (Oxford) 2006;45:1197-200
76. Franck H, Meurer T, Hofbauer LC. Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis. J Rheumatol 2004;31:2236-41
77. Ritchlin CT, Haas-Smith SA, Li P, et al. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 2003;111:821-31
78. Shimizu S, Asou Y, Itoh S, et al. Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis. Arthritis Rheum 2007;56:3358-65
79. Kadri A, Ea HK, Bazille C, et al. Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis. Arthritis Rheum 2008;58:2379-86
80. Pilichou A, Papassotiriou I, Michalakakou K, et al. High levels of synovial fluid osteoprotegerin (OPG) and increased serum ratio of receptor activator of nuclear factor-kappa B ligand (RANKL) to OPG correlate with disease severity in patients with primary knee osteoarthritis. Clin Biochem 2008;41:746-9
81. Haynes DR, Crotti TN, Potter AE, et al. The osteoclastogenic molecules RANKL and RANK are associated with periprosthetic osteolysis. J Bone Joint Surg Br 2001;83:902-11
82. Granchi D, Pellacani A, Spina M, et al. Serum levels of osteoprotegerin and receptor activator of nuclear factor-kappaB ligand as markers of periprosthetic osteolysis. J Bone Joint Surg Am 2006;88:1501-9
83. Moschen AR, Kaser A, Stadlmann S, et al. The RANKL/OPG system and bone mineral density in patients with chronic liver disease. J Hepatol 2005;43:973-83
84. Monegal A, Navasa M, Peris P, et al. Serum osteoprotegerin and its ligand in cirrhotic patients referred for orthotopic liver transplantation: relationship with metabolic bone disease. Liver Int 2007;27:492-7
85. Szalay F, Hegedus D, Lakatos PL, et al. High serum osteoprotegerin and low RANKL in primary biliary cirrhosis. J Hepatol 2003;38:395-400
86. Fábrega E, Orive A, García-Suarez C, et al. Osteoprotegerin and RANKL in alcoholic liver cirrhosis. Liver Int 2005;25:305-10
87. García-Valdecasas-Campelo E, González-Reimers E, Santolaria-Fernández F, et al. Serum osteoprotegerin and RANKL levels in chronic alcoholic liver disease. Alcohol Alcohol 2006;41:261-6
88. Fiore CE, Pennisi P, Ferro G, et al. Altered osteoprotegerin/RANKL ratio and low bone mineral density in celiac patients on long-term treatment with gluten-free diet. Horm Metab Res 2006;38:417-22
89. Taranta A, Fortunati D, Longo M, et al. Imbalance of osteoclastogenesis- regulating factors in patients with celiac disease. J Bone Miner Res 2004;19:1112-21
90. Bernstein C, Sargent M, Leslie W. Serum osteoprotegerin is increased in Crohn's disease: a population-based case control study. Inflamm Bowel Dis 2005;11:325-30
91. Moschen AR, Kaser A, Enrich B, et al. The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss. Gut 2005;54:479-87
92. Franchimont N, Reenaers C, Lambert C, et al. Increased expression of receptor activator of NF-kappaB ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin in the colon of Crohn's disease patients. Clin Exp Immunol 2004;138:491-8
93. Bernstein CN. Inflammatory bowel diseases as secondary causes of osteoporosis. Curr Osteoporos Rep 2006;4:116-23
94. Morabito N, Gaudio A, Lasco A, et al. Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle. J Bone Miner Res 2004;19:722-7
95. Angelopoulos NG, Goula A, Katounda E, et al. Circulating osteoprotegerin and receptor activator of NF-kappaB ligand system in patients with beta-thalassemia major. J Bone Miner Metab 2007;25:60-7
96. Voskaridou E, Terpos E, Spina G, et al. Pamidronate is an effective treatment for osteoporosis in patients with beta-thalassaemia. Br J Haematol 2003;123:730-7
97. Perifanis V, Vyzantiadis T, Tziomalos K, et al. Effect of zoledronic acid on markers of bone turnover and mineral density in osteoporotic patients with beta-thalassaemia. Ann Hematol 2007;86:23-30
98. Voskaridou E, Anagnostopoulos A, Konstantopoulos K, et al. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center, randomized, placebo-controlled trial. Haematologica 2006;91:1193-202
99. Fahrleitner A, Prenner G, Kniepeiss D, et al. Serum osteoprotegerin levels in patients after liver transplantation and correlation to bone turnover, bone mineral density and fracture status. Wien Klin Wochenschr 2002;114:717-24
