RESUMO
Pathogenic variants in valosin-containing protein (VCP) cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature: ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts, and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified 4 compounds that activate VCP primarily by increasing D2 ATPase activity, where pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that impaired nuclear proteostasis may contribute to MSP, and that VCP activation may be a potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.
Assuntos
Proteínas de Ligação a DNA , Miosite de Corpos de Inclusão , Proteostase , Proteína com Valosina , Animais , Humanos , Camundongos , Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/tratamento farmacológico , Corpos de Inclusão Intranuclear/metabolismo , Corpos de Inclusão Intranuclear/patologia , Corpos de Inclusão Intranuclear/genética , Miosite de Corpos de Inclusão/metabolismo , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/tratamento farmacológico , Osteíte Deformante/metabolismo , Osteíte Deformante/genética , Osteíte Deformante/patologia , Osteíte Deformante/tratamento farmacológico , Agregados Proteicos/efeitos dos fármacos , Proteinopatias TDP-43/metabolismo , Proteinopatias TDP-43/patologia , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/tratamento farmacológico , Proteína com Valosina/metabolismo , Proteína com Valosina/genéticaRESUMO
PURPOSE: The aims of the current study were to describe clinical and biochemical features of patients with Paget disease of bone (PDB) followed at our medical center, and to examine the long-term effectiveness of zoledronate. METHODS: Retrospective cohort study included consecutive patients≥18 years with a diagnosis of PDB, followed in the Rabin Medical Center (RMC) Institute of Endocrinology from 1973 to 2023. The cohort comprised two groups: patients treated/not treated with zoledronic acid (ZOL/NZOL). The primary outcome was the percentage of patients who achieved a biochemical therapeutic response. RESULTS: Overall, 101 patients with PDB were included, 68 in the ZOL group and 33 in the NZOL group. The mean age was 65.2 ± 10.0 years, and 47% were female. Notably, 77% exhibited monostotic involvement, and only 3% had experienced fractures attributed to PDB. Mean ALP level at diagnosis was 160 ± 70.6 U/L. The median follow-up duration was 17 years since PDB diagnosis, comparable between the groups. Primary outcome was more prevalent in the ZOL compared to the NZOL group [42 patients (88%) VS 11 patients (52%) respectively, P = 0.004]. At the end of follow-up, mean ALP levels in the NZOL group were significantly higher than the levels in the ZOL group irrespective of the number of infusions received. CONCLUSION: The majority of patients with PDB experience a mild disease course, marked by monostotic involvement and a low prevalence of fractures. Zoledronic acid effectively manages PDB, providing sustained biochemical response. The necessity for multiple zoledronic acid injections remains questionable, often implemented due to osteoporosis.
Assuntos
Conservadores da Densidade Óssea , Osteíte Deformante , Ácido Zoledrônico , Humanos , Ácido Zoledrônico/uso terapêutico , Osteíte Deformante/tratamento farmacológico , Feminino , Masculino , Estudos Retrospectivos , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Estudos de CoortesRESUMO
INTRODUCTION: Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management. METHODS: Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice. RESULTS AND CONCLUSION: Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.
