Materiały źródłowe

• #1 Pathogenesis of Paget’s disease of bone – PubMed

  https://pubmed.ncbi.nlm.nih.gov/18672105/

  Paget’s disease of bone is a common condition characterised by increased and disorganised bone turnover which can affect one or several bones throughout the skeleton. […] Genetic factors play an important role in PDB and mutations or polymorphisms have been identified in four genes that cause classical Paget’s disease and related syndromes. […] All of these genes play a role in the RANK-NFkappaB signalling pathway and it is likely that the mutations predispose to PDB by disrupting normal signalling, leading to osteoclast activation. […] Although Paget’s has traditionally be considered a disease of the osteoclast there is evidence that stromal cell function and osteoblast function are also abnormal, which might account for the fact that the disease is associated with increased bone formation as well as resorption.

• #1 Paget’s disease of bone – Wikipedia

  https://en.wikipedia.org/wiki/Paget%27s_disease_of_bone

  Paget’s disease of bone (commonly known as Paget’s disease or, historically, osteitis deformans) is a condition involving cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the microscopic level, specifically excessive bone breakdown and subsequent disorganized new bone formation. […] The pathogenesis of Paget’s disease is described in four stages: Osteoclastic activity, Mixed osteoclastic osteoblastic activity, Osteoblastic activity, Malignant degeneration. […] Initially, there is a marked increase in the rate of bone resorption in localized areas, caused by large and numerous osteoclasts. […] Some evidence suggests that a paramyxovirus infection is the underlying cause of Paget’s disease, which may support the possible role of inflammation in the pathogenesis. However, no infectious virus has yet been isolated as a causative agent, and other evidence suggests an intrinsic hyperresponsive reaction to vitamin D and RANK ligand is the cause. Further research is therefore necessary.

• #1 Pathogenesis of Paget’s Bone Disease and its Symptoms

  https://www.jcmedu.org/jcmedu-articles/pathogenesis-of-pagets-bone-disease-and-its-symptoms-96461.html

  Pagets disease of bone (commonly known as Pagets disease or historically osteitis deformans) is a condition involving cellular remodeling and deformation of one or more bones. Affected bones show signs of dysregulated bone remodeling at the microscopic level, namely excessive bone resorption and subsequent disorganized new bone formation. […] The pathogenesis of Pagets disease is described as initially, there is a significant increase in the rate of bone resorption in localized areas, caused by large and numerous osteoclasts. These localized areas of pathological destruction of bone tissue (osteolysis) are seen radiographically as a progressive lytic wedge in the long bones or skull. […] Osteolysis is followed by a compensatory increase in bone formation caused by bone-forming cells called osteoblasts that are recruited to the area. This is associated with accelerated deposition of lamellar bone in a disordered manner. This intense cellular activity creates a chaotic pattern of trabecular bone (a mosaic pattern), rather than the normal linear lamellar pattern.

• #1 Paget Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/334607-overview

  The development of Paget disease of bone may be related to a deregulation of autophagy, a catabolic process responsible for the degradation of damaged organelles, cytoplasmic proteins, and protein aggregates. […] The cause of Paget disease is unknown. Both genetic and environmental factors have been implicated. […] Osteoclast precursors in patients with Paget disease also appear to be hyperresponsive to vitamin D (specifically, 1,25(OH)2 D3, the active form of vitamin D3) and calcitonin and have up-regulation of the c-fos proto-oncogene and BC12, the antiapoptosis gene. […] The second phase, the mixed phase, is characterized by rapid increases in bone formation from numerous osteoblasts. […] The final phase of Paget disease, the sclerotic phase, bone formation dominates and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone. […] After a variable amount of time, osteoclastic activity may decrease, but abnormal bone formation continues.

• #1 Pathogenesis of Paget’s Bone Disease and its Symptoms

  https://www.jcmedu.org/jcmedu-articles/pathogenesis-of-pagets-bone-disease-and-its-symptoms-96461.html

  The resorbed bone is replaced and the marrow spaces are filled with an excess of fibrous connective tissue with a significant increase in blood vessels, causing a hypervascular state of the bone. The hypercellularity of the bone can then shrink, leaving dense pagetic bone, also known as burned-out Pagets disease. […] The later stage of the disease is characterized by the replacement of normal bone marrow by highly vascular fibrous tissue. […] Some evidence suggests that paramyxovirus infection is the underlying cause of Pagets disease, which may support a possible role of inflammation in pathogenesis. However, no infectious virus has yet been isolated as the causative agent, and other evidence suggests that an intrinsic hyperresponsiveness to vitamin D and receptor activator of nuclear factor kappa beta ligand is the cause. Therefore, further research is needed.

• #1 Paget’s disease of bone: 1877–2023. Etiology, and management of a disease on epidemiologic transition | Medicina Clínica (English Edition)

  https://www.elsevier.es/en-revista-medicina-clinica-english-edition–462-articulo-pagets-disease-bone-18772023-etiology-S2387020623003352

  The first description of PDB as a possible hereditary disease due to its high prevalence of familial cases was published in 1949. The presence of this familial aggregation is quantified as a 710 times higher risk of developing the disease in first-degree relatives of affected patients than in the general population. This familial aggregation, together with the rarity of the disease in non-Caucasian populations and an increased number of PDB cases in certain rural areas (hotspots of high prevalence), indicates the existence of a predisposition to the development of the disease determined by genetic factors. […] However, the hereditary component is not sufficient to explain the disease and there is evidence supporting the need to consider the interaction with environmental factors. The decline in incidence and severity described in recent decades would favour the environmental theory. This decline has even been demonstrated in SQSTM1 gene mutation carriers. These patients now have a more attenuated phenotype than their progenitors and have a later age of diagnosis than their progenitors. The reason for this delay in genetic penetrance is unknown. Decreased exposure to environmental factors is suggested as the most likely mechanism to explain these phenomena.

