Skip to main content

Paget’s Disease of Bone

Abstract

Paget’s disease of bone (PDB) is a chronic and focal bone disorder, characterized by increased osteoclast-mediated bone resorption and a subsequent compensatory increase in bone formation, resulting in a disorganized mosaic of woven and lamellar bone at one or more affected skeletal sites. As a result, bone pain, noticeable deformities, arthritis at adjacent joints, and fractures can occur. In a small proportion of cases neoplastic degeneration in osteosarcoma, or, less frequently, giant cell tumor has been also described at PDB sites. While recent epidemiological evidences clearly indicate a decrease in the prevalence and the severity of PDB, over the past 2 decades there have been consistent advances on the genetic mechanisms of disease. It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants. As a counterpart to the genetic hypothesis, the focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors are less understood, but recent experimental data from mice models suggest the implication of paramixoviral infections. The clinical management of PDB has also evolved considerably, with the development of potent aminobisphosphonates such as zoledronic acid which, given as a single intravenous infusion, now allows a long-term disease remission in the majority of patients.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Kanis JA (1992) Pathophysiology and treatment of Paget’s disease of bone, 2nd edn. Martin Dunitz, London

    Google Scholar 

  2. 2.

    Paget J (1876) On a form of chronic inflammation of bones (osteitis deformans). Med Chir Trans 60:37–63

    Google Scholar 

  3. 3.

    Gennari L, Rendina D, Picchioni T, Bianciardi S, Materozzi M, Nuti R, Merlotti D (2018) Paget’s disease of bone: an update on epidemiology, pathogenesis and pharmacotherapy. Expert Opin Orphan Drugs 8:485–496. https://doi.org/10.1080/21678707.2018.1500691

    CAS  Article  Google Scholar 

  4. 4.

    Detheridge FM, Guyer PB, Barker DJ (1982) European distribution of Paget’s disease of bone. Br Med J 285:1005–1008

    CAS  Article  Google Scholar 

  5. 5.

    Guyer PB, Chamberlain AT (1988) Paget’s disease of bone in South Africa. Clin Radiol 39:51–52

    CAS  Article  Google Scholar 

  6. 6.

    Cooper C, Harvey NC, Dennison EM, van Staa TP (2006) Update on the epidemiology of Paget’s disease of bone. J Bone Miner Res 21:P3–P8

    Article  Google Scholar 

  7. 7.

    Barker DJ (1981) The epidemiology of Paget’s disease. Metab Bone Dis Relat Res 3:231–233

    CAS  Article  Google Scholar 

  8. 8.

    Altman RD, Bloch DA, Hochberg MC, Murphy WA (2000) Prevalence of pelvic Paget’s disease of bone in the United States. J Bone Miner Res 15(3):461–465

    CAS  Article  Google Scholar 

  9. 9.

    van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C (2002) Incidence and natural history of Paget’s disease of bone in England and Wales. J Bone Miner Res 17:465–471. https://doi.org/10.1359/jbmr.2002.17.3.465

    Article  PubMed  Google Scholar 

  10. 10.

    Barker DJ, Chamberlain AT, Guyer PB, Gardner MJ (1980) Paget’s disease of bone: the Lancashire focus. Br Med J 280:1105–1107

    CAS  Article  Google Scholar 

  11. 11.

    Cooper C, Schafheutle K, Dennison E, Kellingray S, Guyer P, Barker D (1999) The epidemiology of Paget’s disease in Britain: is the prevalence decreasing? J Bone Miner Res 14:192–197

    CAS  Article  Google Scholar 

  12. 12.

    Cundy T, McAnulty K, Wattie D, Gamble G, Rutland M, Ibbertson HK (1997) Evidence for secular change in Paget’s disease. Bone 20:69–71

    CAS  Article  Google Scholar 

  13. 13.

    Lopez-Abente G, Morales-Piga A, Bachiller-Corral FJ, Illera-Martín O, Martín-Domenech R, Abraira V (2003) Identification of possible areas of high prevalence of Paget’s disease of bone in Spain. Clin Exp Rheumatol 21:635–638

    CAS  PubMed  Google Scholar 

  14. 14.

    Merlotti D, Gennari L, Galli B, Martini G, Calabrò A, De Paola V, Ceccarelli E, Nardi P, Avanzati A, Nuti R (2005) Characteristics and familial aggregation of Paget’s disease of bone in Italy. J Bone Miner Res 20:1356–1364. https://doi.org/10.1359/JBMR.050322

    Article  PubMed  Google Scholar 

  15. 15.

    Gennari L, Di Stefano M, Merlotti D, Giordano N, Martini G, Tamone C, Zatteri R, De Lucchi R, Baldi C, Vattimo A, Capoccia S, Burroni L, Geraci S, De Paola V, Calabrò A, Avanzati A, Isaia G, Nuti R (2005) Prevalence of Paget’s disease of bone in Italy. J Bone Miner Res 20:1845–1850

    Article  Google Scholar 

  16. 16.

    Gennari L, Merlotti D, Martini G, Nuti R (2006) Paget’s disease of bone in Italy. J Bone Miner Res 21:P14–P21

    Article  Google Scholar 

  17. 17.

