Wiener Medizinische Wochenschrift

, Volume 167, Issue 1–2, pp 2–8 | Cite as

Epidemiology and pathology of Paget’s disease of bone – a review

  • Elena Nebot Valenzuela
  • Peter Pietschmann
Open Access
main topic


Paget’s disease of bone (PDB) is a noninflammatory, metabolic, skeletal disorder characterized by localized excessive osteoclastic bone resorption that is followed by compensatory increased osteoblastic activity leading to unstructured, fibroblastic, and biomechanically unstable bone. As a result, there is deformity and enlargement of the bone with a defective and disorganized pattern. Here, we review the epidemiology, etiology, pathology, macrostructure, histology, and quantitative histomorphometry findings of PDB. Hyperosteoclastosis and poor definition of the boundary between cortical and medullary bone are the main histological findings in PDB. Additionally, Pagetic bone is also characterized by hypertrophy and alteration of trabecular parameters.


Pagetic bone Bone structure Histology Histomorphometry Skeletal disorder 

Epidemiologie und Pathologie des Morbus Paget – ein Überblick


Der Morbus Paget ist eine nichtentzündliche metabolische Knochenerkrankung, die durch eine lokale, übermäßige Knochenresorption mit kompensatorischer Steigerung der Osteoblastenaktivität gekennzeichnet ist. In Folge kommt es zu einem veränderten, fibrösen und biomechanisch instabilen Knochen sowie zu Deformierungen und Verdickungen des Knochens mit einer gestörten und desorganisierten Struktur. In diesem Beitrag geben wir eine Übersicht über die Epidemiologie, Ätiologie, Pathologie, Makrostruktur, Histologie und die quantitative Histomorphometrie des Morbus Paget. Das Auftreten von Riesenosteoklasten und die schlechte Abgrenzbarkeit von kortikalem und trabekulärem Knochen sind wichtige histologische Kennzeichen der Erkrankung. Darüber hinaus ist der Knochen bei Morbus Paget auch durch eine Hypertrophie und Veränderungen der Trabekelstruktur gekennzeichnet.


Morbus Paget Knochenstruktur Histologie Histomorphometrie Knochenerkrankung 


Paget’s disease of bone (PDB) was originally described in a report that has become a classic in the medical literature. James Paget called the disease osteitis deformans, in part because of the extensive and deforming changes that took place in the skeleton in severe cases [1]. The disease is a chronic bone abnormality, which may affect a single, several, or many bones, but never involves the entire skeleton. The cause remains unknown. Nevertheless, a prevalent hypothesis is that the disease is initiated by a slow virus in a genetically vulnerable patient [2], because nuclear inclusions of viral components have been observed in osteoclasts from affected patients [3].

Paget’s disease of bone is the paradigm of a focal bone disorder with accelerated bone turnover [4]. It is a noninflammatory, metabolic, skeletal disorder characterized by localized excessive osteoclastic bone resorption that is followed by compensatory increased osteoblastic activity [5] leading to unstructured, fibroblastic, and biomechanically unstable bone [6]. As a result, there is deformity and enlargement of the bone with a defective and disorganized pattern (plexiform bone) (Fig. 1 and 2); therefore, Pagetic bone is susceptible to fractures [4]. The axial skeleton is frequently involved and the bones most commonly affected include the pelvis (70 %), femur (55 %), lumbar spine (53 %), skull (42 %), and tibia (32 %) [7, 8]. Nevertheless, Pagetic bone lesions can occur at any site of the skeleton [6].
Fig. 1

Pagetic human femur, unknown gender and age, compared to the healthy femur of the same individual. a Anterior view, b posterior view. The bones were obtained from the Pathologic-Anatomical Collection in The Fools Tower, Museum of Natural History, Vienna, Austria

Fig. 2

Lateral view of a Pagetic human femur, unknown gender and age. The bone was obtained from the Pathologic-Anatomical Collection in The Fools Tower, Museum of Natural History, Vienna, Austria


The diagnosis of PDB is rare before age 50. The disease affects both men and women [9]; in most series males predominate. In 1932, Schmorl [10] found a prevalence of 3 % of PDB in a series of over 4600 autopsies of individuals above 40 years of age.