• #1 Pathogenesis of Paget disease of bone – PubMed

  https://pubmed.ncbi.nlm.nih.gov/22543925/

  Paget disease of bone (PDB) is primarily caused by dysregulation of osteoclast differentiation and function, and there is increasing evidence that this is due, in part, to genetic factors. […] One of the most important predisposing genes is SQSTM1, which harbors mutations that cause osteoclast activation in 5-20 % of PDB patients. […] Seven additional susceptibility loci for PDB have been identified by genomewide association studies on chromosomes 1p13, 7q33, 8q22, 10p13, 14q32, 15q24, and 18q21. […] Although the causal variants remain to be discovered, three of these loci contain CSF1, TNFRSF11A, and TM7SF4, genes that are known to play a critical role in osteoclast differentiation and function. […] Environmental factors are also important in the pathogenesis of PDB, as reflected by the fact that in many countries the disease has become less common and less severe over recent years.

• #1 Paget disease of bone: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/paget-disease-of-bone/

  Paget disease of bone is a disorder that causes bones to grow larger and weaker than normal. […] A combination of genetic and environmental factors likely play a role in causing Paget disease of bone. Researchers have identified changes in several genes that increase the risk of the disorder. […] Researchers have identified variations in three genes that are associated with Paget disease of bone: SQSTM1, TNFRSF11A, and TNFRSF11B. Mutations in the SQSTM1 gene are the most common genetic cause of classic Paget disease of bone, accounting for 10 to 50 percent of cases that run in families and 5 to 30 percent of cases in which there is no family history of the disease. […] The SQSTM1, TNFRSF11A, and TNFRSF11B genes are involved in bone remodeling, a normal process in which old bone is broken down and new bone is created to replace it. Paget disease of bone disrupts the bone remodeling process. Affected bone is broken down abnormally and then replaced much faster than usual.

• #1 Bone scan findings of Paget’s disease of bone in patients with VCP Multisystem Proteinopathy 1 | Scientific Reports

  https://www.nature.com/articles/s41598-024-54526-7

  Multisystem Proteinopathy 1 (MSP1) disease is a rare genetic disorder caused by mutations in the Valosin-Containing Protein (VCP) gene with clinical features of inclusion body myopathy (IBM), frontotemporal dementia (FTD), and Pagets disease of bone (PDB). […] PDB is caused by abnormal bone homeostasis where disorganization of bone by overactive osteoclasts and osteoblasts leads to clinical features of bone pain, bone deformity, deafness, fractures, and rarely osteosarcoma. The detailed mechanism of PDB is currently inconclusive, however, a combination of genetic, viral, and environmental factors has been suspected. One of most important predisposing genetic factor is variants in the SQSTM1 gene that causes osteoclast activation via RANK signaling in 520% of PDB patients. […] The mechanism of PDB pathogenesis however is similar since previous studies have shown that pathogenic variants in VCP can upregulate the NF-kB signaling pathway leading to upregulated osteoclastogenesis and bone resorption and can therefore contribute to PDB. […] Similarly, report of VCP’s role in osteoblast activity involves complex regulation of bone morphogenetic protein (BMP) receptors via the VCP mediated ubiquitin/protein degradation system which may play a part in PDB pathogenesis.

• #1 A FKBP5 mutation is associated with Paget’s disease of bone and enhances osteoclastogenesis | Experimental & Molecular Medicine

  https://www.nature.com/articles/emm201764

  Pagets disease of bone (PDB) is a common metabolic bone disease that is characterized by aberrant focal bone remodeling, which is caused by excessive osteoclastic bone resorption followed by disorganized osteoblastic bone formation. Genetic factors are a critical determinant of PDB pathogenesis, and several susceptibility genes and loci have been reported, including SQSTM1, TNFSF11A, TNFRSF11B, VCP, OPTN, CSF1 and DCSTAMP. […] Although the exact pathogenesis of PDB is still unclear, genetic factors are known to be important in PDB development. Mutations in the SQSTM1 gene, which encodes p62, have been shown to be widely involved in PDB development and in the severity of the disease phenotype. […] Osteoclast dysfunction is the primary defect in PDB. Osteoclasts in pagetic bone lesions display increased size, contain multiple nuclei and possess characteristic intranuclear inclusion bodies.

• #1 Pathogenesis of Paget disease of bone – PubMed

  https://pubmed.ncbi.nlm.nih.gov/22543925/

  The most widely studied environmental trigger is paramyxovirus infection, but attempts to detect viral transcripts in tissues from patients with PDB have yielded mixed results. […] Although our understanding of the pathophysiology of PDB has advanced tremendously over the past 10 years, many questions remain unanswered, such as the mechanisms responsible for the focal nature of the disease and the recent changes in prevalence and severity.