    Rendina D, Gennari L, De Filippo G, Merlotti D, de Campora E, Fazioli F, Scarano G, Nuti R, Strazzullo P, Mossetti G (2006) Evidence for increased clinical severity of familial and sporadic Paget’s disease of bone in Campania, southern Italy. J Bone Miner Res 21:1828–1835

    Article  Google Scholar 

  18. 18.

    Corral-Gudino L, Garcia-Aparicio J, Sanchez-Gonzalez MD, Mirón-Canelo JA, Blanco JF, Ralston SH, del Pino-Montes J (2013) Secular changes in Paget’s disease: contrasting changes in the number of new referrals and in disease severity in two neighboring regions of Spain. Osteoporos Int 24:443–450. https://doi.org/10.1007/s00198-012-1954-5

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Abdulla O, Naqvi MJ, Shamshuddin S, Bukhari M, Proctor R (2018) Prevalence of Paget’s disease of bone in Lancaster: time for an update. Rheumatology 57:931–932. https://doi.org/10.1093/rheumatology/kex505

    Article  PubMed  Google Scholar 

  20. 20.

    Reddy SV, Menaa C, Singer FR, Demulder A, Roodman GD (1999) Cell biology of Paget’s disease. J Bone Miner Res 14:3–8

    Article  Google Scholar 

  21. 21.

    Robey PG, Bianco P (1999) The role of osteogenic cells in the pathophysiology of Paget’s disease. J Bone Miner Res 14:9–16

    Article  Google Scholar 

  22. 22.

    Singer FR, Mills BG, Gruber HE, Windle JJ, Roodman GD (2006) Ultrastructure of bone cells in Paget’s disease of bone. J Bone Miner Res 21(Suppl 2):P51–P54

    Article  Google Scholar 

  23. 23.

    Galson DL, Roodman GD (2014) Pathobiology of Paget’s disease of bone. J Bone Metab 21(2):85–98

    Article  Google Scholar 

  24. 24.

    Demulder A, Takahashi S, Singer FR, Hosking DJ, Roodman GD (1993) Abnormalities in osteoclast precursors and the marrow microenvironment in Paget’s disease. Endocrinology 133:1978–1982. https://doi.org/10.1210/endo.133.5.7691583

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Maldague B, Malghem J (1987) Dynamic radiologic patterns of Paget’s disease of bone. Clin Orthop Relat Res 217:126–151

    Google Scholar 

  26. 26.

    Altman RD (2002) In: Coe FL, Favus MJ (eds) Disorders of bone and mineral metabolism. 2nd edn. Lippincott Williams & Wilkins, Philadelphia, pp 985–1020

    Google Scholar 

  27. 27.

    Tan A, Ralston SH (2014) Clinical presentation of Paget’s disease: evaluation of a contemporary cohort and systematic review. Calcif Tissue Int 95:385–392. https://doi.org/10.1007/s00223-014-9904-1

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Altman RD (1999) Arthritis in Paget’s disease of bone. J Bone Miner Res 14:85–87

    Article  Google Scholar 

  29. 29.

    Meunier PJ, Salson C, Mathieu L, Chapuy MC, Delmas P, Alexandre C, Charhon S (1987) Skeletal distribution and biochemical parameters of Paget’s disease. Clin Orthop Relat Res 217:37–44

    Google Scholar 

  30. 30.

    Poncelet A (1999) The neurologic complications of Paget’s disease. J Bone Miner Res 14:88–91

    Article  Google Scholar 

  31. 31.

    Monsell EM, Cody DD, Bone HG, Divine GW (1999) Hearing loss as a complication of Paget’s disease of bone. J Bone Miner Res 14:92–95

    Article  Google Scholar 

  32. 32.

    Hadjipavlou A, Lander P (1991) Paget disease of the spine. J Bone Joint Surg Am 73:1376–1381

    CAS  Article  Google Scholar 

  33. 33.

    Tuck PS, Layfield R, Walker J, Mekkayil B, Francis R (2017) Adult Paget’s disease of bone: a review. Rheumatology 56(12):2050–2059

    CAS  Article  Google Scholar 

  34. 34.

    Strickenberger SA, Schulman SP, Hutchins GM (1987) Association of Paget’s disease of bone with calcific aortic valve disease. Am J Med 82:953–956

    Article  Google Scholar 

  35. 35.

    Huvos AG (1986) Osteogenic sarcoma of bones and soft tissues in older persons. A clinicopathologic analysis of 117 patients older than 60 years. Cancer 57:1442–1449

    CAS  Article  Google Scholar 

  36. 36.

    Hansen MF, Seton M, Merchant A (2006) Osteosarcoma in Paget’s disease of bone. J Bone Miner Res 21:P58–P63

    CAS  Article  Google Scholar 

  37. 37.

    Rendina D, De Filippo G, Ralston SH, Merlotti D, Gianfrancesco F, Esposito T, Muscariello R, Nuti R, Strazzullo P, Gennari L (2015) Clinical characteristics and evolution of giant cell tumor occurring in Paget’s disease of bone. J Bone Miner Res 30:257–263. https://doi.org/10.1002/jbmr.2349

    Article  PubMed  Google Scholar 

  38. 38.