Its geographical distribution is uneven, with areas of high prevalence with familial aggregation detected in most series [4]. Paget’s disease occurs most commonly in people of British descent. The disease is also common in British migrants to countries like Australia, New Zealand, and North America, as well as in other countries in Europe, such as in France, Germany, Spain, or Italy [11]. Spain is considered to have a medium–low prevalence compared to other European countries, approximately 0.9–1.3 % of the population over 65 years [12]. The study by Poór et al. [13] described the frequency of the disorder in eight European cities, showing the lowest prevalence rate among hospital patients ≥55 years old in the Austrian city of Innsbruck (0.2 %).

A study by Van Staa et al. [14] evaluated the age- and gender-specific incidence of PDB in England and Wales in the adult population. They concluded that the disorder was more frequent among men of all ages over 55 years. The incidence increased steeply with age among both men and women, and was estimated at 0.3 cases per 10,000 person-years among women aged 55–59 years and 0.5 cases per 10,000 person-years among men of similar age. At the age of ≥85 years, this rate rose to 5.4 among women and 7.6 among men. Based on these assumptions, the prevalence of clinically diagnosed PDB is 0.3 % among men and women ≥55 years old.

There is evidence that PDB has become less common and less severe over the past quarter of a century in the UK and many other countries [13]. The decrease in the incidence of canine distemper or measles virus infection due to the introduction of vaccination in Europe may be associated with the decline of PDB [13]. Previous studies described PDB, after osteoporosis, as the second most common metabolic bone disease [10, 15].


Studies of patients with Paget’s disease indicate that there is a family history of the disorder in 5 [16] to 40 % [17]. There is an autosomal dominant transmission pattern [9]. Mutations in the gene-producing sequestosome 1 increase susceptibility to the development of Paget’s disease [18], but there is incomplete penetrance of the disease in some family members who have been found to harbor gene mutations [19]. Other genes have also been implicated in increasing susceptibility to develop the disorder [20], and nearly all of these genes, including the sequestosome 1 gene, are involved in osteoclast biology.

An additional role for sequestosome 1 is in autophagy. Sequestosome 1 has been shown to interact with an autophagic protein. Because of the presence of inclusion bodies found in the osteoclasts of Pagetic bones, dysregulation of the autophagy process may be part of the pathogenesis of PDB [21]. Recently, the study by McManus et al. [22] indicated a strong potential regulatory role for the kinase associated with the response to the receptor activator of NF-κB ligand (RANKL) activation in osteoclast stimulatory pathways and autophagy induction, which may contribute to the osteoclast phenotype in PDB.

Other investigations of the etiology of Paget’s disease have focused on the potential role of chronic paramyxovirus infections contributing to the pathogenesis of the disorder [23]. The most impressive animal model of Paget’s disease has been generated in transgenic mice by targeting the measles virus nucleocapsid protein and a mutated sequestosome 1 gene into the animals [24]. Immunocytochemical studies have shown that Pagetic osteoclasts contain paramyxoviral-like nuclear inclusions that cross-react with antibodies to measles virus, respiratory syncytial virus, and canine distemper virus nucleocapsid antigen [23, 25, 26]. Nevertheless, the issue of whether or not viral infections are related to PDB is not resolved [27].

Although the primary cause of these abnormalities in Paget’s osteoclasts is still unknown [28], osteoclasts are abundant in Paget’s lesions. They are also larger, contain increased nuclei per osteoclast, have increased bone resorbing capacity, increased 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and RANKL responsivity, and secrete high levels of interleukin 6 (IL-6) compared to normal osteoclasts [29, 30]. The increase in osteoclast numbers can be explained in part by the high levels of expression of several factors in Paget’s osteoclasts which are directly related to osteoclast formation and activation, such as the c-fos protooncogene [31], IL-6, IL-6 receptor, and NF-κB [29]. In addition, Paget’s osteoclasts seem to respond differently to osteotropic factors such as calcitonin and 1,25-(OH)2D3 [32]. Pagetic osteoclasts frequently express the measles virus nucleocapsid protein [33], which induces high levels of IL-6 expression in both human and mouse osteoclasts, and results in the development of Pagetic bone lesions in mice in vivo [34].