100. Sato T, Tominaga Y, Iwasaki Y, et al. Osteoprotegerin levels before and after renal transplantation. Am J Kidney Dis 2001;38:S175-7
101. Fahrleitner A, Prenner G, Leb G, et al. Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation. Bone 2003;32:96-106
102. Baek K, Oh K, Lee W, et al. Changes in the serum sex steroids, IL-7 and RANKL-OPG system after bone marrow transplantation: influences on bone and mineral metabolism. Bone 2006;39:1352-60
103. Coen G, Ballanti P, Balducci A, et al. Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant 2002;17:233-8
104. Kazama JJ, Shigematsu T, Yano K, et al. Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure. Am J Kidney Dis 2002;39:525-32
105. Doumouchtsis KK, Kostakis AI, Doumouchtsis SK, et al. sRANKL/osteoprotegerin complex and biochemical markers in a cohort of male and female hemodialysis patients. J Endocrinol Invest 2007;30:762-6
106. Gonnelli S, Montagnani A, Caffarelli C, et al. Osteoprotegerin (OPG) and receptor activator of NF-kB ligand (RANK-L) serum levels in patients on chronic hemodialysis. J Endocrinol Invest 2005;28:534-9
107. Grzegorzewska AE, Mlot M. Using the ratio of serum osteoprotegerin ligand to osteoprotegerin to evaluate renal osteodystrophy in dialysis patients. Adv Perit Dial 2005;21:188-93
108. Avbersek-Luznik I, Balon BP, Rus I, et al. Increased bone resorption in HD patients: is it caused by elevated RANKL synthesis? Nephrol Dial Transplant 2005;20:566-70
109. Sparks AB, Peterson SN, Bell C, et al. Mutation screening of the TNFRSF11A gene encoding receptor activator of NF kappa B (RANK) in familial and sporadic Paget's disease of bone and osteosarcoma. Calcif Tissue Int 2001;68:151-5
110. Neale SD, Schulze E, Smith R, et al. The influence of serum cytokines and growth factors on osteoclast formation in Paget's disease. QJM 2002;95:233-40
111. Alvarez L, Peris P, Guañabens N, et al. Serum osteoprotegerin and its ligand in Paget's disease of bone: relationship to disease activity and effect of treatment with bisphosphonates. Arthritis Rheum 2003;48:824-8
112. Mossetti G, Rendina D, De Filippo G, et al. Interleukin-6 and osteoprotegerin systems in Paget's disease of bone: relationship to risedronate treatment. Bone 2005;36:549-54
113. Martini G, Gennari L, Merlotti D, et al. Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget's disease of bone. Bone 2007;40:457-63
114. Uveges TE, Collin-Osdoby P, Cabral WA, et al. Cellular mechanism of decreased bone in Brtl mouse model of OI: imbalance of decreased osteoblast function and increased osteoclasts and their precursors. J Bone Miner Res 2008;23:1983-94
115. Johnson-Pais TL, Singer FR, Bone HG, et al. Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. J Bone Miner Res 2003;18:376-80
116. Whyte MP, Hughes AE. Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J Bone Miner Res 2002;17:26-9
117. Nakatsuka K, Nishizawa Y, Ralston SH. Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J Bone Miner Res 2003;18:1381-5
118. Whyte MP, Obrecht SE, Finnegan PM, et al. Osteoprotegerin deficiency and juvenile Paget's disease. N Engl J Med 2002;347:175-84
119. Hocking LJ, Lucas GJ, Daroszewska A, et al. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum Mol Genet 2002;11:2735-9
120. Hofbauer L, Khosla S, Dunstan C, et al. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999;140:4367-70
121. Viereck V, Gründker C, Blaschke S, et al. Raloxifene concurrently stimulates osteoprotegerin and inhibits interleukin-6 production by human trabecular osteoblasts. J Clin Endocrinol Metab 2003;88:4206-13
122. Dobnig H, Hofbauer LC, Viereck V, et al. Changes in the RANK ligand/osteoprotegerin system are correlated to changes in bone mineral density in bisphosphonate-treated osteoporotic patients. Osteoporos Int 2006;17:693-703
123. Fernández-García D, Muñoz-Torres M, Mezquita-Raya P, et al. Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis. J Endocrinol Invest 2008;31:416-21
124. Anastasilakis AD, Goulis DG, Polyzos SA, et al. Serum osteoprotegerin and RANKL are not specifically altered in women with postmenopausal osteoporosis treated with teriparatide or risedronate: a randomized controlled trial. Horm Metab Res 2008;40:281-5