    Papapoulos SE, Frolich M, Mudde AH, Harinck HI, vd Berg H, Bijvoet OL (1987) Serum osteocalcin in Paget’s disease of bone: basal concentrations and response to bisphosphonate treatment. J Clin Endocrinol Metab 65:89–94

    CAS  Article  Google Scholar 

  39. 39.

    Singer FR, Bone HG 3rd, Hosking DJ, Lyles KW, Murad MH, Reid IR, Siris ES, Endocrine Society (2014) Paget’s disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99:4408–4422. https://doi.org/10.1210/jc.2014-2910

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Harinck HI, Bijvoet OL, Vellenga CJ, Blanksma HJ, Frijlink WB (1986) Relation between signs and symptoms in Paget’s disease of bone. Q J Med 58:133–151

    CAS  PubMed  Google Scholar 

  41. 41.

    Al Nofal AA, Altayar O, BenKhadra K, Qasim Agha OQ, Asi N, Nabhan M, Prokop LJ, Tebben P, Murad MH (2015) Bone turnover markers in Paget’s disease of the bone: a systematic review and meta-analysis. Osteoporos Int 26:1875–1891. https://doi.org/10.1007/s00198-015-3095-0

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Eekhoff ME, van der Klift M, Kroon HM, Cooper C, Hofman A, Pols HA, Papapoulos SE (2004) Paget’s disease of bone in The Netherlands: a population-based radiological and biochemical survey—the Rotterdam study. J Bone Miner Res 19:566–570

    Article  Google Scholar 

  43. 43.

    Alvarez L, Guanabens N, Peris P, Monegal A, Bedini JL, Deulofeu R, Martinez de Osaba MJ, Muñoz-Gomez J, Rivera-Fillat F, Ballesta AM (1995) Discriminative value of biochemical markers of bone turnover in assessing the activity of Paget’s disease. J Bone Miner Res 10:458–465

    CAS  Article  Google Scholar 

  44. 44.

    Alvarez L, Peris P, Pons F, Guanabens N, Herranz R, Monegal A, Bedini JL, Deulofeu R, Martínez de Osaba MJ, Muñoz-Gómez J, Ballesta AM (1997) Relationship between biochemical markers of bone turnover and bone scintigraphic indices in assessment of Paget’s disease activity. Arthritis Rheum 40:461–468

    CAS  Article  Google Scholar 

  45. 45.

    Guanabens N, Rotes D, Holgado S, Gobbo M, Descalzo MA, Gorordo JM, Martínez-Ferrer MA, Salmoral A, Morales-Piga A (2012) Implications of a new radiological approach for the assessment of Paget disease. Calcif Tissue Int 91:409–415. https://doi.org/10.1007/s00223-012-9652-z

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Fogelman I, Carr D (1980) A comparison of bone scanning and radiology in the assessment of patients with symptomatic Paget’s disease. Eur J Nucl Med 5:417–421

    CAS  PubMed  Google Scholar 

  47. 47.

    Singer FR (2015) Paget’s disease of bone-genetic and environmental factors. Nat Rev Endocrinol 11:662–671. https://doi.org/10.1038/nrendo.2015.138

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Ralston SH, Taylor JP Rare inherited Paget’s disease like disorders. Calcif Tissue Int (in press)

  49. 49.

    Pick A (1883) Osteitis deformans. Lancet 2:1125–1126

    Article  Google Scholar 

  50. 50.

    Montagu MFA (1949) Paget’s disease (osteitis deformans) and hereditary. Am J Hum Genet 1:94–95

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Siris ES, Ottman R, Flaster E, Kelsey JL (1991) Familial aggregation of Paget’s disease of bone. J Bone Miner Res 6:495–500

    CAS  Article  Google Scholar 

  52. 52.

    Siris ES (1994) Epidemiological aspects of Paget’s disease: family history and relationship to other medical conditions. Semin Arthritis Rheum 23:222–225

    CAS  Article  Google Scholar 

  53. 53.

    Morales-Piga AA, Rey-Rey JS, Corres-González J, García-Sagredo JM, López-Abente G (1995) Frequency and characteristics of familial aggregation of Paget’s disease of bone. J Bone Miner Res 10:663–670

    CAS  Article  Google Scholar 

  54. 54.

    Gennari L, Gianfrancesco F, Rendina D, Merlotti D (2014) Molecular genetics of Paget’s disease of bone. Wiley, Chichester. https://doi.org/10.1002/9780470015902.a0024396

    Book  Google Scholar 

  55. 55.

    Laurin N, Brown JP, Morissette J, Raymond V (2002) Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70:1582–1588. https://doi.org/10.1086/340731

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, Nicholson GC, Ward L, Bennett ST, Wuyts W, Van Hul W, Ralston SH (2002) Domain specific mutations in Sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum Mol Genet 11:2735–2739

    CAS  Article  Google Scholar 

  57. 57.