The Pagetic bone lesion


Most patients are asymptomatic [4], whereas some develop complications such as bone pain, osteoarthritis, fracture, deformity, deafness, and nerve compression syndromes [6]. The early lesions are predominantly lytic and osteoporotic; bone resorption predominates with abnormally large osteoclasts containing multiple pleomorphic nuclei and microfilamentous inclusion bodies [35]. Later, a mixed osteolytic-osteoblastic phase with an abundance of osteoblasts forming new matrix in the form of woven bone [36] occurs, where thickening of the cortex by endosteal and periosteal bone deposition with enlargement of the bones is observed (Fig. 3). The trabecular architecture becomes accentuated and its usually smooth outline assumes irregular surface contours in radiographs [1]. Within the diaphyseal cortex, the primary resorption phase of PDB is often limited either to the endosteum or to the central layers of the cortex. This results in primary resorption fronts that are usually discrete, both radiologically and scintigraphically. The subsequent activation of the subperiosteal cortex may be delayed, leading to secondary expanding fronts associated with subperiosteal new bone formation [37]. This alternation of resorptive and sclerotic areas creates a mottled appearance on X‑ray films.
Fig. 3

Inside view of a Pagetic human femur, female, 71 years old. The bone was obtained from the Pathologic-Anatomical Collection in The Fools Tower, Museum of Natural History, Vienna, Austria


A general description of histological findings in Pagetic bones is summarized in Table 1. Most of the studies on the histology of PDB have focused on iliac crest bone [6, 36, 38, 39, 40] or on vertebrae [41, 42]. As mentioned before, PDB has the primary cellular abnormality residing in osteoclasts [43], which are increased in number and size, and contain many more nuclei per cell compared to normal osteoclasts [44]. The histological study by Seitz et al. [6], using the Hamburger Bone Register, described that trabecular bone appeared mostly isolated, with a clumsy composition in Pagetic iliac crests biopsies. Multinucleated osteoclasts with more than 12 nuclei per cell were frequently detected at the trabecular bone surface. Moreover, the authors observed a typical appearance of deep resorption lacunae with the so-called swallowtail pattern. As a sign of accelerated bone formation, they also found an increase in osteoid surfaces and activated cuboidal osteoblasts, and described that collagen fibers were not oriented in one direction, but rather displayed a random distribution indicative of woven bone [6].
Table 1

Description of histological findings in Pagetic bones







Osteoclasts and resorption of bone

Hyperosteoclastosis associated with fibrosis

Number, size, and nuclearity:10-times the number of osteoclasts; large: over 200 µm in diameter, around 150 nuclei per osteoclast (many pyknotic)

Osteoclasts number

Osteoclasts surface


[6, 11, 36, 42, 60]


Rate of bone resorption

Erosion rate of bone




Nuclear inclusions


[61, 62]

Resorption surfaces

Extend irregularly in multiple directions and are unusually deep

Total resorption surfaces




Osteoclastic lacunae



Osteoblasts and deposition of bone

Chaotic fashion resulting in woven bone in typical “mosaic” which is mechanically weak

Poor definition of the boundary between cortical and medullary bone

[11, 36, 64]

Hyperosteoblastosis associated with an extension of the osteoid borders

Osteoblast number

Osteoblast surface

Osteoblastic surfaces

Trabecular osteoid volume

Trabecular osteoid surfaces


[6, 36, 42]

Alternating heavily calcified and fibrotic areas

Isolated areas of poorly mineralized osteoid

Fibrous tissue


[6, 36, 42, 64]


Thickness index of the osteoid borders


[36, 60]

Osteoblastic appositional rate

Calcification rate (mineral apposition rate)




Vascularity and marrow fibrosis


[11, 36]

