title: Emerging strategies and therapies for treatment of Paget's disease of bone.
abstract: Paget's disease of bone (PDB) is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling, with increased bone resorption and excessive, disorganized, new bone formation. PDB rarely occurs before middle age, and it is the second most frequent metabolic bone disorder after osteoporosis, affecting up to 3% of adults over 55 years of age. One of the most striking and intriguing clinical features is the focal nature of the disorder, in that once the disease is established within a bone, there is only local spread within that bone and no systemic dissemination. Despite many years of intense research, the etiology of PDB has still to be conclusively determined. Based on a detailed review of genetic and viral factors incriminated in PDB, we propose a unifying hypothesis from which we can suggest emerging strategies and therapies. PDB results in weakened bone strength and abnormal bone architecture, leading to pain, deformity or, depending on the bone involved, fracture in the affected bone. The diagnostic assessment includes serum total alkaline phosphatase, total body bone scintigraphy, skull and enlarged view pelvis x-rays, and if needed, additional x-rays. The ideal therapeutic option would eliminate bone pain, normalize serum total alkaline phosphatase with prolonged remission, heal radiographic osteolytic lesions, restore normal lamellar bone, and prevent recurrence and complications. With the development of increasingly potent bisphosphonates, culminating in the introduction of a single intravenous infusion of zoledronic acid 5 mg, these goals of treatment are close to being achieved, together with long-term remission in almost all patients. Based on the recent pathophysiological findings, emerging strategies and therapies are reviewed: ie, pulse treatment with zoledronic acid; denosumab, a fully human monoclonal antibody directed against RANK ligand; tocilizumab, an interleukin-6 receptor inhibitor; odanacatib, a cathepsin K inhibitor; and proteasome and Dickkopf-1 inhibitors.
authors: Department of Medicine, CHUQ (CHUL), Research Centre and Division of Rheumatology, Laval University, Quebec City, QC, Canada. laetitia.michou@crchul.ulaval.ca
authors: Laëtitia
authors: L
authors: Michou
authors: Jacques P
authors: JP
authors: Brown
references: Nat Rev Rheumatol. 2009 Sep;5(9):483-9
references: 19652650
references: Nouv Presse Med. 1974 May 18;3(20):1299-301
references: 4843079
references: J Bone Miner Res. 2002 Mar;17(3):465-71
references: 11878305
references: Cell Metab. 2011 Jan 5;13(1):23-34
references: 21195346
references: Curr Pharm Des. 2003;9(32):2643-58
references: 14529538
references: J Bone Miner Res. 2007 Apr;22(4):569-77
references: 17227218
references: Expert Opin Ther Targets. 2008 Nov;12(11):1377-87
references: 18851694
references: Calcif Tissue Int. 2004 Aug;75(2):144-52
references: 15164150
references: J Bone Miner Res. 2006 Dec;21(12):1828-35
references: 17002563
references: Exp Cell Res. 2003 Aug 1;288(1):60-9
references: 12878159
references: Br J Radiol. 2007 Jul;80(955):532-6
references: 17646188
references: Arthritis Rheum. 1980 Oct;23(10):1095-103
references: 7426075
references: J Bone Miner Res. 2006 Dec;21 Suppl 2:P88-91
references: 17229015