    Albagha OM (2015) Genetics of Paget’s disease of bone. Bonekey Rep. https://doi.org/10.1038/bonekey.2015.125

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Ralston SH, Layfield R (2012) Pathogenesis of Paget disease of bone. Calcif Tissue Int 91:97–113

    CAS  Article  Google Scholar 

  59. 59.

    Rea SL, Walsh JP, Layfield R, Ratajczak T, Xu J (2013) New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of Paget’s disease of bone. Endocr Rev 34:501–524. https://doi.org/10.1210/er.2012-1034

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Duran A, Serrano M, Leitges M, Flores JM, Picard S, Brown JP, Moscat J, Diaz-Meco MT (2004) The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell 6:303–309

    CAS  Article  Google Scholar 

  61. 61.

    Jin W, Chang M, Paul EM, Babu G, Lee AJ, Reiley W, Wright A, Zhang M, You J, Sun SC (2008) Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest 118:1858–1866. https://doi.org/10.1172/JCI34257

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Sundaram K, Shanmugarajan S, Rao DS, Reddy SV (2011) Mutant p62P392L stimulation of osteoclast differentiation in Paget’s disease of bone. Endocrinology 152:4180–4189. https://doi.org/10.1210/en.2011-1225

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Kurihara N, Hiruma Y, Zhou H, Subler MA, Dempster DW, Singer FR, Reddy SV, Gruber HE, Windle JJ, Roodman GD (2007) Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease. J Clin Invest 117:133–142. https://doi.org/10.1172/JCI28267

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Hiruma Y, Kurihara N, Subler MA, Zhou H, Boykin CS, Zhang H, Ishizuka S, Dempster DW, Roodman GD, Windle JJ (2008) A SQSTM1/p62 mutation linked to Paget’s disease increases the osteoclastogenic potential of the bone microenvironment. Hum Mol Genet 17:3708–3719. https://doi.org/10.1093/hmg/ddn266

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Kurihara N, Hiruma Y, Yamana K, Michou L, Rousseau C, Morissette J (2011) Contributions of the measles virus nucleocapsid gene and the SQSTM1/p62(P392L) mutation to Paget’s disease. Cell Metab 13:23–34

    CAS  Article  Google Scholar 

  66. 66.

    Daroszewska A, van ‘t Hof RJ, Rojas JA, Layfield R, Landao-Basonga E, Rose L, Rose K, Ralston SH (2011) A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget’s disease-like disorder in mice. Hum Mol Genet 20:2734–2744. https://doi.org/10.1093/hmg/ddr172

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Gennari L, Gianfrancesco F, Di Stefano M, Rendina D, Merlotti D, Esposito T, Gallone S, Fusco P, Rainero I, Fenoglio P, Mancini M, Martini G, Bergui S, De Filippo G, Isaia G, Strazzullo P, Nuti R, Mossetti G (2010) SQSTM1 gene analysis and gene-environment interaction in Paget’s disease of bone. J Bone Miner Res 25:1375–1384. https://doi.org/10.1002/jbmr.31

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Visconti MR, Langston AL, Alonso N, Goodman K, Selby PL, Fraser WD, Ralston SH (2010) Mutations of SQSTM1 are associated with severity and clinical outcome in Paget’s disease of bone. J Bone Miner Res 25:2368–2373. https://doi.org/10.1002/jbmr.132

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Albagha OM, Visconti MR, Alonso N, Wani S, Goodman K, Fraser WD, Gennari L, Merlotti D, Gianfrancesco F, Esposito T, Rendina D, di Stefano M, Isaia G, Brandi ML, Giusti F, Del Pino-Montes J, Corral-Gudino L, Gonzalez-Sarmiento R, Ward L, Rea SL, Ratajczak T, Walsh JP, Ralston SH (2013) Common susceptibility alleles and SQSTM1 mutations predict disease extent and severity in a multinational study of patients with Paget’s disease. J Bone Miner Res 28:2338–2346. https://doi.org/10.1002/jbmr.1975

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Hocking LJ, Lucas GJA, Daroszewska A, Cundy T, Nicholson GC, Donath J, Walsh JP, Finlayson C, Cavey JR, Ciani B, Sheppard PW, Searle MS, Layfield R, Ralston SH (2004) Novel UBA domain mutations of SQSTM1 in Paget’s disease of bone: genotype phenotype correlation, functional analysis and structural consequences. J Bone Miner Res 19:1122–1127. https://doi.org/10.1359/JBMR.0403015

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Goode A, Long JE, Shaw B, Ralston SH, Visconti MR, Gianfrancesco F, Esposito T, Gennari L, Merlotti D, Rendina D, Rea SL, Sultana M, Searle MS, Layfield R (2014) Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function. Biochem Biophys Acta 1842:992–1000. https://doi.org/10.1016/j.bbadis.2014.03.006

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Albagha OM, Visconti MR, Alonso N, Langston AL, Cundy T, Dargie R, Dunlop MG, Fraser WD, Hooper MJ, Isaia G, Nicholson GC, del Pino Montes J, Gonzalez-Sarmiento R, di Stefano M, Tenesa A, Walsh JP, Ralston SH (2010) Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget’s disease of bone. Nat Genet 42:520–524. https://doi.org/10.1038/ng.562