Quantitative histomorphometry findings

Analyses of bone structure in Paget’s disease on a quantitative (histomorphometric) level are surprisingly rare. A histomorphometric study carried out in two medieval preparations with PDB found evidence of an increased trabecular thickness [45]. Histomorphometric results from Seitz et al. [6] showed a high bone turnover with a significant increase in bone resorption and bone formation indices (trabecular number, osteoid volume and osteoid surface, osteoblast number and surface of osteoclasts), and an increased bone volume. However, Lauffenburger et al. [38] stated that in PDB, there is a better correlation between bone formation and bone resorption than in osteoporosis. On the other hand, Cherian et al. [41] observed that bone density was increased in vertebrae affected by PDB, and the contribution from cortical and trabecular bone was in the ratio expected in normal bone. Cortical quantitative computed tomography values were underestimated in PDB compared with physical measurements of density. Furthermore, in the histomorphometric analysis of Petska et al. [42], affected vertebral body biopsies revealed a significant increase both in trabecular bone volume as well as in osteoid parameters. In comparison to histomorphometric data obtained from extraspinal skeletal locations affected by PDB (i. e., iliac crest), a similar bone microarchitecture of the vertebral bodies was observed. They concluded that vertebral body height and the spine bone volume together with bone density might play an important role in the manifestation of Pagetic bone alterations [42]. There is also a histopathology study based on temporal bone [46], in which authors only studied eight subjects; nevertheless, no quantitative results were shown. A general description of structural findings in Pagetic bones is summarized in Table 2.
Table 2

Description of structural findings in Pagetic bones






Bone architecture and lamellar texture

Small patches, scalloped contours and interlocked by polycyclic cement lines: “structure of a puzzle”

Periosteocytic lacunae size in the woven zones



Trabecular microarchitecture

Trabeculae are thick and numerous

Trabecular bone volume

Trabecular number


Iliac crest [6]

Spine [42]


Density of the bone tissue




Trabecular separation


Iliac crest [6]

Spine [42]


Trabecular thickness

Not altered

Iliac crest [6]

Spine [42]

Hypertrophy of the bones

Thickening and elongation of the bones

[36, 60]

Non-mineralized bone (osteoid)

Osteoid volume

Osteoid surface

Osteoblast surface relative to the osteoid surface


Iliac crest [6]

Spine [42]

An understanding of the normal skeletal distribution and the architecture of cancellous bone seems to be essential for further knowledge of both the role of bone cellular activity and also the diagnostic interpretation of bone volume measurements [47]. There are striking differences between peripheral and axial measurement sites, and even between local areas of both. For instance, in normal subjects, trabecular bone volume at the femoral neck is higher than at the lumbar spine or the iliac crest. Of note, there is a systematic variation in trabecular microarchitecture of the iliac crest, showing the highest bone mass within the anterior part and lower values for the medial and dorsal parts [47].

The functional attribution is most remarkable for peripheral cancellous bone, such as in the metaphysis of the long bones [48]. Thus, the relationship between the trabecular bone mass at different skeletal sites has been the subject of several previous studies [49, 50, 51, 52]. Although these studies helped to gain an insight into bone mass, bone structure, and bone diminution at different sites under different diseases, their results were conflicting [53, 54, 55, 56]. An improvement of knowledge about pathological skeletal conditions will depend on a better understanding of the physiological distribution of trabecular bone throughout the skeleton [47]. Considering the fact that the structure of trabecular bone is complex and that considerable skeletal heterogeneity exists [50], studies of Pagetic bone structure in different regions of the skeleton are of major interest.

Nevertheless, there are no histomorphometric studies based on long bones, only a case report [57] of a femur fracture associated with PDB in an Asian patient. Long bones are commonly affected by Paget’s disease (55 % femur and 32 % tibia) [58], thus it is crucial to get pertinent information about the basis of skeletal complications including bowing deformities, fractures of the Pagetic bone, and osteosarcoma [58].

