Archaeological skeletons support a northwest European origin for Paget's disease of bone

Mays, Simon

doi:10.1002/jbmr.64

Cited by 58 publications

(24 citation statements)

References 10 publications

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“…Conversely, PDB is rare in Scandinavia, the Indian subcontinent, China, Japan, and other countries in the Far East [9]. These observations are consistent with recent archeological studies that have indicated that PDB most probably originated in Britain and spread to other parts of the world as the result of migration and genetic admixture [10]. Genetic studies in patients with the P392L mutation of SQSTM1 (the most common causal mutation of PDB, see later) also support this hypothesis in demonstrating that most patients who carry this mutation do so on a shared ancestral haplotype [11,12].…”

supporting

confidence: 85%

Pathogenesis of Paget Disease of Bone

2012

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Paget disease of bone (PDB) is a common disease characterized by focal areas of increased and disorganized bone turnover. Some patients are asymptomatic, whereas others develop complications such as pain, osteoarthritis, fracture, deformity, deafness, and nerve compression syndromes. 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. 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.

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supporting

confidence: 85%

Pathogenesis of Paget Disease of Bone

2012

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“…Subsequently investigators have highlighted that the same mutation is often present on a conserved haplotype, which is consistent with a stable genetic change occurred in the affected population (16). This observation of a founder effect perfectly matches the epidemiology of Paget's disease (17), but only in the case of the SQSTM1 mutation. In Europe, Australia, and the United States, comparable rates of SQSTM1 mutation have been reported in or around the ubiquitin-associated domain.…”

mentioning

confidence: 65%

Paget’s disease

et al. 2014

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Paget’s disease of bone is the most common metabolic bone disease after osteoporosis and affects 2-4% of adults over 55 years of age. Its etiology is only partly understood and includes both genetic and environmental factors. The disease may be asymptomatic and can be uncovered incidentally on x-ray or in biochemical tests performed for another condition. It can also manifest itself with bone pain, deformity, fracture or other complications. Paget’s disease is diagnosed by x-rays and in general has very typical radiological features, but occasionally the clinical picture may be unusual and a differential diagnosis of sclerotic or lytic metastases needs to be considered. Plasma total alkaline phosphatase activity is the most clinically useful indicator of disease activity. It is elevated in most untreated patients, but may be within the normal range in patients with monostotic or limited disease. Bisphosphonate therapy is indicated for patients with symptoms and should also be considered in patients with disease sites that suggest a risk of complications, such as long bones, vertebrae or base of the skull. Orthopedic surgery in Paget’s disease patients includes almost exclusively the correction of fractures and arthroplasty.

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“…Archeological studies of skeletal remains suggest that these differences in prevalence could be consistent with PDB having arisen as the result of genetic mutations that predispose to the disease in people from North-West Europe many centuries ago, with spread to other regions of the world through emigration. (4) At a cellular level, PDB is characterized by increased numbers and activity of osteoclasts coupled with an increase in osteoblast activity. (5) Bone formation is increased but disorganized, with formation of woven bone, which is mechanically weak and subject to deformity and fracture.…”

Section: Introductionmentioning

confidence: 99%

Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline

Ralston

Corral‐Gudino

Cooper

et al. 2019

Journal of Bone and Mineral Research

132

169

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An evidence based clinical guideline for the diagnosis and management of Paget’s disease of Bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget’s Association (UK). A systematic review of diagnostic tests, pharmacological and non-pharmacological treatment options was conducted which sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made but there was insufficient evidence to address eight of the questions posed. The following recommendations were identified as the most important. Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of the metabolically active disease in patients with PDB.Serum total alkaline phosphatase (ALP) is recommended as a first line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB.Bisphosphonates are recommended for the treatment of bone pain associated with Paget’s disease. Zoledronic acid is recommended as the bisphosphonate most likely to give a favourable pain response.Treatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalising total ALP in PDB.Total hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical approach over another. The guideline was endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone research Society (UK) and the British Geriatric Society. The GDG noted that there had been a lack of research on patient-focused clinical outcomes in PDB and identified several areas where further research was needed.

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Archaeological skeletons support a northwest European origin for Paget's disease of bone

Cited by 58 publications

References 10 publications

Pathogenesis of Paget Disease of Bone

Pathogenesis of Paget Disease of Bone

Paget’s disease

Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline

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