• #1

  https://www.omim.org/entry/167250

  A number sign (#) is used with this entry because of evidence that Paget disease of bone-3 (PDB3) is caused by heterozygous mutation in the SQSTM1 gene (601530) on chromosome 5q35. […] Paget disease (PDB) is a metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. […] See 147620 for evidence that interleukin-6 is involved in the hyperplasia and hypertrophy of osteoclasts in Paget disease. […] In addition to the genetic etiology of Paget disease, electron microscopic demonstration of virus-like bodies in bone cells of patients with Paget disease suggests a viral etiology (Mills and Singer, 1976).

• #1

  https://www.jci.org/articles/view/24281

  A striking feature of pagetic osteoclasts is the characteristic nuclear inclusions, which consist of paracrystalline arrays that are similar to nucleocapsids of paramyxoviruses. […] In vitro studies of bone marrow samples obtained from affected bones of Paget patients have identified several unique differences between pagetic and normal osteoclast precursors. […] The pagetic phenotype is characterized by hypersensitivity of osteoclast precursors to several osteoclastogenic factors, including 1,25-(OH)2D3 and RANKL. […] The cause of PD is currently an area of intensive investigation, and both genetic and nongenetic factors have been implicated in the pathogenesis of this disease. […] Genetic factors are clearly an important component of the etiology of PD, since 15-40% of affected patients have a first-degree relative with PD.

• #1

  https://omim.org/entry/167250

  The frequency of occurrence of inclusions in osteoclasts and in their individual nuclei correlated with the histologic severity of the disease process. The similarity of the inclusions to paramyxovirus inclusion bodies (particularly those of measles) supported, in the view of the authors, the hypothesis that Paget disease is a slow virus infection. […] Cody et al. (1997) reviewed the evidence suggesting a viral etiology of Paget disease.

• #1

  https://link.springer.com/article/10.1007/s10354-016-0496-4

  Pagetic osteoclasts frequently express the measles virus nucleocapsid protein, 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. […] The early lesions are predominantly lytic and osteoporotic; bone resorption predominates with abnormally large osteoclasts containing multiple pleomorphic nuclei and microfilamentous inclusion bodies. Later, a mixed osteolytic-osteoblastic phase with an abundance of osteoblasts forming new matrix in the form of woven bone occurs, where thickening of the cortex by endosteal and periosteal bone deposition with enlargement of the bones is observed. […] The histological study by Seitz et al. 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. […] Most patients are asymptomatic, whereas some develop complications such as bone pain, osteoarthritis, fracture, deformity, deafness, and nerve compression syndromes.

• #1 Pathogenesis and management of Paget’s disease of bone. | SOGACOT – Sociedad Gallega de Cirugía Ortopédica y Traumatología

  https://sogacot.org/articulos/pathogenesis-and-management-of-pagets-disease-of-bone/

  Paget’s disease of bone is a common disease characterised by focal areas of increased bone turnover, affecting one or several bones throughout the skeleton. […] Genetic factors have an important role in this disease, and mutations have been identified in four genes that cause Paget’s disease and related syndromes. The most important of these is Sequestosome 1 (SQSTM1), which is a scaffold protein in the nuclear factor kappaB (NFkappaB) signalling pathway. Patients with SQSTM1 mutations have severe Paget’s disease of bone and a high degree of penetrance with increasing age. […] Environmental factors also contribute. Most research has focused on paramyxovirus infection as a possible trigger, but evidence for this notion is conflicting. Other potential triggers include deficiency of dietary calcium and repetitive mechanical loading of the skeleton.

• #1 Updates on Paget’s Disease of Bone

  https://www.e-enm.org/journal/view.php?number=2339

  Pagets disease of the bone is a prevalent bone disease characterized by disorganized bone remodeling; however, it is comparatively uncommon in East Asian countries, including China, Japan, and Korea. The exact cause still remains unknown. In genetically susceptible individuals, environmental triggers such as paramyxoviral infections are likely to cause the disease. Increased osteoclast activity results in increased bone resorption, which attracts osteoblasts and generates new bone matrix. Fast bone resorption and formation lead to the development of disorganized bone tissue. […] PDB is characterized by anomalies in all phases of bone remodeling. The fundamental problem comprises the control of osteoclasts, which are enlarged in number and size, and are hypernucleated (up to 50 nuclei per cell). In response to rapid bone resorption, bone production accelerates by 6- to 7-fold, according to tetracycline-based histomorphometric estimations. The new bone formation is disorganized and lacks the normal lamellar pattern; thus, the affected bones are larger and more sclerotic than the normal bones. However, they are of poor quality, which leads to deformity and fracture.

• #1 Paget disease of bone – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/paget-disease-of-bone/

  Paget disease of bone (PDB, or osteitis deformans) is a slowly progressive skeletal disease; it can be monostotic or polyostotic. […] In PDB, increased bone turnover causes normal lamellar bone to be replaced by weak woven bone. […] PDB is common but underdiagnosed, and its etiology is not known. […] Associated with a high rate of bone remodeling: RANKL-RANK activity NF-B signaling osteoclast activity osteoblast activity formation of disorganized (woven) bone. […] Bone remodeling in Paget disease occurs in three phases, followed by a quiescent stage: Lytic phase: number of osteoclasts appear in bone osteoclastic activity rate of bone resorption. […] Mixed lytic and blastic phase: osteoclastic activity is accompanied by an number of osteoblasts, which infiltrate the lacunae: rate of bone formation with haphazardly laid collagen fibers; formation of abnormal hypervascular woven bone. […] Sclerotic phase: Osteoblastic activity overtakes osteoclastic activity, which leads to formation of dense, sclerotic bone. […] Quiescent stage: Both osteoclastic and osteoblastic activity cease (quiet phase of the disease). […] Mechanism: induce apoptosis of osteoclasts.