references: Calcif Tissue Int. 2006 May;78(5):271-7
references: 16691492
references: Science. 1969 Sep 19;165(3899):1262-4
references: 5803538
references: J Bone Miner Metab. 2006;24(5):359-67
references: 16937267
references: J Bone Miner Res. 2004 Sep;19(9):1506-11
references: 15312251
references: Bone. 2002 Sep;31(3):366-73
references: 12231408
references: J Bone Miner Res. 2007 Feb;22(2):298-309
references: 17129176
references: J Bone Miner Res. 2002 Jun;17(6):1127-34
references: 12054169
references: J Clin Invest. 2000 Mar;105(5):607-14
references: 10712432
references: Bone. 2009 May;44(5):858-64
references: 19442618
references: Am J Hum Genet. 2002 Feb;70(2):517-25
references: 11742440
references: Virus Res. 2005 Aug;111(2):132-47
references: 15893837
references: Virology. 1990 May;176(1):1-7
references: 2158685
references: J Clin Pathol. 2010 Mar;63(3):199-203
references: 19858527
references: Cytokine. 2010 Dec;52(3):146-50
references: 20709566
references: J Bone Miner Res. 1995 Apr;10(4):663-70
references: 7610939
references: Exp Hematol. 1999 Oct;27(10):1528-32
references: 10517494
references: Expert Opin Ther Targets. 2010 Feb;14(2):221-30
references: 20055719
references: Bone. 2004 Apr;34(4):747-54
references: 15050907
references: J Clin Invest. 1992 Jan;89(1):46-52
references: 1729280
references: J Bone Miner Res. 2006 Dec;21 Suppl 2:P9-13
references: 17229016
references: J Bone Miner Res. 2010 Jun;25(6):1463-4; author reply 1465-6
references: 20499373
references: Semin Oncol. 2010 Jun;37 Suppl 1:S3-11
references: 20682369
references: J Bone Miner Res. 2003 Aug;18(8):1519-24
references: 12929942
references: Bone. 2001 Nov;29(5):447-52
references: 11704497
references: Hum Mol Genet. 2008 Dec 1;17(23):3708-19
references: 18765443
references: Immunol Rev. 2010 Jul;236:176-89
references: 20636817
references: Bone. 1998 Aug;23(2):171-5
references: 9701477
references: Bone. 2011 Jul;49(1):103-10
references: 21236370
references: Rheumatology (Oxford). 2010 Jan;49(1):15-24
references: 19854855
references: Bone. 2006 Feb;38(2):280-5
references: 16199218
references: J Bone Miner Res. 2004 Jul;19(7):1154-64
references: 15176999
references: J Virol Methods. 2003 May;109(2):253-9
references: 12711070
references: Calcif Tissue Res. 1976 Apr 20;(2):187-99
references: 177153
references: Nat Rev Rheumatol. 2009 Dec;5(12):663-5
references: 19946296
references: Osteoporos Int. 2009 Jan;20(1):141-50
references: 18536953
references: Trends Endocrinol Metab. 2008 Sep;19(7):246-53
references: 18691901
references: Am J Med. 1999 May;106(5):513-20
references: 10335722
references: J Clin Invest. 2007 Jan;117(1):133-42
references: 17187080
references: J Bone Miner Res. 2005 Apr;20(4):588-95
references: 15765177
references: Bone. 2011 Mar 1;48(3):456-60
references: 21073987
references: Joint Bone Spine. 2006 May;73(3):243-8
references: 16574459
references: Hum Mol Genet. 2002 Oct 15;11(22):2735-9
references: 12374763
references: Nat Genet. 2010 Jun;42(6):520-4
references: 20436471
references: Nat Clin Pract Rheumatol. 2006 May;2(5):270-7
references: 16932700
references: Annu Rev Cell Dev Biol. 2006;22:159-80
references: 16753028
references: Rev Endocr Metab Disord. 2006 Jun;7(1-2):123-39
references: 16951988
references: J Clin Invest. 1990 Apr;85(4):1280-6
references: 2318982
references: Mol Endocrinol. 2009 Oct;23(10):1668-80