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Albagha OM, Wani SE, Visconti MR, Alonso N, Goodman K, Brandi ML, Cundy T, Chung PY, Dargie R, Devogelaer JP, Falchetti A, Fraser WD, Gennari L, Gianfrancesco F, Hooper MJ, Van Hul W, Isaia G, Nicholson GC, Nuti R, Papapoulos S, Montes J, Ratajczak T, Rea SL, Rendina D, Gonzalez-Sarmiento R, Di Stefano M, Ward LC, Walsh JP, Ralston SH; Genetic Determinants of Paget’s Disease (GDPD) Consortium (2011) Genome-wide association identifies three new susceptibility loci for Paget’s disease of bone. Nat Genet 43:685–689. https://doi.org/10.1038/ng.845

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Kukita T, Wada N, Kukita A, Kakimoto T, Sandra F, Toh K, Nagata K, Iijima T, Horiuchi M, Matsusaki H, Hieshima K, Yoshie O, Nomiyama H (2004) RANKL-induced DC-STAMP is essential for osteoclastogenesis. J Exp Med 200:941–946. https://doi.org/10.1084/jem.20040518

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, Morita K, Ninomiya K, Suzuki T, Miyamoto K, Oike Y, Takeya M, Toyama Y, Suda T (2005) DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med 202:345–351. https://doi.org/10.1084/jem.20050645

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Zhu G, Wu CJ, Zhao Y, Ashwell JD (2007) Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP. Curr Biol 17:1438–1443. https://doi.org/10.1016/j.cub.2007.07.041

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Obaid R, Wani S, Azfer A, Hurd T, Jones R, Cohen P, Ralston SH, Albagha OME (2015) Optineurin negatively regulates osteoclast differentiation by modulating NFkB and interferon signalling; implication for Paget’s disease. Cell Rep 13:1096–1102. https://doi.org/10.1016/j.celrep.2015.09.071

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Vallet M, Soares DC, Wani S, Sophocleous A, Warner J, Salter DM, Ralston SH, Albagha OM (2015) Targeted sequencing of the Paget’s disease associated 14q32 locus identifies several missense coding variants in RIN3 that predispose to Paget’s disease of bone. Hum Mol Genet 24:3286–3295. https://doi.org/10.1093/hmg/ddv068

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Gianfrancesco F, Rendina D, Di Stefano M, Mingione A, Esposito T, Merlotti D, Gallone S, Magliocca S, Goode A, Formicola D, Morello G, Layfield R, Frattini A, De Filippo G, Nuti R, Searle M, Strazzullo P, Isaia G, Mossetti G, Gennari L (2012) A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget’s disease. J Bone Miner Res 27:443–452. https://doi.org/10.1002/jbmr.542

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Divisato G, Formicola D, Esposito T, Merlotti D, Pazzaglia L, Del Fattore A, Siris E, Orcel P, Brown JP, Nuti R, Strazzullo P, Benassi MS, Cancela ML, Michou L, Rendina D, Gennari L, Gianfrancesco F (2016) ZNF687 mutations in severe Paget disease of bone associated with giant cell tumor. Am J Hum Genet 98:275–286. https://doi.org/10.1016/j.ajhg.2015.12.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Malovannaya A, Lanz RB, Jung SY, Bulynko Y, Le NT, Chan DW, Ding C, Shi Y, Yucer N, Krenciute G, Kim BJ, Li C, Chen R, Li W, Wang Y, O’Malley BW, Qin J (2011) Analysis of the human endogenous coregulator complexome. Cell 145:787–799. https://doi.org/10.1016/j.cell.2011.05.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Lu B, Jiao Y, Wang Y, Dong J, Wei M, Cui B, Sun Y, Wang L, Zhang B, Chen Z, Zhao Y (2017) A FKBP5 mutation is associated with Paget’s disease of bone and enhances osteoclastogenesis. Exp Mol Med. https://doi.org/10.1038/emm.2017.64

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (2004) A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 6:97–105. https://doi.org/10.1038/ncb1086

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Mills BG, Singer FR (1976) Nuclear inclusions in Paget’s disease of bone. Science 194:201–202

    CAS  Article  Google Scholar 

  85. 85.

    Mee AP, Sharpe PT (1993) Dogs, distemper and Paget’s disease. Bioessays 15:783–789. https://doi.org/10.1002/bies.950151203

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    López-Abente G, Morales-Piga A, Elena-Ibáñez A, Rey-Rey JS, Corres-González J (1997) Cattle, pets, and Paget’s disease of bone. Epidemiology 8:247–251

    Article  Google Scholar 

  87. 87.

    Mills BG, Singer FR, Weiner LP, Suffin SC, Stabile E, Holst P (1984) Evidence for both respiratory syncytial virus and measles virus antigens in the osteoclasts of patients with Paget’s disease of bone. Clin Orthop Relat Res 183:303–311

    Google Scholar 

  88. 88.