• #1

  https://journals.lww.com/ijoh/fulltext/2020/10010/paget_s_disease_of_bone_with_special_reference_to.7.aspx

  The leading hypothesis is the slow virus theory, The measles virus messenger RNA sequences have been found in osteoclasts and other mononuclear cells of pagetic bones. […] In PDB, osteoclast precursors have also been shown to be hyper-responsive to the RANKL, a member of the tumor necrosis factor- superfamily, which promotes osteoclast genesis. […] Several studies have reported increased levels of IL-6 and/or macrophage colony-stimulating factor (M-CSF) in patients with PDB. Osteoclasts formed in bone marrow cultures from patients with PDB secrete large quantities of IL-6 into the conditioned media, with IL-6 levels reaching up to 2000 pg/ml. […] The Pittsburg group model for Paget’s etiology involves both genetic and nongenetic factors. […] Paget disease begins with the lytic phase, an increase in bone resorption with an increase in the number of osteoclasts in a space known as Howship’s lacunae.

• #1 Paget’s disease of bone: an osteoimmunological disorder? | DDDT

  https://www.dovepress.com/pagetrsquos-disease-of-bone-an-osteoimmunological-disorder-peer-reviewed-fulltext-article-DDDT

  However, the exact role of the immune system in Pagets disease of bone is not very well understood, except for cellular responses to MNVP. […] Increasing expression of IFN-, IFN-, and IFN- messenger (m)RNA, STAT-1, IFN- receptors 1 and 2, and mitogen-activated protein kinase were found in monocytes and lymphocytes from patients with Pagets disease in comparison with healthy controls, suggesting a possible post-viral reaction in Pagets disease of bone. […] The treatment of Pagets disease of bone may also benefit from progresses in targeted therapies. For instance, denosumab, a monoclonal antibody inhibiting RANKL, could be relevant to treat Pagets disease of bone as it prevents the osteoclastogenesis and promotes the apoptosis of mature osteoclasts. […] The cytokine profiles observed in this disease are also very similar to those observed in other osteoimmunological disorders that should probably be classified accordingly.

• #1 Paget’s disease of bone: A clinical update

  https://www1.racgp.org.au/ajgp/2021/january-february/pagets-disease-of-bone

  The pathognomonic feature of PDB is the abnormally active osteoclasts, which are increased in size and number. These osteoclasts secrete enzymes that dissolve mineralised bone and matrix to form lytic lesions, and stimulate increased numbers of osteoblasts to form disorganised, highly vascular cancellous bone that is prone to fracture (Figure 1).19 Unlike the lamellar distribution of mature adult bone, pagetic bone is a mixture of abnormal woven bone, disorganised cement lines and increased volume of unmineralised osteoid. The marrow is sclerosed and hypervascular.1,6 […] In the early stages, pagetic bone appears as lytic lesions radiographically. As osteoblasts form new bone, the lesions then become progressively sclerosed and deformed.

• #1

  https://www.jci.org/articles/view/24281

  Paget disease of bone (PD) is characterized by excessive bone resorption in focal areas followed by abundant new bone formation, with eventual replacement of the normal bone marrow by vascular and fibrous tissue. […] The etiology of PD is not well understood, but one PD-linked gene and several other susceptibility loci have been identified, and paramyxoviral gene products have been detected in pagetic osteoclasts. […] The initial phase of PD is characterized by excessive bone resorption in a focal region, and radiological examination in the early stages of the disease frequently shows an osteolytic lesion. […] The poor quality of pagetic bone accounts for the bowing or even fracture of bones affected by PD. […] Osteoclasts in pagetic lesions are increased in both number and size, and in cross-section are seen to contain up to 100 nuclei, in contrast to normal osteoclasts, which contain 3-20 nuclei.

• #1 Paget’s disease of bone: Report of 11 cases

  https://www.wjgnet.com/2307-8960/full/v9/i14/3478.htm

  Finally, new bone is formed and absorbed repeatedly as the disease progresses, which leads to a disorganized architecture and the production of woven bone. […] A mosaic appearance can be seen in which there is an admixture of woven and lamellar bone. […] In this study, the bone biopsy pathological findings showed typical changes in PDB, such as a mosaic structure in the bone trabeculae with irregular cement lines and multinuclear osteoclasts. […] The diagnosis of PDB is usually made by X-ray and elevated serum ALP levels, particularly in asymptomatic patients. […] The characteristic features on radionuclide bone scintigraphy are osteolysis during the initial stage, followed by osteogenesis and osteosclerosis. […] PDB is prone to misdiagnosis because of its various nonspecific clinical manifestations and rarity in China. […] The treatment for PDB is aimed at suppressing osteoclast activity and reducing bone turnover from a pathophysiological standpoint. […] Bisphosphonates suppress increased bone resorption and decrease serum ALP and are an ideal choice for treating PDB.