In addition to long bones, Paget’s disease affecting the skull is of particular clinical importance due to its proximity to the nervous system. Neurologic syndromes associated with Paget’s disease include headache, dementia, brainstem and cerebellar dysfunction, cranial neuropathies, myelopathy, cauda equina syndrome, and radiculopathies [59].

Future research directions

Since several studies of Pagetic bone structure in different regions of the skeleton reveal similar findings, we put forward the hypothesis that—despite the phenomenon of skeletal heterogeneity—in PDB, bone microarchitecture is altered independent of the anatomic localization of the lesion in a uniform manner. Identification of microstructure of Pagetic bones and analyses of histological samples not only helps to clarify the pathogenesis of PDB, but may also contribute to a better knowledge about the physiological distribution of cortical and trabecular bone throughout the skeleton.

The scientific community needs further research on bone microarchitecture, skeletal distribution, and histological and histomorphometric characteristics in bone samples with Paget’s disease.



Authors thank Prof. Dr. Maria Teschler-Nicola for her great help and for providing the permission to study the Pagetic bones from the Pathologic–Anatomical Collection in The Fools Tower, Museum of Natural History, Vienna, Austria. EN was supported by a postdoctoral fellowship awarded by the University of Granada, Spain.

Open access funding provided by Medical University of Vienna.

