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Journal of Bone and Mineral Research :... Dec 2006Paget's disease of bone (PDB) is a common condition with a strong genetic component that is characterized by focal increases in bone turnover, leading to bone deformity,... (Review)
Review
Paget's disease of bone (PDB) is a common condition with a strong genetic component that is characterized by focal increases in bone turnover, leading to bone deformity, pathological fractures, and various other complications. Several rare disorders have also been described that show phenotypic overlap with PDB. Genome-wide searches have identified several susceptibility loci for PDB and PDB-like disorders, and mutations that cause these disorders have now been identified in four genes, all of which are involved in the RANK-NF-kappaB signaling pathway. Mutations in SQSTM1, which encodes an important scaffold protein in this pathway, have been found to be a common cause of classical PDB. Thus far, all disease-causing mutations in SQSTM1 affect the ubiquitin-associated (UBA) domain of the gene product and cause loss of ubiquitin binding. The rare PDB-like disorders of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by duplication mutations in exon 1 of the TNFRSF11A gene, which encodes the RANK receptor. This gene does not seem to be involved in the pathogenesis of classical PDB. Inactivating mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB, and TNFRSF11B polymorphisms seem to increase the risk of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and frontotemporal dementia (IBMPFD) is caused by mutations in the VCP gene, which is involved in regulating I-kappaB degradation by the proteasome. The disease-causing mutations in VCP cluster in and around a domain involved in ubiquitin binding. Whereas SQSTM1 has emerged as an important gene for classical PDB, most kindreds with familial PDB do not carry SQSTM1 mutations, indicating that additional genes for PDB remain to be discovered. In light of the molecular defects that have been identified thus far, it seems likely that these genes will also be involved in the RANK-NF-kappaB signaling pathway or its interactions with the ubiquitin-proteasome system.
Topics: Genetic Predisposition to Disease; Humans; Mutation; Osteitis Deformans
PubMed: 17229006
DOI: 10.1359/jbmr.06s206 -
Journal of Bone and Mineral Research :... Dec 2006
Review
Topics: Humans; Hyperparathyroidism; Osteitis Deformans
PubMed: 17229012
DOI: 10.1359/jbmr.06s213 -
Journal of Bone and Mineral Research :... Oct 1999One of the most serious complications of Paget's disease is a significant increase in the incidence of osteosarcoma. Approximately 1% of Paget's patients develop... (Review)
Review
One of the most serious complications of Paget's disease is a significant increase in the incidence of osteosarcoma. Approximately 1% of Paget's patients develop osteosarcoma, an increase in risk that is several thousand-fold higher than the general population. This risk contributes significantly to the mortality and morbidity of Paget's disease patients. We examined several cases of pagetic and sporadic osteosarcoma for tumor-specific loss of constitutional heterozygosity (LoH) on chromosome 18q. Our analysis found that both pagetic and sporadic osteosarcoma tumors showed LoH for all or part of the distal portion of chromosome 18q. The pattern of LoH in both types of tumors identified a region between loci D18S60 and D18S42 that must contain the putative tumor suppressor locus. This region is tightly linked to familial Paget disease and familial expansile osteolysis (FEO). Our hypothesis is that the predisposition locus for Paget's disease and the tumor suppressor locus for osteosarcoma are either the same gene or that osteosarcoma in Paget's disease represents a deletion affecting two adjacent genes. In either model, localization of the osteosarcoma tumor suppressor gene would be of benefit in the eventual isolation of the predisposition locus for Paget's disease. We have begun to isolate and test candidate genes from within the region defined by both the familial Paget's disease families and the minimal region of LoH in osteosarcomas for evidence that one or more of them is responsible for predisposition to Paget's disease and/or osteosarcoma.