• #1 Pagets Disease: Etiology and Pathogenesis : Wheeless’ Textbook of Orthopaedics

  https://www.wheelessonline.com/arthritis/pagets-disease-etiology-and-pathogenesis/

  disease may be caused by a virus; – paramyxovirus infection of osteoblasts may activate of the c-fos proto-oncogene, resulting in localized abnormal osteoclastic activity typical of Paget’s disease; […] – in Paget’s disease, primary defect is in the remodeling system of isolated areas of skeleton; – it is characterized by massive turnover of bone in the affected areas w/ marked increase in both bone resorption bone formation; – owing to rapid turnover, the bone formed is immature bone; – in the bones affected, there may be either little change in the shape of the bone or very marked change in the bone contour resulting from both lack of appropriate remodeling change in quality of bone; – small increased risk of osteosarcoma; […] – initial phase of disorder involves bone resorption by osteoclasts; – subsequently there is vigorous osteoblastic response, producing excessive, poorly organized, structurally weak, highly vascular woven bone; – disease causes significant increase in blood flow of involved bones; – this increase may be so extensive, due to small arteriovenous shunts, that cardiac output is significantly increased; – degenerative arthritis is assoc w/ hypervascularity of ends of bones; – after some time osteoclastic activity subsides woven bone is replaced by lamellar bone as the osteoblastic action persists;

• #1 Paget’s disease of bone: 1877–2023. Etiology, and management of a disease on epidemiologic transition | Medicina Clínica (English Edition)

  https://www.elsevier.es/en-revista-medicina-clinica-english-edition–462-articulo-pagets-disease-bone-18772023-etiology-S2387020623003352

  Several possible environmental factors may be involved in the pathogenesis of PDB, although there is no clear evidence for any of them. One of the most documented environmental factors is the involvement of viral infections. The presence of inclusions in osteoclasts reminiscent of paramyxovirus-related particles has led to the hypothesis of viral aetiology. Evidence for the origin of these inclusions is conflicting, with the initial demonstration of viral particles in osteoclasts or in circulating blood cells not being replicated in subsequent studies. There is no agreement on their role. […] In any case, the theory that seems most feasible in order to understand the complexity of the aetiopathogenesis of PDB is that there may be a genetic susceptibility associated with the participation of different, as yet unconfirmed, environmental factors that lead to the development of the disease over the course of years. This theory is known as the unified theory. These environmental factors, in addition to acting on patients with a genetic predisposition, could also lead to local epigenetic changes in other patients without such a predisposition.

• #1

  https://www.jci.org/articles/view/24281

  Several susceptibility loci for PD have been recently identified, including 2q36, 5q31, 5q35, 10p13, 18q21-22, and 18q23. […] The PD-associated p62 mutations could potentially affect a number of cell processes, including signaling, ubiquitin-dependent proteolysis, and others. […] Several observations suggest that environmental factors may also contribute to the pathogenesis of PD. […] Ultrastructural, immunohistochemical, in situ hybridization, and biological studies have all suggested a possible viral etiologic factor in PD, although an infectious virus has not been isolated. […] These results suggest that if involved, a viral infection by itself does not cause PD. […] A proposed model for the development of PD must take into account both genetic and nongenetic factors, the highly localized nature of the disease, and its late onset.

• #1 Paget Disease of Bone – Musculoskeletal and Connective Tissue Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/paget-disease-of-bone/paget-disease-of-bone

  Bone turnover is accelerated at involved sites. Pagetic lesions are metabolically active and highly vascular. Excessively active osteoclasts are often large and contain many nuclei. Osteoblastic repair is also hyperactive, causing coarsely woven, thickened lamellae and trabeculae. This abnormal structure weakens the bone, despite bone enlargement and areas of bone sclerosis. […] Pharmacologic therapy is indicated to treat pain clearly related to the pagetic process and not to another source (eg, osteoarthritis). […] Several antiresorptive agents that suppress osteoclast activity and decrease bone pain are available for treating Paget disease. […] Bisphosphonates are the medication class of choice. The amino-bisphosphonates (bisphosphonates with an extra nitrogen atom) more effectively suppress markers of disease activity and provide more prolonged response. […] Synthetic salmon calcitonin is an alternative to bisphosphonates for patients intolerant of or resistant to them. […] Because bone turnover is increased, patients should ensure adequate intake of calcium and vitamin D, and supplements are often needed.

• #1 Pathogenesis and management of Paget’s disease of bone. | SOGACOT – Sociedad Gallega de Cirugía Ortopédica y Traumatología

  https://sogacot.org/articulos/pathogenesis-and-management-of-pagets-disease-of-bone/

  Medical management of Paget’s disease of bone is based on giving inhibitors of osteoclastic bone resorption, and bisphosphonates are the treatment of first choice. Bisphosphonate therapy is primarily indicated for patients who have bone pain arising from increased metabolic activity in affected bones. Bisphosphonate therapy is highly effective at reducing bone turnover, and it has been shown to heal radiological lesions and restore normal histology; however, the long-term effects of bisphosphonates on disease progression have not been adequately studied. No firm evidence as yet exists to show that bisphosphonates can prevent the development of complications of Paget’s disease of bone, and further work is needed to address the effects of treatment on long-term clinical outcome.

• #1 SciELO Brazil – Paget’s disease of bone Paget’s disease of bone

  https://www.scielo.br/j/abem/a/JcpDDXx5tZC66sBkNWrV9Lw/?format=html

  The first bisphosphonate to be used in PDB was etidronate. New, more potent biphosphonates have proved to be more effective, leading to more prolonged periods of remission. […] Zoledronic acid, also known as zoledronate, is 10,000 times more potent than etidronate and 100 times more potent than pamidronate. It is used intravenously for 15-20 minutes. Patients with resistance to other bisphosphonates usually respond to zoledronic acid, which is highly effective in reducing the biochemical markers of bone remodeling.