Conflict of interest

E. Nebot Valenzuela and P. Pietschmann declare that they have no competing interests.


  1. 1.
    Ortner DJ. Miscellaneous bone diseases. In: Ortner DJ, editor. Identification of pathological conditions in human skeletal remains, 2nd edn. Amsterdam: Elsevier; 2003.Google Scholar
  2. 2.
    Mundy GR. Bone remodeling and its disorders. Boca Raton: CRC Press; 1999.Google Scholar
  3. 3.
    Singer FR. Update on the viral etiology of paget’s disease of bone. J Bone Miner Res. 1999;14(S2):29–33. doi: 10.1002/jbmr.5650140207.CrossRefPubMedGoogle Scholar
  4. 4.
    Lojo Oliveira L, Torrijos Eslava A. Treatment of Paget’s disease of bone. Reumatol Clin. 2012;8(4):220–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Cortis K, Micallef K, Mizzi A. Imaging Paget’s disease of bone–from head to toe. Clin Radiol. 2011;66(7):662–72.CrossRefPubMedGoogle Scholar
  6. 6.
    Seitz S, Priemel M, Zustin J, et al. Paget’s disease of bone: histologic analysis of 754 patients. J Bone Miner Res. 2009;24(1):62–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Kanis JA. Pathophysiology and treatment of Paget’s disease of bone, 1st ed. London: Martin Dunitz; 1992.Google Scholar
  8. 8.
    Ralston SH, Layfield R. Pathogenesis of Paget disease of bone. Calcif Tissue Int. 2012;91(2):97–113.CrossRefPubMedGoogle Scholar
  9. 9.
    Singer FR, Bone HG 3rd, Hosking DJ, et al. Paget’s disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(12):4408–22.CrossRefPubMedGoogle Scholar
  10. 10.
    Schmorl G. Über Ostitis deformans Paget. Virchows Arch Pathol Anat Physiol Klin Med. 1932;283(3):694–751. doi: 10.1007/bf01887990.CrossRefGoogle Scholar
  11. 11.
    Vallet M, Ralston SH. Biology and treatment of Paget’s disease of bone. J Cell Biochem. 2016;117(2):289–99.CrossRefPubMedGoogle Scholar
  12. 12.
    Mironón-Canelo JA, Del Pino-Montes J, Vicente-Arroyo M, et al. Epidemiological study of Paget’s disease of bone in a zone of the Province of Salamanca (spain). Eur J Epidemiol. 1997;13(7):801–5.CrossRefGoogle Scholar
  13. 13.
    Poor G, Donath J, Fornet B, et al. Epidemiology of Paget’s disease in Europe: the prevalence is decreasing. J Bone Miner Res. 2006;21(10):1545–9.CrossRefPubMedGoogle Scholar
  14. 14.
    van Staa TP, Selby P, Leufkens HG, et al. Incidence and natural history of Paget’s disease of bone in England and Wales. J Bone Miner Res. 2002;17(3):465–71.CrossRefPubMedGoogle Scholar
  15. 15.
    Ringe J. Epidemiologie der Osteitis deformans Paget. Munch Med Wschr. 1984;126:683–9.Google Scholar
  16. 16.
    Eekhoff EW, Karperien M, Houtsma D, et al. Familial Paget’s disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations. Arthritis Rheum. 2004;50(5):1650–4.CrossRefPubMedGoogle Scholar
  17. 17.
    Morales-Piga AA, Rey-Rey JS, Corres-Gonzalez J, et al. Frequency and characteristics of familial aggregation of Paget’s disease of bone. J Bone Miner Res. 1995;10(4):663–70.CrossRefPubMedGoogle Scholar
  18. 18.
    Laurin N, Brown JP, Morissette J, et al. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. 2002;70(6):1582–8.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Morissette J, Laurin N, Brown JP. Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget’s disease of bone. J Bone Miner Res. 2006;Suppl 2:P38–P44. doi: 10.1359/jbmr.06s207.CrossRefGoogle Scholar
  20. 20.
    Ralston SH, Albagha OM. Genetic determinants of Paget’s disease of bone. Ann N Y Acad Sci. 2011;1240:53–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Helfrich MH, Hocking LJ. Genetics and aetiology of Pagetic disorders of bone. Arch Biochem Biophys. 2008;473(2):172–82.CrossRefPubMedGoogle Scholar
  22. 22.
    McManus S, Bisson M, Chamberland R, et al. Autophagy and phospho-inositide dependent kinase 1 (PDK1)-related kinome in Pagetic osteoclasts. J Bone Miner Res. 2016;31(7):1334–43. doi: 10.1002/jbmr.2806.CrossRefPubMedGoogle Scholar
  23. 23.
    Mills BG, Singer FR, Weiner LP, et al. 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. 1984;(183):303–11. doi: 10.1097/00003086-198403000-00044.PubMedGoogle Scholar
  24. 24.