references: 19589897
references: Hum Mol Genet. 1994 Feb;3(2):359-61
references: 7911698
references: J Clin Endocrinol Metab. 1996 Mar;81(3):961-7
references: 8772558
references: J Bone Miner Res. 1991 May;6(5):495-500
references: 2068956
references: Leuk Res. 2010 Nov;34(11):1403-9
references: 20674016
references: Nature. 2006 Jun 15;441(7095):880-4
references: 16625205
references: J Bone Miner Res. 2008 Feb;23(2):253-9
references: 18197754
references: Bone. 2001 Jan;28(1):104-7
references: 11165949
references: Microbes Infect. 2002 Jul;4(8):785-94
references: 12270725
references: Nat Genet. 2004 Apr;36(4):377-81
references: 15034582
references: J Clin Invest. 2005 Feb;115(2):200-8
references: 15690073
references: J Bone Miner Res. 2010 Jan;25(1):20-31
references: 19580457
references: Immunity. 2009 Apr 17;30(4):588-98
references: 19362021
references: Bone. 2004 Jul;35(1):224-30
references: 15207761
references: Intern Med J. 2009 Feb;39(2):110-6
references: 19356186
references: Ann Intern Med. 2006 Nov 7;145(9):676-84
references: 17088581
references: N Engl J Med. 2005 Sep 1;353(9):898-908
references: 16135834
references: Semin Oncol. 2001 Aug;28(4 Suppl 11):15-21
references: 11544571
references: Osteoporos Int. 2011 Jan;22(1):1-20
references: 20458572
references: Autophagy. 2011 Mar;7(3):260-5
references: 21150267
references: J Bone Miner Res. 2009 Apr;24(4):632-42
references: 19049332
references: J Bone Miner Res. 2006 Mar;21(3):446-55
references: 16491293
references: J Bone Miner Res. 2007 Feb;22(2):310-7
references: 17129171
references: J Pathol. 2003 Nov;201(3):504-12
references: 14595764
references: Dev Cell. 2004 Feb;6(2):303-9
references: 14960283
references: Bone. 2000 Mar;26(3):263-7
references: 10709999
references: J Bone Joint Surg Am. 2002 Nov;84(11):2056-61
references: 12429770
references: J Nucl Med. 1981 Jun;22(6):510-7
references: 7229723
references: Curr Opin Rheumatol. 2009 Jul;21(4):380-5
references: 19461517
references: J Bone Miner Res. 2006 Dec;21 Suppl 2:P22-7
references: 17229003
references: Sarcoma. 2010;2010:174528
references: 20981142
references: J Bone Miner Res. 2008 Jun;23(6):819-25
references: 18269308
references: J Clin Invest. 2000 Jun;105(12):1833-8
references: 10862799
references: J Bone Miner Res. 2001 Aug;16(8):1379-87
references: 11499860
references: J Bone Miner Res. 2007 Oct;22(10):1510-7
references: 17605632
references: Reumatismo. 2007 Apr-Jun;59(2):153-68
references: 17603696
references: Am J Hum Genet. 2001 Sep;69(3):528-43
references: 11473345
references: J Bone Miner Res. 2008 Jan;23(1):58-63
references: 17907922
references: J Bone Miner Res. 1992 May;7(5):475-8
references: 1615755
references: Am J Hum Genet. 2001 Nov;69(5):1055-61
references: 11555792
references: Rev Prat. 1989 Apr 27;39(13):1125-8
references: 2786643
references: Rev Rhum Engl Ed. 1995 Oct;62(9):571-5
references: 8574629
references: Am J Hum Genet. 1997 Nov;61(5):1117-22
references: 9345096
references: Clin Invest Med. 2007;30(5):E210-23
references: 17892763
references: Vaccine. 2010 Aug 23;28(37):5939-46
references: 20619381
references: Epidemiology. 1997 May;8(3):247-51
references: 9115018
references: Bone. 2011 Feb;48(2):281-5
references: 20858558
references: J Bone Miner Res. 2002 Jan;17(1):145-51
references: 11771661
references: J Bone Miner Res. 2006 Nov;21(11):1750-6