    Ralston SH, Digiovine FS, Gallacher SJ, Boyle IT, Duff GW (1991) Failure to detect paramyxovirus sequences in Paget’s disease of bone using polymerase chain reaction. J Bone Miner Res 6:1243–1248. https://doi.org/10.1002/jbmr.5650061115

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Birch MA, Taylor W, Fraser WD, Ralston SH, Hart CA, Gallagher JA (1994) Absence of paramyxovirus RNA in cultures of pagetic bone cells and in pagetic bone. J Bone Miner Res 9:11–16. https://doi.org/10.1002/jbmr.5650090103

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Reddy SV, Singer FR, Mallette L, Roodman GD (1996) Detection of measles virus nucleocapsid transcripts in circulating blood cells from patients with Paget disease. J Bone Miner Res 11:1602–1607. https://doi.org/10.1002/jbmr.5650111103

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Mee AP, Dixon JA, Hoyland JA, Davies M, Selby PL, Mawer EB (1998) Detection of canine distemper virus in 100% of Paget’s disease samples by in situ-reverse transcriptase-polymerase chain reaction. Bone 23:171–175

    CAS  Article  Google Scholar 

  92. 92.

    Gordon MT, Mee AP, Sharpe PT (1994) Paramyxoviruses in Paget’s disease. Semin Arthritis Rheum 23:232–234

    CAS  Article  Google Scholar 

  93. 93.

    Ooi CG, Walsh CA, Gallagher JA, Fraser WD (2000) Absence of measles virus and canine distemper virus transcripts in long-term bone marrow cultures from patients with Paget’s disease of bone. Bone 27:417–421

    CAS  Article  Google Scholar 

  94. 94.

    Ralston SH, Afzal MA, Helfrich MH, Fraser WD, Gallagher JA, Mee A, Rima B (2007) Multicenter blinded analysis of RT-PCR detection methods for paramyxoviruses in relation to Paget’s disease of bone. J Bone Miner Res 22:569–577. https://doi.org/10.1359/jbmr.070103

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Vallet M, Ralston SH (2016) Biology and treatment of Paget’s disease of bone. J Cell Biochem 117:289–299. https://doi.org/10.1002/jcb.25291

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Kurihara N, Reddy SV, Menaa C, Anderson D, Roodman GD (2000) Osteoclasts expressing the measles virus nucleocapsid gene display pagetic phenotype. J Clin Invest 105:607–614. https://doi.org/10.1172/JCI8489

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Gordon MT, Mee AP, Anderson DC, Sharpe PT (1992) Canine distemper virus transcripts sequenced from pagetic bone. Bone Miner 19:159–174

    CAS  Article  Google Scholar 

  98. 98.

    Kurihara N, Zhou H, Reddy SV, Garcia Palacios V, Subler MA, Dempster DW, Windle JJ, Roodman GD (2006) Expression of measles virus nucleocapsid protein in osteoclasts induces Paget’s disease-like bone lesions in mice. J Bone Miner Res 21:446–455. https://doi.org/10.1359/JBMR.051108

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Teramachi J, Nagata Y, Mohammad K, Inagaki Y, Ohata Y, Guise T, Michou L, Brown JP, Windle JJ, Kurihara N, Roodman GD (2016) Measles virus nucleocapsid protein increases osteoblast differentiation in Paget’s disease. J Clin Invest 126:1012–1022. https://doi.org/10.1172/JCI82012

    Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Cundy T, Rutland MD, Naot D, Bolland M (2015) Evolution of Paget’s disease of bone in adults inheriting SQSTM1 mutations. Clin Endocrinol 83:315–319. https://doi.org/10.1111/cen.12741

    CAS  Article  Google Scholar 

  101. 101.

    Solomon LR (1979) Billiard-player’s fingers: an unusual case of Paget’s disease of bone. Br Med J 1:931

    CAS  Article  Google Scholar 

  102. 102.

    Michou L, Collet C, Morissette J, Audran M, Thomas T, Gagnon E, Launay JM, Laplanche JL, Brown JP, Orcel P (2012) Epidemiogenetic study of French families with Paget’s disease of bone. Joint Bone Spine 79:393–398. https://doi.org/10.1016/j.jbspin.2011.07.005

    Article  PubMed  Google Scholar 

  103. 103.

    Barker DJ, Gardner MJ (1974) Distribution of Paget’s disease in England, Wales and Scotland and a possible relationship with vitamin D deficiency in childhood. Br J Prev Soc Med 28:226–232

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Lever JH (2002) Paget’s disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis. Bone 31:434–436

    CAS  Article  Google Scholar 

  105. 105.

    Audet MC, Jean S, Beaudoin C, Guay-Bélanger S, Dumont J, Brown JP, Michou L (2017) Environmental factors associated with familial or non-familial forms of Paget’s disease of bone. Joint Bone Spine 84:719–723. https://doi.org/10.1016/j.jbspin.2016.11.010

    Article  PubMed  Google Scholar 

  106. 106.

    Bijvoet OL, van der Sluys Veer J, Jansen AP (1968) Effects of calcitonin on patients with Paget’s disease, thyrotoxicosis, or hypercalcaemia. Lancet 1(7548):876–881

    CAS  Article  Google Scholar 

  107. 107.

