[Paget's disease of bone: 1877-2023. Etiology, and management of a disease on epidemiologic transition]. / Enfermedad ósea de Paget: 1877-2023. Etiología y abordaje de una enfermedad en transición epidemiológica.

Paget's disease of bone is characterized by the alteration, in one or several bone locations, of the equilibrium between bone formation and bone resorption. This imbalance results in a disorganized, widened bone, in many cases with increased bone density, although more fragile. A genetic predisposition for Paget's disease of bone could explain between 5% and 40% of the cases. Different environmental factors should explain the rest of the cases. Paget's disease of bone was classically considered the second most common metabolic bone disease. However, in recent decades there has been a marked decrease in both incidence and clinical severity. These changes have led to believe that the influence of some environmental factor may have diminished or even disappeared. This decrease in incidence should not be an excuse for abandoning Paget's disease of bone research, but rather it should be the reason to remain searching to try to understand better its pathogenesis.

Paget disease of bone in an elderly patient with chronic renal disease and weight loss: A case report.

RATIONALE: Asymptomatic Paget disease of bone (PDB) is mostly diagnosed by accidental finding of osteolytic lesion on the plain film. However, in elderly patient with chronic renal insufficiency and weight loss, it is crucial to differentiate PDB from metabolic and metastatic bone diseases for further treatment and better outcome. PATIENT CONCERNS: An 80-year-old man with chronic kidney disease presented to our emergency department due to fever with chillness for a day, while the abdominal fullness, anorexia, and weight loss had been noted for 3 months. Mixed osteoblastic and lytic changes in the pelvic bone were accidentally found on the abdominal plain film. DIAGNOSIS: The patient was diagnosed as asymptomatic PDB and urinary tract infection of Pseudomonas aeruginosa. INTERVENTIONS AND OUTCOME: The patient received 7 days intravenous and followed by 7 days oral antibiotic treatment, which lead to clinical improvement of his urinary tract infection. No pharmacological treatment was initiated for the asymptomatic and localized PDB. The patient was discharged under stable condition afterward. LESSONS: In patients with mixed osteolytic and blastic lesions, the differential diagnoses include metabolic and metastatic bone disease. Thorough understanding of the morphology of the bone lesions in high risk patient, not only helps to make differential diagnosis, but it also leads to precise treatment and better outcome.

Gene-environment interactions in Paget's disease of bone.

OBJECTIVES: This study explored the role of outdoor and indoor air pollutants in Paget's disease of bone (PDB). METHODS: We performed a survey in 140 French-Canadian patients with PDB, including 39 carriers of p.Pro392Leu mutation (SQSTM1 gene) and 113 healthy not mutated controls. The survey covered outdoor air pollution near the residence and indoor air pollutants by focusing on heating fuels and exposure to tobacco smoke. In a subgroup of patients, urinary concentrations of 17 heavy metals and 11 polycyclic aromatic hydrocarbons were measured by mass spectrometry. In light of what we learned from the survey and urinary assays, we explored the in vitro effects of certain toxics on osteoclasts in PDB. We conducted in vitro monocytes differentiation from peripheral blood of more than 40 participants, whose osteoclasts were treated with or without the toxic. The morphology of osteoclasts, their bone resorption abilities, gene and protein expression levels, and cellular oxidative stress levels were assayed. RESULTS: An inhibitory effect of cigarette smoke condensate and heavy metals was observed on morphology and bone resorption activity of patients' osteoclasts. SQSTM1 gene expression was upregulated in osteoclasts from patients with PDB versus healthy controls in presence of cadmium, and SQSTM1 protein expression was upregulated in presence of bismuth and tobacco smoke condensates, in particular in osteoclasts from carriers of the SQSTM1 mutation. Furthermore, high levels of oxidative stress in patients' osteoclasts were observed. CONCLUSIONS: Our in vitro experiments suggest an interaction between SQSTM1 gene and exposure to cadmium and tobacco smoke condensates.

Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy.

p97 is a "segregase" that plays a key role in numerous ubiquitin (Ub)-dependent pathways such as ER-associated degradation. It has been hypothesized that p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the fundamental basis for this activity. To address this issue, we developed a soluble p97 substrate-Ub-GFP modified with K48-linked ubiquitin chains-for in vitro p97 activity assays. We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. Furthermore, we show that a p97 mutant that causes inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia in humans unfolds substrate faster, suggesting that excess activity may underlie pathogenesis. This work overcomes a significant barrier in the study of p97 and will allow the future dissection of p97 mechanism at a level of detail previously unattainable.