Topics: Bone Neoplasms; Chromosome Mapping; Humans; Osteitis Deformans; Osteosarcoma
PubMed: 10510212
DOI: 10.1002/jbmr.5650140209 -
Annals of the Royal College of Surgeons... Dec 1956
Topics: Osteitis Deformans
PubMed: 13382108
DOI: No ID Found -
Journal of Bone and Mineral Research :... Dec 2006
Review
Topics: Humans; Osteitis Deformans; Osteoblasts; Osteoclasts; Osteocytes
PubMed: 17229009
DOI: 10.1359/jbmr.06s209 -
Journal of Orthopaedics and... Mar 2021Total hip arthroplasty (THA) in patients with Paget's disease can be associated with technical difficulties related to deformities and altered mechanical bone... (Observational Study)
Observational Study
Clinical and radiological outcomes of total hip arthroplasty in patients affected by Paget's disease: a combined registry and single-institution retrospective observational study.
BACKGROUND
Total hip arthroplasty (THA) in patients with Paget's disease can be associated with technical difficulties related to deformities and altered mechanical bone properties, and hypervascularity leads to significative intra-operative bleeding. The purpose of this registry and single-institution study was to investigate overall survival and causes of failure of THA in pagetic patients, together with an analysis of the clinical and radiological complications.
MATERIAL AND METHODS
Registry-based survival and complication analysis, type of fixation, intra- and post-operative complications, clinical (pharmacological history, blood transfusions, Harris hip score [HHS]) and radiographic (cup orientation, stem axial alignment, osteolysis around the cup and the stem and heterotopic ossification [HO]) data were reviewed.
RESULTS
In total, 66 patients (27 males and 39 females, mean age at surgery 71.1 years for males and 74.8 years for female) from the registry study presented a 10-year survival of 89.5%. In the institutional study, involving 26 patients (14 males and 12 females, 69 years average) and 29 THAs, hip function improved significantly. Average cup orientation was 40.5°, while varus stem alignment was 13.8%. In total, 52% of hips had heterotopic ossifications. Peri-acetabular osteolysis was in 13.8% of implants and in 45% of hips was found around the stem. Allogenic and autologous blood transfusion rate were 68.2% and 31.8%, respectively, with an average transfusion of 2 units of blood (range 1-6 units). HHS improved by an average of 34 points, with excellent result in 64.3% of patients. Two implants failed, one due to traumatic ceramic head fracture 64 months after surgery, and one due to mobilization of the cup on the second post-operative day.
CONCLUSION
THA surgery in Paget's patients is a safe procedure, and implant survival is only partly affected by bone remodelling and choice of fixation. The post-operative functional outcome is largely similar to that of other patients. Bleeding-related complications are the main complications; a careful pharmacological strategy should be recommended to decrease the risk of transfusions and of HO development.
LEVEL OF EVIDENCE
Level III.
Topics: Acetabulum; Aged; Arthroplasty, Replacement, Hip; Female; Hip Joint; Hip Prosthesis; Humans; Male; Osteitis Deformans; Postoperative Complications; Prosthesis Failure; Radiography; Registries; Retrospective Studies
PubMed: 33733386
DOI: 10.1186/s10195-021-00574-y -
The American Journal of Medicine Oct 1996
Topics: Alendronate; Female; Humans; Male; Middle Aged; Osteitis Deformans
PubMed: 8873502
DOI: 10.1016/S0002-9343(97)89432-6 -
Biochimica Et Biophysica Acta Dec 2008Inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) and frontotemporal dementia (FTD) (now called IBMPFD), is a progressive autosomal dominant... (Review)
Review
Inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) and frontotemporal dementia (FTD) (now called IBMPFD), is a progressive autosomal dominant disorder that was recently identified as being caused by mutations in the VCP (p97 or CDC48) gene which plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retro translocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. Approximately 90% of the affected persons in the study have myopathy or muscle weakness particularly of the shoulder and hip girdles, which can lead to loss of walking ability and even death by complications of respiratory and cardiac failure. About half of affected study participants have Paget disease of bone characterized by abnormal rates of bone growth that can result in bone pain, enlargement and fractures. Findings of premature FTD affecting behavior and personality are seen in a third of affected individuals. Within 20 IBMPFD families whose data was analyzed for this study, ten missense mutations have been identified, the majority of which are located in the N-terminal ubiquitin binding domain. Inclusions seen in the muscle, brain and heart in VCP disease contain ubiquitin, beta amyloid and TDP-43, also seen in other neurodegenerative disorders thus implicating common pathways in their pathogenesis.