• #2 Paget Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/334607-overview

  Paget disease is a localized disorder of bone remodeling that typically begins with excessive bone resorption followed by an increase in bone formation. […] This osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. […] Although the etiology of Paget disease is unknown, both genetic and environmental contributors have been suggested. […] Variants of several genes, such as SQSTM1, VCP, and OPTN, have been linked with Paget disease; for example, approximately 80% of individuals who carry pathogenic variants in SQSTM1 develop Paget disease by their seventh decade of life. […] An environmental trigger for Paget disease has long been considered but never proven.

• #2

  https://step1.medbullets.com/msk/112027/paget-disease-of-bone

  genetic and environmental factors may be involved […] increased multinucleated osteoclastic and osteoblastic activity leads to a high bone remodeling rate, leading to abnormal bone architecture […] lytic phase intense osteoclastic resorption […] mixed phase resorption and compensatory bone formation […] sclerotic phase osteoblastic bone formation predominates […] all three phases may co-exist in the same bone.

• #2 Paget disease of bone – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/paget-disease-of-bone/

  Paget disease of bone (PDB, or osteitis deformans) is a slowly progressive skeletal disease; it can be monostotic or polyostotic. […] In PDB, increased bone turnover causes normal lamellar bone to be replaced by weak woven bone. […] PDB is common but underdiagnosed, and its etiology is not known. […] Associated with a high rate of bone remodeling: RANKL-RANK activity NF-B signaling osteoclast activity osteoblast activity formation of disorganized (woven) bone. […] Bone remodeling in Paget disease occurs in three phases, followed by a quiescent stage: Lytic phase: number of osteoclasts appear in bone osteoclastic activity rate of bone resorption. […] Mixed lytic and blastic phase: osteoclastic activity is accompanied by an number of osteoblasts, which infiltrate the lacunae: rate of bone formation with haphazardly laid collagen fibers; formation of abnormal hypervascular woven bone. […] Sclerotic phase: Osteoblastic activity overtakes osteoclastic activity, which leads to formation of dense, sclerotic bone. […] Quiescent stage: Both osteoclastic and osteoblastic activity cease (quiet phase of the disease). […] Mechanism: induce apoptosis of osteoclasts.

• #2 Pagets Disease: Etiology and Pathogenesis : Wheeless’ Textbook of Orthopaedics

  https://www.wheelessonline.com/arthritis/pagets-disease-etiology-and-pathogenesis/

  disease may be caused by a virus; – paramyxovirus infection of osteoblasts may activate of the c-fos proto-oncogene, resulting in localized abnormal osteoclastic activity typical of Paget’s disease; […] – in Paget’s disease, primary defect is in the remodeling system of isolated areas of skeleton; – it is characterized by massive turnover of bone in the affected areas w/ marked increase in both bone resorption bone formation; – owing to rapid turnover, the bone formed is immature bone; – in the bones affected, there may be either little change in the shape of the bone or very marked change in the bone contour resulting from both lack of appropriate remodeling change in quality of bone; – small increased risk of osteosarcoma; […] – initial phase of disorder involves bone resorption by osteoclasts; – subsequently there is vigorous osteoblastic response, producing excessive, poorly organized, structurally weak, highly vascular woven bone; – disease causes significant increase in blood flow of involved bones; – this increase may be so extensive, due to small arteriovenous shunts, that cardiac output is significantly increased; – degenerative arthritis is assoc w/ hypervascularity of ends of bones; – after some time osteoclastic activity subsides woven bone is replaced by lamellar bone as the osteoblastic action persists;

• #2

  https://journals.lww.com/ijoh/fulltext/2020/10010/paget_s_disease_of_bone_with_special_reference_to.7.aspx

  This significant increase in bone resorption leads to a second phase (known as the mixed phase) of rapid increases in bone formation with numerous osteoblasts, which are increased in number but remain morphologically normal. In the final phase of PDB, known as the sclerotic phase, bone formation dominates, and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone.

• #2 Paget’s disease of bone: A clinical update

  https://www1.racgp.org.au/ajgp/2021/january-february/pagets-disease-of-bone

  The pathognomonic feature of PDB is the abnormally active osteoclasts, which are increased in size and number. These osteoclasts secrete enzymes that dissolve mineralised bone and matrix to form lytic lesions, and stimulate increased numbers of osteoblasts to form disorganised, highly vascular cancellous bone that is prone to fracture (Figure 1).19 Unlike the lamellar distribution of mature adult bone, pagetic bone is a mixture of abnormal woven bone, disorganised cement lines and increased volume of unmineralised osteoid. The marrow is sclerosed and hypervascular.1,6 […] In the early stages, pagetic bone appears as lytic lesions radiographically. As osteoblasts form new bone, the lesions then become progressively sclerosed and deformed.

• #2 Paget’s disease of bone: when and why to refer to specialist care | British Journal of General Practice

  https://bjgp.org/content/70/700/561

  Pagets disease of bone (PDB) is caused by increased osteoclast activity that is coupled with increased, but disorganised, bone formation, causing the affected bones to become deformed and more susceptible to fracture. […] Pagets disease has a strong genetic component and particularly targets people of British descent. […] Emerging evidence indicates that susceptibility to PDB is accounted for, in part, by inheritance of variants in genes that cause upregulation of osteoclast activity. […] Environmental factors also contribute, however, as evidenced by a reduction in prevalence and severity of the disease over the past 50 years. […] Suggested environmental triggers include viral infections and calcium and vitamin deficiency during skeletal growth and skeletal trauma. […] The viral hypothesis has been studied experimentally but the data are conflicting and the role of other environmental factors has not been rigorously studied.