125. Liu J, Xu K, Wen G, et al. Comparison of the effects of genistein and zoledronic acid on the bone loss in OPG-deficient mice. Bone 2008;42:950-9
126. Crisafulli A, Altavilla D, Squadrito G, et al. Effects of the phytoestrogen genistein on the circulating soluble receptor activator of nuclear factor κB ligand-osteoprotegerin system in early postmenopausal women. J Clin Endocrinol Metab 2004;89:188-92
127. Khosla S, Atkinson EJ, Dunstan CR, et al. Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men. J Clin Endocrinol Metab 2002;87:1550-4
128. Uemura H, Yasui T, Umino Y, et al. Circulating osteoprotegerin in women during GnRH-agonist treatment and their relationships with mineral components and biomarkers of bone turnover. Bone 2003;33:860-6
129. Hofbauer L, Schoppet M, Schuller P, et al. Effects of oral contraceptives on circulating osteoprotegerin and soluble RANK ligand serum levels in healthy young women. Clin Endocrinol (Oxf ) 2004;60:214-9
130. Cheung J, Mak YT, Papaioannou S, et al. Interleukin-6 (IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene. J Endocrinol 2003;177:423-33
131. Bashir A, Mak YT, Sankaralingam S, et al. Changes in RANKL/OPG/RANK gene expression in peripheral mononuclear cells following treatment with estrogen or raloxifene. Steroids 2005;70:847-55
132. Messalli EM, Mainini G, Scaffa C, et al. Raloxifene therapy interacts with serum osteoprotegerin in postmenopausal women. Maturitas 2007;56:38-44
133. Viereck V, Emons G, Lauck V, et al. Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun 2002;291:680-6
134. Pan B, Farrugia AN, To LB, et al. The nitrogen-containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-alpha converting enzyme (TACE). J Bone Miner Res 2004;19:147-54
135. Kim YH, Kim GS, Jeong-Hwa B. Inhibitory action of bisphosphonates on bone resorption does not involve the regulation of RANKL and OPG expression. Exp Mol Med 2002;34:145-51
136. Valleala H, Mandelin J, Laasonen L, et al. Effect of cyclical intermittent etidronate therapy on circulating osteoprotegerin levels in patients with rheumatoid arthritis. Eur J Endocrinol 2003;148:527-30
137. Kananen K, Volin L, Laitinen K, et al. Serum osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) concentrations in allogeneic stem cell transplant-recipients: a role in bone loss? Osteoporos Int 2006;17:724-30
138. Atkins GJ, Welldon KJ, Halbout P, et al. Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response. Osteoporos Int 2009;20:653-64
139. Brennan T, Rybchyn MS, Conigrave AD, et al. Strontium ranelate effect on proliferation and OPG expression in osteoblasts. Calcif Tissue Int 2006;78:S129
140. Iida-Klein A, Zhou H, Lu SS, et al. Anabolic action of parathyroid hormone is skeletal site specific at the tissue and cellular levels in mice. J Bone Miner Res 2002;17:808-16
141. Wang L, Quarles LD, Spurney RF. Unmasking the osteoinductive effects of a G-protein-coupled receptor (GPCR) kinase (GRK) inhibitor by treatment with PTH(1-34). J Bone Miner Res 2004;19:1661-70
142. Buxton EC, Yao W, Lane NE. Changes in serum receptor activator of nuclear factor-κB ligand, osteoprotegerin, and interleukin-6 levels in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1-34). J Clin Endocrinol Metab 2004;89:3332-6
143. Anastasilakis AD, Goulis DG, Polyzos SA, et al. Acute changes in serum osteoprotegerin and receptor activator for nuclear factor κB ligand levels in women with established osteoporosis treated with teriparatide. Eur J Endocrinol 2008;158:411-15
144. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008;29:155-92
145. Bekker PJ, Holloway D, Nakanishi A, et al. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 2001;16:348-60
146. Morony S, Capparelli C, Lee R, et al. A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1β, TNF-α, PTH, PTHrP, and 1,25(OH)2D3. J Bone Miner Res 1999;14:1478-85
147. Body JJ, Greipp P, Coleman RE, et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003;97:887-92