Paget Disease of Bone.

The current understanding of Paget disease of bone (PDB) has vastly changed since Paget described the first case in 1877. Medical management of this condition remains the mainstay of treatment. Surgical intervention is usually only used in fractures through pagetic bone, need for realignment to correct deformity in major long bones, prophylactic treatment of impending fractures, joint arthroplasty in severe arthritis, or spinal decompression in cases of bony compression of neural elements. Advances in surgical technique have allowed early return to function and mobilization. Despite medical and surgical intervention, a small subset of patients with PDB develops Paget sarcoma.

Diagnosis and management of Paget?s disease of bone / Diagnóstico e tratamento da doença de Paget óssea

Objective: To conduct a literature review on the diagnosis and management of Paget’s disease of bone. Materials and methods: This scientific statement was generated by a request from the Brazilian Medical Association (AMB) to the Brazilian Society of Endocrinology and Metabolism (SBEM) as part of its Clinical Practice Guidelines program. Articles were identified by searching in PubMed and Cochrane databases as well as abstracts presented at the Endocrine Society, Brazilian Society for Endocrinology Annual Meetings and the American Society for Bone and Mineral Research Annual Meeting during the last 5 years. Grading quality of evidence and strength of recommendation were adapted from the first report of the Oxford Centre for Evidence-based Medicine. All grades of recommendation, including “D”, are based on scientific evidence. The differences between A, B, C and D, are due exclusively to the methods employed in generating evidence. Conclusion: We present a scientific statement on Paget’s disease of bone providing the level of evidence and the degree of recommendation regarding causes, clinical presentation as well as surgical and medical treatment. Arq Bras Endocrinol Metab. 2014;58(6):587-99 .

Objetivo: Conduzir uma atualização das últimas evidências científicas a respeito da apresentação, diagnóstico e manejo clínico da doença de Paget óssea. Materiais e métodos: Este documento foi concebido pelo Departamento de Metabolismo Ósseo da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) a partir daquele oriundo do Programa de Diretrizes da Associação Médica Brasileira (AMB). Realizamos uma revisão dos artigos mais relevantes obtidos nos bancos de dados PubMed e Cochrane, além de abstracts apresentados nos encontros anuais da Endocrine Society, Sociedade Brasileira de Endocrinologia e da American Society for Bone and Mineral Research dos últimos cinco anos e classificamos as evidências em níveis de recomendações de acordo com a força científica por tipo de estudo, adaptando o primeiro relato do “Oxford Centre for Evidence-based Medicine”. Todos os graus de recomendação, incluindo-se o “D”, foram baseados em evidência científica, sendo as diferenças entre o A, B, C e D devidas exclusivamente ao desenho empregado na geração da evidência. Conclusão: Apresentamos uma atualização científica a respeito da doença de Paget óssea, classificando e graduando em níveis de recomendações as principais evidências científicas sobre as suas causas, as variadas formas de apresentação, seu diagnóstico e tratamento. .

Paget's disease.

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.

Paget's disease of bone.

Paget's disease of bone is a common disorder characterized by increased but disorganized bone remodelling. Some patients are asymptomatic but others present with bone pain or other complications such as fracture and deformity. Major advances have been made in understanding the pathophysiology of Paget's disease in recent years and highly effective agents are now available with which to suppress the abnormal bone turnover that causes the disease. Here we review recent advances in the epidemiology, pathogenesis, clinical features and management of Paget's disease. We also reflect upon the future challenges that remain to be overcome to explain the unusual distribution of the disease and to favourably alter the natural history and prevent the development of complications.

Estrías angioides y tumor hipofisario: ¿asociación o hallazgo incidental? / Angioid streaks and pituitary tumor: ¿association or incidental finding?

Las estrias angioides de la retina se aprecian como líneas dentelladas rosadas u oscuras radiando irregularmente en todas direcciones desde el área peripapilar hacia la periferia de la retina. Corresponden a roturas del componente elástico de la membrana de Bruch. Su presencia indica una enfermedad sistémica siendo las más importantes el pseudoxantoma elástico, la enfermedad de Paget ósea y la drepanocitosis, Los tumores hipofisiarios raramente se han asociado a está condición existiendo apenas tres descriptores en la literatura. A estas adicionamos tres pacientes más, no obstante, aun no puede asegurarse si se trata de una asociación o de un simple hallazgo incidental.