    Kurihara N, Hiruma Y, Yamana K, et al. Contributions of the measles virus nucleocapsid gene and the SQSTM1/p62(P392L) mutation to Paget’s disease. Cell Metab. 2011;13(1):23–34.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Basle MF, Russell WC, Goswami KK, et al. Paramyxovirus antigens in osteoclasts from Paget’s bone tissue detected by monoclonal antibodies. J Gen Virol. 1985;66(Pt 10):2103–10.CrossRefPubMedGoogle Scholar
  26. 26.
    Mee AP, Hoyland JA, Baird P, et al. Canine bone marrow cell cultures infected with canine distemper virus: an in vitro model of Paget’s disease. Bone. 1995;17(4 Suppl):S461–S466. doi: 10.1097/00003086-198403000-00044.Google Scholar
  27. 27.
    Shaker JL. Paget’s disease of bone: a review of epidemiology, pathophysiology and management. Ther Adv Musculoskelet Dis. 2009;1(2):107–25.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Menaa C, Barsony J, Reddy SV, et al. 1,25-Dihydroxyvitamin D3 hypersensitivity of osteoclast precursors from patients with Paget’s disease. J Bone Miner Res. 2000;15(2):228–36.CrossRefPubMedGoogle Scholar
  29. 29.
    Hoyland JA, Freemont AJ, Sharpe PT. Interleukin-6, IL-6 receptor, and IL-6 nuclear factor gene expression in Paget’s disease. J Bone Miner Res. 1994;9(1):75–80.CrossRefPubMedGoogle Scholar
  30. 30.
    Teramachi J, Zhou H, Subler MA, et al. Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget’s disease of bone. J Bone Miner Res. 2014;29(6):1456–65.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hoyland J, Sharpe PT. Upregulation of c‑fos protooncogene expression in pagetic osteoclasts. J Bone Miner Res. 1994;9(8):1191–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Kukita A, Chenu C, McManus LM, et al. Atypical multinucleated cells form in long-term marrow cultures from patients with Paget’s disease. J Clin Invest. 1990;85(4):1280–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest. 2005;115(2):200–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kurihara N, Zhou H, Reddy SV, et al. Expression of measles virus nucleocapsid protein in osteoclasts induces Paget’s disease-like bone lesions in mice. J Bone Miner Res. 2006;21(3):446–55.CrossRefPubMedGoogle Scholar
  35. 35.
    Rebel A, Malkani K, Basle M, Bregeon C. The classic. Osteoclast ultrastructure in Paget’s disease. Clin Orthop Relat Res. 1987;(217):4–8. doi: 10.1097/00003086-198704000-00002.PubMedGoogle Scholar
  36. 36.
    Meunier PJ, Coindre JM, Edouard CM, et al. Bone histomorphometry in Paget’s disease. Quantitative and dynamic analysis of pagetic and nonpagetic bone tissue. Arthritis Rheum. 1980;23(10):1095–103.CrossRefPubMedGoogle Scholar
  37. 37.
    Maldague B, Malghem J. Dynamic radiologic patterns of Paget’s disease of bone. Clin Orthop Relat Res. 1987;(217):126–51. doi: 10.1097/00003086-198704000-00012.PubMedGoogle Scholar
  38. 38.
    Lauffenburger T, Olah AJ, Dambacher MA, et al. Bone remodeling and calcium metabolism: a correlated histomorphometric, calcium kinetic, and biochemical study in patients with osteoporosis and Paget’s disease. Metabolism. 1977;26(6):589–606.CrossRefPubMedGoogle Scholar
  39. 39.
    Meunier PJ, Chapuy M‑C, Delmas P, et al. Intravenous disodium etidronate therapy in Paget’s disease of bone and hypercalcemia of malignancy: effects on biochemical parameters and bone histomorphometry. Am J Med. 1987;82(2, Suppl 1):71–8. doi: 10.1016/0002-9343(87)90489-x.CrossRefPubMedGoogle Scholar
  40. 40.
    Delmas PD, Chapuy MC, Vignon E, et al. Long term effects of dichloromethylene diphosphonate in Paget’s disease of bone. J Clin Endocrinol Metab. 1982;54(4):837–44.CrossRefPubMedGoogle Scholar
  41. 41.
    Cherian RA, Haddaway MJ, Davie MW, et al. Effect of Paget’s disease of bone on areal lumbar spine bone mineral density measured by DXA, and density of cortical and trabecular bone measured by quantitative CT. Br J Radiol. 2000;73(871):720–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Pestka JM, Seitz S, Zustin J, et al. Paget disease of the spine: an evaluation of 101 patients with a histomorphometric analysis of 29 cases. Eur Spine J. 2012;21(5):999–1006.CrossRefPubMedGoogle Scholar
  43. 43.
    Sulzbacher I. Pathology of Paget’s disease. J Mineralstoffwechs. 2012;19(2):63–6.Google Scholar
  44. 44.
    Hosking DJ. Paget’s disease of bone. BMJ. 1981;283(6293):686–8.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Aaron JE, Rogers J, Kanis JA. Paleohistology of Paget’s disease in two medieval skeletons. Am J Phys Anthropol. 1992;89(3):325–31.CrossRefPubMedGoogle Scholar