148. Capparelli C, Morony S, Warmington K, et al. Sustained antiresorptive effects after a single treatment with human recombinant osteoprotegerin (OPG): a pharmacodynamic and pharmacokinetic analysis in rats. J Bone Miner Res 2003;18:852-8
149. Ominsky MS, Kostenuik PJ, Cranmer P, et al. The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys. Osteoporos Int 2007;18:1073-82
150. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337-42
151. Bekker P, Holloway D, Rasmussen A, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 2004;19:1059-66
152. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821-31
153. Terpos E, Christoulas D, Dimopoulos MA. Antibodies to receptor activator of nuclear factor-kappa B ligand (RANKL). Expert Opin Ther Patents 2008;18:1265-9
154. Spohn G, Schwarz K, Maurer P, et al. Protection against osteoporosis by active immunization with TRANCE/RANKL displayed on virus-like particles. J Immunol 2005;175:6211-8
155. Kostenuik PJ, Bolon B, Morony S, et al. Gene therapy with human recombinant osteoprotegerin reverses established osteopenia in ovariectomized mice. Bone 2004;34:656-64
156. Samadfam R, Xia Q, Goltzman D. Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice. J Bone Miner Res 2007;22:55-63
157. Ominsky MS, Li X, Asuncion FJ, et al. RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. J Bone Miner Res 2008;23:672-82
158. Kostenuik P, Nguyen H, McCabe J, et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases bone density in knock-in mice that express himeric (murine/human) RANKL. J Bone Miner Res 2009 In press
159. Ominsky MS, Schroeder J, Smith SY, et al. Denosumab (AMG 162, a fully human RANKL antibody) increases cortical and cancellous bone mass in aged ovariectomized cynomolgus monkeys. J Bone Miner Res 2006;21:S72
160. Ominsky MS, Schroeder J, Smith SY, et al. Denosumab (AMG 162), a fully human RANKL antibody, improves cortical and cancellous bone mass and bone strength in ovariectomized cynomolgus monkeys. J Bone Miner Res 2007;22:S23
161. Morony S, Lu J, Capparelli C, et al. Osteoprotegerin (OPG) prevents bone loss in a rat model of glucocorticoid-induced osteopenia. J Bone Miner Res 2001;16:S148
162. Warner SA, Sanford DA, Becker BA, et al. Botox induced muscle paralysis rapidly degrades bone. Bone 2006;38:257-64
163. Ichinose Y, Tanaka H, Inoue M, et al. Osteoclastogenesis inhibitor factor/osteoprotegerin reduced bone loss induced by mechanical unloading. Calcif Tissue Int 2004;75:338-43
164. Delos D, Yang X, Ricciardi BF, et al. The effects of RANKL inhibition on fracture healing and bone strength in a mouse model of osteogenesis imperfecta. J Orthop Res 2008;26:153-64
165. Gerstenfeld LC, Sacks DJ, Pelis M, et al. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res 2009 In press
166. Ulrich-Vinther M, Schwarz EM, Pederson FS, et al. Gene therapy with human osteoprotegerin decreases callus remodeling with limited effects on biomechanical properties. Bone 2005;37:751-8
167. Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol 2001;159:1689-99
168. Neumann T, Oelzner P, Petrow PK, et al. Osteoprotegerin reduces the loss of periarticular bone mass in primary and secondary spongiosa but does not influence inflammation in rat antigen-induced arthritis. Inflamm Res 2006;55:32-9
169. Saidenberg-Kermanac'h N, Corrado A, Lemeiter D, et al. TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone 2004;35:1200-7
170. Romas E, Sims NA, Hards DK, et al. Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 2002;161:1419-27
171. Padagas J, Colloton M, Shalhoub V, et al. The receptor activator of nuclear factor-kappaB ligand inhibitor osteoprotegerin is a bone-protective agent in a rat model of chronic renal insufficiency and hyperparathyroidism. Calcif Tissue Int 2006;78:35-44
172. Kim HK, Morgan-Bagley S, Kostenuik P. RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis. J Bone Miner Res 2006;21:1946-54
173. Jin Q, Cirelli JA, Park CH, et al. RANKL inhibition through osteoprotegerin blocks bone loss in experimental periodontitis. J Periodontol 2007;78:1300-8
174. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 2008;93:2149-57
175. Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009;24:153-61
176. Lewiecki EM, Miller PD, McClung MR, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res 2007;22:1832-41
177. Brown JP, Kendler DL, McClung MR, et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002;71:103-11
178. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 1999;282:1344-52
179. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653-61
180. Beck TJ, Lewiecki EM, Miller PD, et al. Effects of denosumab on the geometry of the proximal femur in postmenopausal women in comparison with alendronate. J Clin Densitom 2008;11:351-9
181. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 2008;43:222-9
182. Anastasilakis AD, Toulis KA, Goulis DG, et al. Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis. Horm Metab Res 2009 In press
183. Cummings SR, McClung MR, Christiansen C, et al. A Phase III study of the effects of denosumab on vertebral, nonvertebral, and hip fracture in women with osteoporosis: results from the FREEDOM trial. J Bone Miner Res 2008;23:S80
184. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 2008;26:4875-82
185. Cohen SB, Dore RK, Lane NE, et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum 2008;58:1299-309
186. Stolina M, Dwyer D, Ominsky MS, et al. Continuous RANKL inhibition in OPG transgenic mice and rats suppresses bone resorption without impairing lymphorganogenesis or functional immune responses. J Immunol 2007;179:7497-505
187. Stolina M, Guo J, Faggioni R, et al. Regulatory effects of osteoprotegerin on cellular and humoral immune responses. Clin Immunol 2003;109:347-54
188. Miller RE, Branstetter D, Armstrong A, et al. Receptor activator of NF-kappa B ligand inhibition suppresses bone resorption and hypercalcemia but does not affect host immune responses to influenza infection. J Immunol 2007;179:266-74
189. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995;3:673-82
190. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998;273:14363-7
191. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-301
192. Visekruna M, Wilson D, McKiernan FE. Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 2008;93:2948-52
193. Flick LM, Weaver JM, Ulrich-Vinther M, et al. Effects of receptor activator of NFkappaB (RANK) signaling blockade on fracture healing. J Orthop Res 2003;21:676-84
194. Cramer JA, Gold DT, Silverman SL, et al. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int 2007;18:1023-31
195. Cramer JA, Amonkar MM, Hebborn A, et al. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin 2005;21:1453-60
196. Childs LM, Paschalis EP, Xing L, et al. In vivo RANK signaling blockade using the receptor activator of NF-kappaB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis. J Bone Miner Res 2002;17:192-9
197. Kostenuik PJ, Capparelli C, Morony S, et al. OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology 2001;142:4295-304
198. Lindsay R, Nieves J, Formica C, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997;350:550-5
199. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207-15
200. Deal C, Omizo M, Schwartz EN, et al. Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial. J Bone Miner Res 2005;20:1905-11
201. Ralston SH, Hacking L, Willocks L, et al. Clinical, biochemical, and radiographic effects of aminohydroxypropylidene bisphosphonate treatment in rheumatoid arthritis. Ann Rheum Dis 1989;48:396-9
202. Jarrett SJ, Conaghan PG, Sloan VS, et al. Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum 2006;54:1410-4
203. Kodama Y, Nakayama K, Fuse H, et al. Inhibition of bone resorption by pamidronate cannot restore normal gain in cortical bone mass and strength in tailsuspended rapidly growing rats. J Bone Miner Res 1997;12:1058-67
204. Kostenuik PJ, Harris J, Halloran BP, et al. Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I. J Bone Miner Res 1999;14:21-31
205. Rubin J, Murphy TC, Fan X, et al. Activation of extracellular signal-regulated kinase is involved in mechanical strain inhibition of RANKL expression in bone stromal cells. J Bone Miner Res 2002;17:1452-60