Retinal angioid streaks can be seen as rough lines pink or dark, irregularly radiating in all directions from the peripapilar area to the periphery of the retina. They correspond of breaks in the elastic component of the Bruch membrane. Its presence indicates a systemic disease being the most important pseudoxanthoma elasticum, bone Paget's disease and sickle cell disease. Pituitary tumors have rarely been associated with this condition and exist just three descriptions in the literature. To these we add three more patients, however, still not be tightened if it's an association or a simple incidental finding.

Cytokine profiling in patients with VCP-associated disease.

Valosin containing protein (VCP) disease (also known as Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia [IBMPFD] syndrome) is caused by mutations in the gene encoding VCP classically affecting the muscle, bone and brain. Although the genetic cause has been identified, details regarding the pathogenesis of IBMPFD have not been fully determined. Muscle wasting observed in VCP disease is suggestive of cytokine imbalance. We hypothesized that dysfunctional protein homeostasis caused by VCP mutations leads to cytokine imbalances thereby contributing to the muscle wasting phenotype. Circulating levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF a) and epidermal growth factor (EGF) were measured in plasma of patients with VCP disease or controls. TNF a and EGF were significantly altered in VCP disease as compared to control. TNF a was up-regulated, consistent with a cachexia phenotype and EGF levels were increased. No significant differences were observed in IL-4 and IL-6. Cytokine imbalances may be associated with VCP disease and may play a contributory role in VCP myopathy. Further understanding of how VCP dysfunction leads to aberrant protein homeostasis and subsequent cytokine imbalances may also aid in the understanding of other proteinopathies and in the development of novel treatments.

[Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia].

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disease caused by mutations in the VCP gene. VCP encodes a well-conserved multifunctional protein, valosin containing protein (VCP), which has important roles in protein quality control via proteasome and autophagy, protein aggregation, quality control of mitochondria, cell proliferation, and so on. Clinically, muscle weakness is the most common symptom of which disease onset is around 40 years. Affected muscles are variable, and the patients are sometimes diagnosed as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows characteristic features including cytoplasmic/nuclear inclusions, rimmed vacuoles, and disorganized myofibrills, together with neurogenic changes. Paget's disease of bone is reported to be observed in a half of the patients around the age of 40 years, but less common in Japanese patients. Frontotemporal dementia is seen around one third of the patients which appears nearly 10 years later than muscle or bone disease. In addition to cognitive dysfunctions, motor neuron involvement and cerebellar signs were also seen in our series. IBMPFD is not so rare disease as previously thought, but complicate clinical findings may make its diagnosis difficult.

[Paget's disease of bone: new therapeutic strategies]. / La malattia di Paget: a proposito di nuove strategie terapeutiche.

Paget's disease of bone is a chronic disorder of unknown etiology that can result in enlarged and misshapen bones. The excessive breakdown and formation of bone tissue cause affected bones to weaken, resulting in pain, misshapen bones, fractures, and arthritis in the joints. In most cases the diagnosis is achieved casually, as only 5% of patients develop burning pain at the level of affected bones. As regards therapy, the use of anti-reabsorbing drugs, such as bisphosphonates and calcitonin, appears reasonable. Given the disease pathogenesis, the administration of denosumab and tocilizumab may be a valuable alternative to inhibit RANK expression, and thus osteoclast formation, and interleukin-6 production.

Pathogenesis of Paget disease of bone.

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.

[Paget's disease: clinical update]. / A Paget-kór aktuális kérdései.

Paget's disease is a chronic disorder of bone remodeling, characterized by an abnormal increase of osteoclast and, hence, osteoblast activity. The imbalance of bone turnover results in the formation of unhealthy and fragile bone. It also leads to impairment of adjacent joints and to a risk of various complications. Current research focuses on the elucidation of the etiologic role viral infection and predisposing genetic factors. Paget's disease is commonly discovered by chance; its suspicion is raised either by high level of alkaline phosphatase or by the X-ray of the pathological bone. Bisphosphonates have proven to be effective in controlling disease activity because they inhibit osteoclast function. Their use is recommended when bone-derived serum alkaline phosphatase is high and/or when disease localizations are highly suspected for the development of complications.

Paget's disease of bone and calcium homeostasis: focus on bisphosphonate treatment.