references: 17002577
references: Cell. 2009 May 15;137(4):721-35
references: 19427028
references: Bone. 2011 Jul;49(1):89-94
references: 20832512
references: J Clin Endocrinol Metab. 1995 Jul;80(7):2108-11
references: 7608263
references: Q J Med. 1987 Sep;64(245):755-67
references: 2966965
references: Bone. 2010 Mar;46(3):598-603
references: 19925894
references: J Bone Miner Res. 2004 Apr;19(4):566-70
references: 15005843
references: J Bone Miner Res. 2005 Aug;20(8):1356-64
references: 16007333
references: QJM. 2002 Apr;95(4):233-40
references: 11937650
references: Bone Miner. 1992 Nov;19(2):159-74
references: 1345324
references: Immunol Rev. 2005 Dec;208:252-66
references: 16313353
references: J Pathol. 1982 Jan;136(1):27-39
references: 7057295
references: J Bone Miner Res. 2007 Jan;22(1):142-8
references: 17032148
references: Calcif Tissue Int. 2001 Mar;68(3):151-5
references: 11351498
references: Bone. 2011 Jan;48(1):135-40
references: 20601285
references: Bone. 2008 Nov;43(5):819-25
references: 18672105
references: Scand J Clin Lab Invest. 2010 Apr;70(2):128-35
references: 20175736
references: Hum Genet. 2010 Dec;128(6):615-26
references: 20839008
references: Ann Rheum Dis. 2009 Oct;68(10):1580-4
references: 19019888
references: J Bone Miner Res. 2004 Mar;19(3):523
references: 15049284
references: Ann N Y Acad Sci. 2010 Mar;1192:176-80
references: 20392234
references: J Bone Miner Res. 2005 Oct;20(10):1845-50
references: 16160742
references: Am J Hum Genet. 2002 Jun;70(6):1582-8
references: 11992264
references: Postgrad Med J. 1997 Aug;73(862):496-502
references: 9307742
references: Bone. 2004 Jul;35(1):277-82
references: 15207768
references: Clin Biochem. 2009 Jul;42(10-11):965-9
references: 19389391
references: Lancet. 2008 Jul 12;372(9633):155-163
references: 18620951
references: J Bone Miner Res. 2007 Jul;22(7):1062-71
references: 17388729
references: Mol Genet Metab. 2001 Dec;74(4):458-75
references: 11749051
references: Calcif Tissue Int. 1986 Jan;38(1):60-1
references: 3079654
references: Cancer Res. 2004 Aug 1;64(15):5378-84
references: 15289345
references: Best Pract Res Clin Rheumatol. 2003 Dec;17(6):1019-41
references: 15123049
references: Adv Drug Deliv Rev. 2005 May 25;57(7):959-71
references: 15876398
references: Experientia. 1992 Feb 15;48(2):158-72
references: 1740188
references: Br J Haematol. 2010 Oct;151(1):3-15
references: 20618339
references: Exp Cell Res. 2007 Jun 10;313(10):2033-49
references: 17531973
references: Calcif Tissue Int. 1999 Feb;64(2):93-9
references: 9914313
references: Clin Orthop Relat Res. 1987 Apr;(217):37-44
references: 3103964
references: Bone. 2006 Oct;39(4):954-8
references: 16769264
references: Bone. 1991;12(3):195-201
references: 1910961
references: J Bone Miner Res. 2006 Dec;21 Suppl 2:P38-44
references: 17229007
references: Bone. 1999 May;24(5 Suppl):69S-71S
references: 10321933
references: J Bone Miner Res. 2006 Dec;21 Suppl 2:P3-8
references: 17229005
references: Transplant Proc. 1977 Dec;9(4):1867-8
references: 146288
references: Semin Arthritis Rheum. 1994 Feb;23(4):273-5
references: 8009254
references: Expert Rev Mol Med. 2007 Oct 01;9(27):1-13
references: 17903332
references: Bone. 1995 Nov;17(5 Suppl):489S-491S
references: 8573424
references: Trends Cell Biol. 2004 Feb;14(2):70-7
references: 15102438