• #2

  https://journals.lww.com/ijoh/fulltext/2020/10010/paget_s_disease_of_bone_with_special_reference_to.7.aspx

  Paget’s disease of bone (PDB) is a relatively common disorder of uncertain etiology. It is characterized by abnormal resorption and apposition of osseous tissue in one or more bones of the skeleton. PDB begins with a period of increased osteoclastic activity and bone resorption, followed by increased osteoblast production of woven bone that is poorly mineralized. In the final phase of the disease process, dense cortical and trabecular bone deposition predominates, but the bone is sclerotic and poorly organized and lacks the structural integrity and strength of normal bone. […] The cause of PDB is currently an area of intensive investigation, with both genetic and environmental factors being implicated in the pathogenesis of this disease. […] Mutations or polymorphisms have been identified in four genes that cause classical Paget’s disease and related syndromes. These include TNFRSF11A, which encodes RANK, TNFRSF11B, which encodes OPG, Valocin containing protein (VCP), which encodes p97, and SQSTM1 which encodes p62. All of these genes play a role in the RANK-NF-B signaling pathway and it is likely that the mutations predispose to PDB by disrupting normal signaling, leading to osteoclast activation.

• #2 Pathogenesis and management of Paget’s disease of bone. | SOGACOT – Sociedad Gallega de Cirugía Ortopédica y Traumatología

  https://sogacot.org/articulos/pathogenesis-and-management-of-pagets-disease-of-bone/

  Paget’s disease of bone is a common disease characterised by focal areas of increased bone turnover, affecting one or several bones throughout the skeleton. […] Genetic factors have an important role in this disease, and mutations have been identified in four genes that cause Paget’s disease and related syndromes. The most important of these is Sequestosome 1 (SQSTM1), which is a scaffold protein in the nuclear factor kappaB (NFkappaB) signalling pathway. Patients with SQSTM1 mutations have severe Paget’s disease of bone and a high degree of penetrance with increasing age. […] Environmental factors also contribute. Most research has focused on paramyxovirus infection as a possible trigger, but evidence for this notion is conflicting. Other potential triggers include deficiency of dietary calcium and repetitive mechanical loading of the skeleton.

• #2 Paget Disease of Bone – Musculoskeletal and Connective Tissue Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/paget-disease-of-bone/paget-disease-of-bone

  About 10% of patients with Paget disease have mutations of the SQSTM1 (sequestosome-1) gene, resulting in increased nuclear factor kappa-B activity, which increases osteoclast activity. […] Several other mutations associated with Paget disease have been identified, many affecting the RANK (receptor activator of nuclear factor kappa-B) signaling pathway that is critical for osteoclast generation and activity. […] A viral etiology, such as measles, has been proposed because nuclear inclusions in diseased osteoclasts that are similar to those seen in paramyxovirus-infected cells have been seen on electron microscopy. […] Although a viral cause remains controversial, it is hypothesized that in genetically predisposed patients an as yet unidentified virus triggers abnormal osteoclast activity.

• #2 Paget’s disease of bone | The Medical Journal of Australia

  https://www.mja.com.au/journal/2004/181/5/pagets-disease-bone

  Mutations in the SQSTM1/p62 gene are therefore a plausible cause of Pagets disease, but it is unclear how germline DNA mutations (present in every osteoclast) cause bone disease that is focal in nature. […] Environmental factors may also play a role. Several studies have postulated that viruses, particularly paramyxoviruses such as canine distemper or measles virus, play a role in pathogenesis, but definitive evidence for this is lacking. […] Presumably, the declining incidence of Pagets disease reflects a decline in one or more as yet unidentified environmental influences.

• #2

  https://www.omim.org/entry/167250

  The frequency of occurrence of inclusions in osteoclasts and in their individual nuclei correlated with the histologic severity of the disease process. The similarity of the inclusions to paramyxovirus inclusion bodies (particularly those of measles) supported, in the view of the authors, the hypothesis that Paget disease is a slow virus infection. […] Concentration of cases in Lancashire, England (Barker et al., 1980) and in Australia (Gardner et al., 1978) suggests an important environmental factor in etiology. […] Cody et al. (1997) noted similarities between Paget disease and familial expansile osteolysis (FEO; 174810). The histologic bone lesions of FEO appeared to be similar to pagetic lesions, although they occurred at a much earlier age and were more severe. Furthermore, as in Paget disease, the osteoclasts in patients with FEO contain paramyxoviral-like nuclear inclusions. Cody et al. (1997) reviewed the evidence suggesting a viral etiology of Paget disease.

• #2 Sporadic Paget’s disease of the bone. Case series and literature review | Revista Colombiana de Reumatología (English Edition)

  https://www.elsevier.es/en-revista-revista-colombiana-reumatologia-english-edition–474-articulo-sporadic-paget-s-disease-bone-case-S2444440520300455

  The mechanism responsible for the development of the disease is not clear either. It has been considered that factors such as mechanical stress is a potential cause for bone lesions, and hence its predominant presentation in the axial skeleton and lower extremities. […] Some environmental factors have been described as potential triggers of PD. Observational studies and hypothesis include: low calcium and vitamin D intake during childhood, occupational exposure to toxins, zoonotic and viral infections, of which the most broadly studied is paramyxovirus infection, particularly the canine virus distemper and measles virus.