Paget's disease of bone (PDB) is the second most common metabolic bone disease. Bisphosphonates (BPs) are currently the drugs of choice for PDB. PDB and osteomalacia are both common in the elderly. The concept of relative vitamin D deficiency in patients with PDB was suggested long ago, but it has not yet elucidated. Both diseases predispose to fractures, but their combined action to fragility has not been studied yet. The older BPs, mainly etidronate, further inhibit bone mineralization. Mineralization defects have also been described in patients with PDB treated with pamidronate. Moreover, hypocalcemia and secondary hyperparathyroidism after treatment with BPs have been described in PDB. Hypocalcemia seems to be more severe after treatment with the more potent, intravenous zoledronic acid, which is currently the treatment of choice for PDB. The counteracting hyperparathyroidism pathophysiologically intends to increase renal reabsorption of calcium and 1.25-dihydroxy vitamin D production and to stimulate osteoclasts in order to prevent long-term hypocalcemia. However, the effect of PTH on osteoclasts is, at least partly, restricted in patients taking BPs. Secondary hyperparathyroidism is a potentially detrimental condition, especially in patients already suffering from another bone disease. Serum calcium and vitamin D deficiency should be restored before BP treatment and calcium and vitamin D administration should be possibly continued for longer after achieving normocalcemia, which may shorten the duration of secondary hyperparathyroidism. QUICK SUMMARY: Mineralization defects and hypocalcemia with secondary hyperparathyroidism have been described in patients with Paget's disease of bone treated with bisphosphonates. Secondary hyperparathyroidism may be a potentially detrimental condition for patients with Paget's disease of bone.

Synchronous Paget disease of bone and hyperparathyroidism: report of a case with extensive craniofacial involvement.

Paget disease of bone (PDB) and hyperparathyroidism (HPT) are metabolic osseous disorders which affect ≥2% of the population. As these diseases may share clinical, radiographic, biochemical, and histopathologic features, knowledge of their phenotypic overlap may provide diagnostic utility and improve clinical outcome. Scant information is available in the dental literature regarding patients concurrently affected with both pathologies. We present an unusual case report of a 63-year-old woman coaffected with primary HPT, attributed to a functional oxyphilic parathyroid adenoma, and PDB. Bone scintigraphy revealed pagetoid lesions of the skull, humeral head, spine, sacrum, and hemipelvis. Salient craniofacial features noted were bony involvement of the calvarium and midface, resulting in extensive maxillary overgrowth, hearing loss, telecanthus and consequent visual impairment, nasal deformity, and leontiasis ossea. The patient underwent a partial parathyroidectomy and bisphosphonate administration was to be initiated upon extraction of the remaining dentition.

Insights into the pathogenesis of Paget's disease.

Paget's disease (PD) affects approximately 1.5 million persons in the United States and is characterized by grossly distorted bone remodeling, with increases in bone resorption and formation. Both environmental and genetic factors may contribute to the pathogenesis of PD. Mutations in sequestosome-1 (p62) occur in 25-30% of patients with familial PD, and in approximately 10% of patients with sporadic PD. Preclinical studies suggest that the p62(P392L) mutation predisposes patients to developing PD rather than causing it. Other studies have suggested that PD results from a chronic paramyxoviral infection. Transgenic mice expressing the measles virus nucleocapsid gene (MVNP) in osteoclasts (OCLs) develop pagetic bone lesions. Further, approximately 70% of patients harboring the p62(P392L) mutation we studied have detectable MVNP transcripts, and inhibiting MVNP expression in bone marrow cultures from those patients blocked pagetic OCL formation. These studies suggest that both genetic and environmental factors contribute to PD.

Dickkopf-1 as a potential therapeutic target in Paget's disease of bone.

IMPORTANCE OF THE FIELD: Wnt signalling plays a role in maintaining healthy bone mass. Dickkopf-1 (DKK-1) is a soluble inhibitor of Wnt signalling and its excessive expression contributes to bone loss in rheumatoid arthritis and multiple myeloma. New therapeutics have been developed for treatment of these conditions that target DKK-1 expression. DKK-1 is elevated in serum of patients with Paget's disease of the bone (PDB) and evidence is accumulating for a role of DKK-1 in PDB. AREAS COVERED IN THIS REVIEW: The role of Wnt signalling and DKK-1 in bone health and disease and the aetiology of PDB in the light of recent advances in understanding of Wnt signalling. WHAT THE READER WILL GAIN: PDB is a disorder of unknown aetiology characterised by localised increase in unregulated bone remodelling resulting in osteolytic and osteosclerotic lesions. Evidence is adduced for the involvement of Wnt signalling, DKK-1 and osteoblasts in PDB pathogenesis. TAKE HOME MESSAGE: At present there is no cure for PDB and the current treatment of choice are bisphosphonates. These treat the resorptive phase of PDB but do not prevent its return. We present a new perspective on the aetiology of PDB and speculate on DKK-1 as a therapeutic target.