  46. 46.
    Dimitriadis PA, Bamiou D‑E, Bibas AG. Hearing loss in Paget’s disease: a temporal bone histopathology study. Otol Neurotol. 2012;33(2):142–6. doi: 10.1097/MAO.0b013e318241c3bd.CrossRefPubMedGoogle Scholar
  47. 47.
    Amling M, Herden S, Posl M, et al. Heterogeneity of the skeleton: comparison of the trabecular microarchitecture of the spine, the iliac crest, the femur, and the calcaneus. J Bone Miner Res. 1996;11(1):36–45.CrossRefPubMedGoogle Scholar
  48. 48.
    Meyer G. Die Architektur der Spongiosa. Arch Anat Physiol Wiss Med. 1987;34:615–28.Google Scholar
  49. 49.
    Delling G, Amling M. Biomechanical stability of the skeleton-it is not only bone mass, but also bone structure that counts. Nephrol Dial Transplant. 1995;10(5):601–6.PubMedGoogle Scholar
  50. 50.
    Amling M, Grote HJ, Posl M, et al. Polyostotic heterogeneity of the spine in osteoporosis. Quantitative analysis and three-dimensional morphology. Bone Miner. 1994;27(3):193–208.CrossRefPubMedGoogle Scholar
  51. 51.
    Aaron JE, Makins NB, Sagreiya K. The microanatomy of trabecular bone loss in normal aging men and women. Clin Orthop Relat Res. 1987;(215):260–71. doi: 10.1097/00003086-198702000-00038.Google Scholar
  52. 52.
    Amling M, Hahn M, Wening VJ, et al. The microarchitecture of the axis as the predisposing factor for fracture of the base of the odontoid process. A histomorphometric analysis of twenty-two autopsy specimens. J Bone Joint Surg Am. 1994;76(12):1840–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Wright CD, Crawley EO, Evans WD, et al. The relationship between spinal trabecular bone mineral content and iliac crest trabecular bone volume. Calcif Tissue Int. 1990;46(3):162–5.CrossRefPubMedGoogle Scholar
  54. 54.
    Mautalen C, Vega E, Ghiringhelli G, et al. Bone diminution of osteoporotic females at different skeletal sites. Calcif Tissue Int. 1990;1990(46):217–21.CrossRefGoogle Scholar
  55. 55.
    Wilson CR. Bone-mineral content of the femoral neck and spine versus the radius or ulna. J Bone Joint Surg Am. 1977;59(5):665–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Uitewaal PJ, Lips P, Netelenbos JC. An analysis of bone structure in patients with hip fracture. Bone Miner. 1987;3(1):63–73.PubMedGoogle Scholar
  57. 57.
    Takigami I, Ohara A, Matsumoto K, et al. Functional bracing for delayed union of a femur fracture associated with Paget’s disease of the bone in an Asian patient: a case report. J Orthop Surg Res. 2010;5:33.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Siris E, Roodman GD. Paget’s disease of bone. In: Rosen CJ, Compston JE, Lian JB, editors. Primer on the metabolic bone diseases and disorders of mineral metabolism, 7th edn. Washington, DC: American Society for Bone and Mineral Research; 2008. pp. 335–43.CrossRefGoogle Scholar
  59. 59.
    Poncelet A. The neurologic complications of paget’s disease. J Bone Minera Res. 1999;14(S2):88–91. doi: 10.1002/jbmr.5650140218.CrossRefGoogle Scholar
  60. 60.
    Altman RD. Paget’s disease of bone. In: Coe FL, Favus MJ, editors. Disorders of bone and mineral metabolism. New York: Raven Press; 1992. pp. 1027–64.Google Scholar
  61. 61.
    Helfrich MH, Hobson RP, Grabowski PS, et al. A negative search for a paramyxoviral etiology of Paget’s disease of bone: molecular, immunological, and ultrastructural studies in UK patients. J Bone Miner Res. 2000;15(12):2315–29.CrossRefPubMedGoogle Scholar
  62. 62.
    Rebel A, Malkani K, Basle M. Nuclear anomalies in osteoclasts in Paget’s bone disease. Nouv Presse Med. 1974;3(20):1299–301.PubMedGoogle Scholar
  63. 63.
    Chappard D, Alexandre C, Laborier JC, et al. Paget’s disease of bone. A scanning electron microscopic study. J Submicrosc Cytol. 1984;16(2):341–8.PubMedGoogle Scholar
  64. 64.
    Williams ED, Barr WT, Rajan KT. Relative vitamin D deficiency in Paget’s disease. Lancet. 1981;1(8216):384–5.CrossRefPubMedGoogle Scholar

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© The Author(s) 2016

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and ImmunologyMedical University of ViennaViennaAustria
  2. 2.Department of Physiology, School of Pharmacy, and Institute of Nutrition and Food TechnologyUniversity of GranadaGranadaSpain

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