Paget Disease of Bone

Artist/ Title/ Date

Quienten Massys''. An Old Woman (‘The Ugly Duchess’)''. 1513. Oil on wood (Baltic/Polish oak, identified). 62.4 x 45.4 cm. London: The National Gallery

Description of Disease & Etiology

Paget’s disease of bone (PDB) is a chronic disorder with an unknown origin first described by Sir James Paget in 1877 and initially described as osteitis deformans due to its deforming skeletal changes in severe cases.1 It is the second most common metabolic disorder following osteoporosis. It is characterized by bone turnover defects in osteoclasts which destroy bone and trigger excessive bone formation, leading to disorganized bone remodeling.2 It typically develops after the age of 55, slightly affects more males than females,3 is most common in Great Britain (3-5% of population),2 and mostly affects Europeans.4 The exact cause is unknown, but a prevalent hypothesis implicates a slow paramyxoviral infection (measles, respiratory syncytial, and canine distemper) in genetically susceptible individuals,5-6 although the literature still debates this etiology. Genetic factors play an important role in the development of PDB. 15% of patients with PDB have a family history, and approximately half of those with a family history and 5-10% of patients with a sporadic form carry mutations in the SQSTM1 gene.7 PDB has an autosomal dominant inheritance pattern for those with a family history.8 There has been a demonstrated association between SQSTM1 mutations and PDB disease severity and complications.9

Signs/Signifiers of Illness

The most common biochemical marker is the serum alkaline phosphatase level, which reflects osteoblast activity. Paget’s disease of bone is often detected incidentally with a rising serum alkaline phosphatase level on routine blood work or when characteristic radiographic features are seen on imaging.8 Characteristic radiographic findings include ‘blade of grass’ appearance, osteolytic areas in the skull, a ‘cotton wool’ appearance indicating mixed osteolytic/osteoblastic areas, and a ‘picture frame’ appearance of the vertebral body thickening in the spine.10 Approximately 20-25% of patients are asymptomatic.11 The classic symptoms of Paget’s disease include bone pain, nerve root compression symptoms, headaches, bowing of long bones, symptoms from bone fractures, hearing loss, and bone deformities.8 The most commonly affected bones are the pelvis, spine, femora, and the skull.3 Bone pain is the most common symptom,11 either caused by pagetic lesions themselves or complications that arise from the disease, such as osteoarthritis or osteosarcoma. Skull involvement can lead to a characteristic deformity, osteoporosis circumscripta, which causes an enlarged skull. Pagetic involvement of the facial bones can cause facial deformity, dental problems, and rarely, airway narrowing.12 The most common bone tumor complication from Paget’s disease of bone is osteosarcoma. A classic case of Paget’s disease of bone is a typically healthy older adult with an elevated alkaline phosphatase, normal serum calcium, and normal 25-hydroxy-vitamin-D level with no evidence of hepatobiliary disease.11, 13-14

Pathology

Paget’s disease of the bone is caused by an increase in the number and size of osteoclasts in affected sites which excessively resorb bone. This resorption is associated with greater osteoblast recruitment to the remodeling sites, while the rest of the skeleton remains normal. Increased osteoblast activity leads to increased bone formation in the affected areas. The accelerated bone turnover causes bone deposition with disorganized architecture and structural weakness. Osteoclast precursors and marrow stromal cells in patients express high levels of bone resorbing factors, IL-6 and RANKL, which contribute to osteoclastogenesis.15 The disease typically progresses through three phases: (1) Osteolytic (intense bone resorption and hypervascularization); (2) Mixed osteoblastic/osteolytic (increased osteoblastic new bone matrix production with incomplete mineralization whilst osteoclasts continue to resorb bone); and (3) Sclerotic or ‘burned out’ (bone resorption diminishes, leaving a dense, sclerotic, ‘disorganized’ weak bone).16-19

Treatment

Most patients are asymptomatic and don’t require treatment. For those that require treatment, the treatment of choice is antiresorptive therapy with bisphosphonates.20 Bisphosphonates have specific pharmacological properties including selective uptake at active skeletal lesions, specific inhibition of bone resorption, and effect persistence after discontinuation. Most symptomatic patients are treated for pain relief.3

Social Determinants of Illness

Numerous environmental factors have been implicated in Paget’s disease of bone, including insufficient childhood intakes of calcium and/or Vitamin D.21 Other factors include mechanical overloading of involved bones, contact with domestic animals, a rural lifestyle, and organ meat consumption during childhood.5 Another environmental risk implicated in the developed of PDB involves childhood exposure to industrial waste and products of combustion.22 The incidence and prevalence of the disease has decreased, and while the cause of these changes is still unclear, it is likely due to a mix of genetic and environmental triggers which may differ between regions.4

Author(s): Maria Burdjalov, BS

Citations:

* 1) Paget, J. (1877). On a Form of Chronic Inflammation of Bones (Osteitis Deformans). Medico-Chirurgical Transactions, 60, 37-64.9. https://doi.org/10.1177/095952877706000105 * 2) Menéndez-Bueyes, L. R., & Soler Fernández, M. D. C. (2017). Paget’s Disease of Bone: Approach to Its Historical Origins. Reumatología Clínica (English Edition), 13(2), 66–72. https://doi.org/10.1016/j.reumae.2016.02.009 * 3) Appelman-Dijkstra, N. M., & Papapoulos, S. E. (2018). Paget’s disease of bone. Best Practice & Research Clinical Endocrinology & Metabolism, 32(5), 657–668. https://doi.org/10.1016/j.beem.2018.05.005 * 4) Corral-Gudino, L., Borao-Cengotita-Bengoa, M., Del Pino-Montes, J., & Ralston, S. (2013). Epidemiology of Paget’s disease of bone: A systematic review and meta-analysis of secular changes. Bone, 55(2), 347–352. https://doi.org/10.1016/j.bone.2013.04.024 * 5) Galson, D. L., & Roodman, G. D. (2014). Pathobiology of Paget’s Disease of Bone. Journal of Bone Metabolism, 21(2), 85. https://doi.org/10.11005/jbm.2014.21.2.85 * 6) Ralston, S. H. (2008). Pathogenesis of Paget’s disease of bone. Bone, 43(5), 819–825. https://doi.org/10.1016/j.bone.2008.06.015 * 7) Ralston, S. H., & Layfield, R. (2012). Pathogenesis of Paget Disease of Bone. Calcified Tissue International, 91(2), 97–113. https://doi.org/10.1007/s00223-012-9599-0 * 8) Kravets, I. (2018). Paget’s Disease of Bone: Diagnosis and Treatment. The American Journal of Medicine, 131(11), 1298–1303. https://doi.org/10.1016/j.amjmed.2018.04.028 * 9) Visconti, M. R., Langston, A. L., Alonso, N., Goodman, K., Selby, P. L., Fraser, W. D., & Ralston, S. H. (2010). Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone. Journal of Bone and Mineral Research, 25(11), 2368–2373. https://doi.org/10.1002/jbmr.132 * 10) Theodorou, D. J., Theodorou, S. J., & Kakitsubata, Y. (2011). Imaging of Paget Disease of Bone and Its Musculoskeletal Complications: Review. American Journal of Roentgenology, 196(6_supplement), S64–S75. https://doi.org/10.2214/AJR.10.7222 * 11) Tan, A., & Ralston, S. H. (2014). Clinical Presentation of Paget’s Disease: Evaluation of a Contemporary Cohort and Systematic Review. Calcified Tissue International, 95(5), 385–392. https://doi.org/10.1007/s00223-014-9904-1 * 12) Siris, E. S., & Roodman, D. G. (2013). Paget’s Disease of Bone. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (Eighth, pp. 659–668). Wiley. * 13) Shankar, S., & Hosking, D. J. (2006). Biochemical Assessment of Paget’s Disease of Bone. Journal of Bone and Mineral Research, 21(S2), P22–P27. https://doi.org/10.1359/jbmr.06s204 * 14) Ralston, S. H., Langston, A. L., & Reid, I. R. (2008). Pathogenesis and management of Paget’s disease of bone. The Lancet, 372(9633), 155–163. https://doi.org/10.1016/S0140-6736(08)61035-1 * 15) Reddy, S. V., Menaa, C., Singer, F. R., Demulder, A., & Roodman, G. D. (1999). Cell biology of paget’s disease. Journal of Bone and Mineral Research, 14(S2), 3–8. https://doi.org/10.1002/jbmr.5650140203 * 16) Ankrom, M. A., & Shapiro, J. R. (1998). Paget’s disease of bone (osteitis deformans). Journal of the American Geriatrics Society, 46(8), 1025–1033. https://doi.org/10.1111/j.1532-5415.1998.tb02763.x * 17) Ooi, C. G., & Fraser, W. D. (1997). Paget’s disease of bone. Postgraduate Medical Journal, 73(856), 69–74. https://doi.org/10.1136/pgmj.73.856.69 * 18) Roodman, G. D. (1996). Paget’s disease and osteoclast biology. Bone, 19(3), 209–212. https://doi.org/10.1016/8756-3282(96)00211-6 * 19) Schneider, D., Hofmann, M. T., & Peterson, J. A. (2002). Diagnosis and treatment of Paget’s disease of bone. American Family Physician, 65(10), 2069–2072. * 20) Lyles, K. W., Siris, E. S., Singer, F. R., & Meunier, P. J. (2001). A Clinical Approach to Diagnosis and Management of Paget’s Disease of Bone. Journal of Bone and Mineral Research, 16(8), 1379–1387. https://doi.org/10.1359/jbmr.2001.16.8.1379 * 21) Tiegs, R. D., Lohse, C. M., Wollan, P. C., & Melton, L. J. (2000). Long-term trends in the incidence of Paget’s disease of bone. Bone, 27(3), 423–427. https://doi.org/10.1016/S8756-3282(00)00333-1 * 22) Michou, L., & Orcel, P. (2016). The changing countenance of Paget’s Disease of bone. Joint Bone Spine, 83(6), 650–655. https://doi.org/10.1016/j.jbspin.2016.02.011