    Merlotti D, Gennari L, Martini G, Nuti R (2009) Current options for the treatment of Paget’s disease of the bone. Open Access Rheumatol 1:107–120

    CAS  Article  Google Scholar 

  108. 108.

    Corral-Gudino L, Tan AJ, Del Pino-Montes J, Ralston SH (2017) Bisphosphonates for Paget’s disease of bone in adults. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD004956.pub3

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Siris ES, Lyles KW, Singer FR, Meunier PJ (2006) Medical management of Paget’s disease of bone: implications for treatment and review of current therapies. J Bone Miner Res 21:P94–P97. https://doi.org/10.1359/jbmr.06s218

    CAS  Article  PubMed  Google Scholar 

  110. 110.

    Gennari L, Merlotti D, Mossetti G, Rendina D, De Paola V, Martini G, Nuti R (2009) The use of intravenous aminobisphosphonates for the treatment of Paget’s disease of bone. Mini Rev Med Chem 9:1052–1063

    CAS  Article  Google Scholar 

  111. 111.

    Selby PL, Davie MWJ, Ralston SH, Stone MD (2002) Guidelines on the management of Paget’s disease of bone. Bone 31:366–373

    CAS  Article  Google Scholar 

  112. 112.

    Siris ES, Feldman F (1997) Natural history of untreated Paget’s disease of the tibia. J Bone Miner Res 12:691–692. https://doi.org/10.1359/jbmr.1997.12.4.691

    CAS  Article  PubMed  Google Scholar 

  113. 113.

    Dodd GW, Ibbertson HK, Fraser TR, Holdaway IM, Wattie D (1987) Radiological assessment of Paget’s disease of bone after treatment with the bisphosphonates EHDP and APD. Br J Radiol 60:849–860

    CAS  Article  Google Scholar 

  114. 114.

    Reid IR, Nicholson GC, Weinstein RS, Hosking DJ, Cundy T, Kotowicz MA, Murphy WA Jr, Yeap S, Dufresne S, Lombardi A, Musliner TA, Thompson DE, Yates AJ (1996) Biochemical and radiologic improvement in Paget’s disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med 101:341–348

    CAS  Article  Google Scholar 

  115. 115.

    Gutteridge DH, Retallack RW, Ward LC, Stuckey BG, Stewart GO, Prince RL, Kent GN, Bhagat CI, Price RI, Thompson RI, Nicholson GC (1996) Clinical, biochemical, hematologic, and radiographic responses in Paget’s disease following intravenous pamidronate disodium: a 2-year study. Bone 19:387–394

    CAS  Article  Google Scholar 

  116. 116.

    Brown JP, Chines AA, Myers WR, Eusebio RA, Ritter-Hrncirik C, Hayes CW (2000) Improvement of pagetic bone lesions with risedronate treatment: a radiologic study. Bone 26:263–267

    CAS  Article  Google Scholar 

  117. 117.

    Peris P, Alvarez L, Vidal S, Martínez MA, Monegal A, Guañabens N (2007) Treatment with tiludronate has a similar effect to risedronate on Paget’s disease activity assessed by bone markers and bone scintigraphy. Clin Exp Rheumatol 25:206–210

    CAS  PubMed  Google Scholar 

  118. 118.

    Siris E, Weinstein RS, Altman R, Conte JM, Favus M, Lombardi A, Lyles K, McIlwain H, Murphy WA Jr, Reda C, Rude R, Seton M, Tiegs R, Thompson D, Tucci JR, Yates AJ, Zimering M (1996) Comparative study of alendronate versus etidronate for the treatment of Paget’s disease of bone. J Clin Endocrinol Metab 81:961–967. https://doi.org/10.1210/jcem.81.3.8772558

    CAS  Article  PubMed  Google Scholar 

  119. 119.

    Bickerstaff DR, Douglas DL, Burke PH, O’Doherty DP, Kanis JA (1990) Improvement in facial deformity of Paget disease treated with diphosphonates. J Bone Joint Surg Br 72:132–136

    CAS  Article  Google Scholar 

  120. 120.

    Murdin LM, Yeoh LH (2005) Hearing loss treated with pamidronate. J R Soc Med 98:272–274. https://doi.org/10.1258/jrsm.98.6.272

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Meunier PJ, Vignot E (1995) Therapeutic strategy in Paget’s disease of bone. Bone 17:489S–491S

    CAS  Article  Google Scholar 

  122. 122.

    Gianfrancesco F, Rendina D, Merlotti D, Esposito T, Amyere M, Formicola D, Muscariello R, De Filippo G, Strazzullo P, Nuti R, Vikkula M, Gennari L (2013) Giant cell tumor occurring in familial Paget’s disease of bone: report of clinical characteristics and linkage analysis of a large pedigree. J Bone Miner Res 28:341–350. https://doi.org/10.1002/jbmr.1750

    CAS  Article  PubMed  Google Scholar 

  123. 123.