Topics: Adenosine Triphosphatases; Cell Cycle Proteins; Dementia; Frontal Lobe; Genetic Predisposition to Disease; Humans; Muscular Diseases; Mutation; Osteitis Deformans; Valosin Containing Protein
PubMed: 18845250
DOI: 10.1016/j.bbadis.2008.09.003 -
Journal of Bone and Mineral Research :... May 2004The RANK-RANKL-OPG system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's... (Review)
Review
Loss of chaotic trabecular structure in OPG-deficient juvenile Paget's disease patients indicates a chaogenic role for OPG in nonlinear pattern formation of trabecular bone.
The RANK-RANKL-OPG system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's disease patients deficient in functional OPG shows parallel, anisotropic structure instead of normal chaotic structure. Evidence from experimental systems suggests that RANK-RANKL-OPG controls key nonlinear "chaogenic" parameters, such as friction, forcing frequency, feedback, and boundary forcing. The RANK-RANKL-osteoprotegerin (OPG) system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's disease (JPD) patients deficient in functional OPG shows parallel, anisotropic structure instead of normal chaotic structure. Evidence from experimental systems suggests that RANK-RANKL-OPG controls key nonlinear "chaogenic" parameters, such as friction, forcing frequency, feedback, and boundary forcing. The Belousov-Zhabotinsky reaction-diffusion system, the catalytic oxidation of CO on platinum surfaces, and thermal diffusion in liquid helium allow visualization of nonlinear emergent patterns such as labyrinthine structures, turbulence, and cellular structures, all of which bear some resemblance to trabecular bone. In JPD, the gene for OPG (TNFRSF11B) is subject to an inactivating mutation, leading to increased resorption and accelerated remodeling. Histomorphometric images of iliac crest trabecular bone from teenagers suffering from JPD show a highly unusual array of parallel, regular trabecular plates, instead of the typical chaotic, fractal patterns of normal trabecular bone. Loss of OPG function is associated with a change from chaotic to regular structure, suggesting that the RANK-RANKL-OPG system is controlling key nonlinear "chaogenic" parameters. Looking at trabecular bone from the perspective of nonlinear pattern formation may help understand other phenomena, such as the marked dependence of trabecular bone's architectural and mechanical quality on remodeling rate independent of the trabecular bone mass.
Topics: Adolescent; Bone Remodeling; Bone and Bones; Glycoproteins; Humans; Osteitis Deformans; Osteoclasts; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor
PubMed: 15068491
DOI: 10.1359/JBMR.040210 -
Acta Bio-medica : Atenei Parmensis Dec 2022Paget's disease (PDB) is a chronic osteopathy more common in male, Caucasic, European population, after the age of 50 years, that can lead to bone deformities. A... (Review)
Review
Paget's disease (PDB) is a chronic osteopathy more common in male, Caucasic, European population, after the age of 50 years, that can lead to bone deformities. A challenging surgical solution for affected hip with severe hip osteoarthritis is total hip replacement (THA). We describe a case of THA in a 71-year-old patient with PDB and we present a literature review. In particular we find out that more studies comparing cementless THA with cemented one are necessary, in order to understand if one implant is better than the other.
Topics: Male; Humans; Middle Aged; Aged; Arthroplasty, Replacement, Hip; Osteoarthritis, Hip; Osteitis Deformans; Hip Prosthesis
PubMed: 36533759
DOI: 10.23750/abm.v93i6.13426