• #2 Paget Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/334607-overview

  The development of Paget disease of bone may be related to a deregulation of autophagy, a catabolic process responsible for the degradation of damaged organelles, cytoplasmic proteins, and protein aggregates. […] The cause of Paget disease is unknown. Both genetic and environmental factors have been implicated. […] Osteoclast precursors in patients with Paget disease also appear to be hyperresponsive to vitamin D (specifically, 1,25(OH)2 D3, the active form of vitamin D3) and calcitonin and have up-regulation of the c-fos proto-oncogene and BC12, the antiapoptosis gene. […] The second phase, the mixed phase, is characterized by rapid increases in bone formation from numerous osteoblasts. […] The final phase of Paget disease, the sclerotic phase, bone formation dominates and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone. […] After a variable amount of time, osteoclastic activity may decrease, but abnormal bone formation continues.

• #2

  https://www.omim.org/entry/167250

  A number sign (#) is used with this entry because of evidence that Paget disease of bone-3 (PDB3) is caused by heterozygous mutation in the SQSTM1 gene (601530) on chromosome 5q35. […] Paget disease (PDB) is a metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. […] See 147620 for evidence that interleukin-6 is involved in the hyperplasia and hypertrophy of osteoclasts in Paget disease. […] In addition to the genetic etiology of Paget disease, electron microscopic demonstration of virus-like bodies in bone cells of patients with Paget disease suggests a viral etiology (Mills and Singer, 1976).

• #2

  https://link.springer.com/article/10.1007/s10354-016-0496-4

  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. […] Other investigations of the etiology of Pagets disease have focused on the potential role of chronic paramyxovirus infections contributing to the pathogenesis of the disorder. […] Although the primary cause of these abnormalities in Pagets osteoclasts is still unknown, osteoclasts are abundant in Pagets 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.

• #2

  https://link.springer.com/article/10.1007/s10354-016-0496-4

  Pagetic osteoclasts frequently express the measles virus nucleocapsid protein, 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. […] The early lesions are predominantly lytic and osteoporotic; bone resorption predominates with abnormally large osteoclasts containing multiple pleomorphic nuclei and microfilamentous inclusion bodies. Later, a mixed osteolytic-osteoblastic phase with an abundance of osteoblasts forming new matrix in the form of woven bone occurs, where thickening of the cortex by endosteal and periosteal bone deposition with enlargement of the bones is observed. […] The histological study by Seitz et al. 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. […] Most patients are asymptomatic, whereas some develop complications such as bone pain, osteoarthritis, fracture, deformity, deafness, and nerve compression syndromes.

• #2 Paget’s disease of bone: Report of 11 cases

  https://www.wjgnet.com/2307-8960/full/v9/i14/3478.htm

  Finally, new bone is formed and absorbed repeatedly as the disease progresses, which leads to a disorganized architecture and the production of woven bone. […] A mosaic appearance can be seen in which there is an admixture of woven and lamellar bone. […] In this study, the bone biopsy pathological findings showed typical changes in PDB, such as a mosaic structure in the bone trabeculae with irregular cement lines and multinuclear osteoclasts. […] The diagnosis of PDB is usually made by X-ray and elevated serum ALP levels, particularly in asymptomatic patients. […] The characteristic features on radionuclide bone scintigraphy are osteolysis during the initial stage, followed by osteogenesis and osteosclerosis. […] PDB is prone to misdiagnosis because of its various nonspecific clinical manifestations and rarity in China. […] The treatment for PDB is aimed at suppressing osteoclast activity and reducing bone turnover from a pathophysiological standpoint. […] Bisphosphonates suppress increased bone resorption and decrease serum ALP and are an ideal choice for treating PDB.

• #2 Paget Disease of Bone – Rheumatology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.16.19.

  Paget disease of bone (PDB) is a chronic metabolic bone disease of unknown etiology. Research suggests that mutations in sequestosome 1 increase the susceptibility to the development of PDB, and the potential role of paramyxovirus infection in causing the disease has been studied. PDB is characterized by a disruption in normal osteoclastic bone resorption and osteoblastic bone formation, which leads to disorganized bone remodeling, with vascularized foci of osteopenia interwoven with focal osteosclerosis and secondary myelofibrosis. […] Osteolytic and osteosclerotic lesions usually coexist.

• #2 Frequently Asked Questions – Bone Health & Osteoporosis Foundation

  https://www.bonehealthandosteoporosis.org/pagets/pagets-frequently-asked-questions/

  Alkaline phosphatase is a chemical (enzyme) that is produced by bone cells and is over-produced by pagetic bone. An elevated alkaline phosphatase level indicates abnormal bone cell activity that can suggest Paget’s disease. […] Paget’s disease can cause arthritis by changing bones around joints: (1) Long bones such as in the thigh or leg may become bowed and distort the normal alignment and pressures within the adjacent joints; (2) Pagetic bone may become enlarged, causing the joint surfaces to undergo excessive wear and tear. […] A variety of disturbances of the nervous system can be associated with Paget’s disease of the skull and spinal column. Enlarged pagetic bones can cause pressure on the brain, spinal cord, or nerves. Paget’s disease may cause reduced blood flow to the brain and spinal cord.

Zobacz więcej