    Langston AL, Campbell MK, Fraser WD, MacLennan GS, Selby PL, Ralston SH, PRISM Trial Group (2010) Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget’s disease of bone. J Bone Miner Res 25:20–31. https://doi.org/10.1359/jbmr.090709

    CAS  Article  PubMed  Google Scholar 

  124. 124.

    Tan A, Goodman K, Walker A, Hudson J, MacLennan GS, Selby PL, Fraser WD, Ralston SH, PRISM-EZ Trial Group (2017) Long-term randomized trial of intensive versus symptomatic management in Paget’s disease of bone: the PRISM-EZ study. J Bone Miner Res 32:1165–1173. https://doi.org/10.1002/jbmr.3066

    CAS  Article  PubMed  Google Scholar 

  125. 125.

    Cundy T (2017) Treating Paget’s disease—why and how much? J Bone Miner Res 32:1163–1164. https://doi.org/10.1002/jbmr.3156

    Article  PubMed  Google Scholar 

  126. 126.

    Papapoulos SE, Eekhoff EM, Zwinderman AH (2006) Acquired resistance to bisphosphonates in Paget’s disease of bone. J Bone Miner Res 21:88–91. https://doi.org/10.1359/jbmr.06s216

    Article  Google Scholar 

  127. 127.

    Merlotti D, Gennari L, Martini G, Valleggi F, De Paola V, Avanzati A, Nuti R (2007) Comparison of different intravenous bisphosphonate regimens for Paget’s disease of bone. J Bone Miner Res 22:1510–1517. https://doi.org/10.1359/jbmr.070704

    CAS  Article  PubMed  Google Scholar 

  128. 128.

    Buckler HM, Mercer SJ, Davison CE (1998) Evaluation of adverse experiences related to pamidronate infusion in Paget disease of bone. Ann Rheum Dis 57:572

    CAS  Article  Google Scholar 

  129. 129.

    Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, Mesenbrink P, Su G, Pak J, Zelenakas K, Luchi M, Richardson P, Hosking D (2005) Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 353:898–908. https://doi.org/10.1056/NEJMoa044241

    CAS  Article  PubMed  Google Scholar 

  130. 130.

    Reid IR, Lyles K, Su G, Brown JP, Walsh JP, del Pino-Montes J, Miller PD, Fraser WD, Cafoncelli S, Bucci-Rechtweg C, Hosking DJ (2011) A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res 26:2261–2270. https://doi.org/10.1002/jbmr.438

    CAS  Article  PubMed  Google Scholar 

  131. 131.

    Cundy T, Maslowski K, Grey A, Reid IR (2017) Durability of response to zoledronate treatment and competing mortality in Paget’s disease of bone. J Bone Miner Res 32:753–756. https://doi.org/10.1002/jbmr.3029

    CAS  Article  PubMed  Google Scholar 

  132. 132.

    Merlotti D, Rendina D, Gennari L, Mossetti G, Gianfrancesco F, Martini G, De Filippo G, Avanzati A, Franci B, Campagna MS, Strazzullo P, Nuti R (2011) Comparison of intravenous and intramuscular neridronate regimens for the treatment of Paget disease of bone. J Bone Miner Res 26:512–518. https://doi.org/10.1002/jbmr.237

    CAS  Article  PubMed  Google Scholar 

  133. 133.

    Reid IR, Wattie D, Gamble GD, Kalluru R, Cundy T (2017) Long-term effects of intravenous ibandronate in Paget’s disease of bone. Calcif Tissue Int 100:250–254. https://doi.org/10.1007/s00223-016-0214-7

    CAS  Article  PubMed  Google Scholar 

  134. 134.

    Reid IR, Sharma S, Kalluru R, Eagleton C (2016) Treatment of Paget’s disease of bone with denosumab: case report and literature review. Calcif Tissue Int 99:322–325. https://doi.org/10.1007/s00223-016-0150-6

    CAS  Article  PubMed  Google Scholar 

  135. 135.

    De Nagant Deuxchaisnes C, Maldague B, Malghem J, Devogelaer JP, Huaux JP, Rombouts-Lindemans C (1980) The action of the main therapeutic regimens on Paget’s disease of bone, with a note on the effect of vitamin D deficiency. Arthritis Rheum 23:1215–1234

    Article  Google Scholar 

  136. 136.

    Chen JR, Rhee RS, Wallach S, Avramides A, Flores A (1979) Neurologic disturbances in Paget disease of bone: response to calcitonin. Neurology 29:448–457

    CAS  Article  Google Scholar 

  137. 137.

    Wallace E, Wong J, Reid IR (1995) Pamidronate treatment of the neurologic sequelae of pagetic spinal stenosis. Arch Intern Med 155:1813–1815

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Luigi Gennari.

Ethics declarations

Conflict of interest

Luigi Gennari, Domenico Rendina, Alberto Falchetti, and Daniela Merlotti declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gennari, L., Rendina, D., Falchetti, A. et al. Paget’s Disease of Bone. Calcif Tissue Int 104, 483–500 (2019). https://doi.org/10.1007/s00223-019-00522-3

Download citation

Keywords

  • Paget’s disease of bone
  • SQSTM1 gene
  • Bisphosphonates
  • Bone pain