Assuntos
Osteíte Deformante , Humanos , Osteíte Deformante/diagnóstico , Osteíte Deformante/terapia , Osteíte Deformante/epidemiologia , Osteíte Deformante/tratamento farmacológico , Itália/epidemiologia , Conservadores da Densidade Óssea/uso terapêutico , Sociedades Médicas/normas , Difosfonatos/uso terapêuticoRESUMO
INTRODUCTION: We conducted an all-case postmarketing surveillance study between 2008 and 2017 to evaluate the safety and effectiveness of risedronate for Paget's disease of bone (PDB) in Japan. MATERIAL AND METHODS: This study registered all patients who received once-daily risedronate 17.5 mg for the treatment of PDB and collected data over a 48-week follow-up period per treatment cycle for each patient. RESULTS: The safety analysis set included 184 patients (mean age, 63.7 years), 81 (44.0%) of whom previously received a bisphosphonate. Of them, 41 (22.3%) experienced 72 adverse drug reactions (ADRs), and 8 (4.3%) experienced 14 serious ADRs. Common ADRs included gastrointestinal disorders (20 patients, 10.9%) and hypocalcemia (6 patients, 3.3%). The effectiveness analysis set included 182 patients, 124 of whom completed only one treatment cycle and 58 of whom completed multiple treatment cycles. The proportions of patients who normalized serum alkaline phosphatase (ALP) concentration were 71.1% (113/159 patients) and 67.3% (33/49 patients) for the first and second treatment cycles, respectively. The relapse rate according to ALP levels after the end of treatment for the first cycle was 5.0% (95% confidence interval [CI] = 2.1-11.5) at 24 weeks and 12.9% (95% CI = 7.5-21.7) at 40 weeks. Regarding pain relief, the achievement rates were 70.0% (49/70 patients) and 30.8% (4/13 patients) for the first and second treatment cycles, respectively. CONCLUSION: To conclude, risedronate 17.5 mg/day is safe and effective for treating patients with PDB in daily practice.
Assuntos
Osteíte Deformante , Humanos , Pessoa de Meia-Idade , Ácido Risedrônico/efeitos adversos , Osteíte Deformante/tratamento farmacológico , Ácido Etidrônico/efeitos adversos , Japão , Difosfonatos/efeitos adversosRESUMO
INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.
Assuntos
Difosfonatos , Osteíte Deformante , Humanos , Difosfonatos/efeitos adversos , Osteíte Deformante/complicações , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/genética , Proteína Sequestossoma-1/genética , Ácido Zoledrônico/uso terapêutico , Testes Genéticos , BiomarcadoresRESUMO
INTRODUCTION: Paget's disease of bone (PDB) is a focal bone disorder caused by a marked dysregulation of osteoblasts and osteoclasts in basic multicellular units, leading to abnormal and disorganized deposition of collagen fibers (the so-called 'woven bone'). Therefore, pagetic bones are increased in size, and at increased risk for bone pain, deformities, fractures, osteoarthritis, and, more rarely, neoplastic degeneration. AREAS COVERED: In this review, we revise the available information concerning the pharmacological treatment of PDB. EXPERT OPINION: PDB progresses slowly within the affected skeletal sites and, if untreated, often leads to bone overgrowth, with bone pain, deformity, and a likely increased risk of complications. Thus, the primary goal of treatment is the restoration of a normal bone turnover, in order to relieve bone pain or other symptoms and possibly prevent the complications. PDB long remained a poorly treatable disorder until the discovery of antiresorptive agents such as calcitonin first and bisphosphonates (BPs) later. With the recent development of potent intravenous BPs like zoledronate, allowing a better control of disease activity over the long term with a single infusion, has contributed to a marked improvement of the clinical management of this invalidating disorder.
Assuntos
Conservadores da Densidade Óssea , Osteíte Deformante , Humanos , Osteíte Deformante/complicações , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/induzido quimicamente , Difosfonatos/uso terapêutico , Difosfonatos/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Ácido Zoledrônico/uso terapêutico , Dor/tratamento farmacológico , Dor/etiologiaRESUMO
INTRODUCTION: Ultra-rare mendelian osteolytic disorders caused by different length in-frame activating duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) comprise familial expansile osteolysis (FEO), expansile skeletal hyperphosphatasia (ESH), early-onset familial Paget's disease of bone (PDB2), juvenile Paget's disease 2 (JPD2), and panostotic expansile bone disease (PEBD). FEO typically presents with childhood-onset deafness followed by resorption of permanent dentition, and then appendicular bone pain, fractures, and deformities from progressive focal expansile osteolytic lesions emerging from a background of generalized high bone turnover. An 18-bp duplication in TNFRSF11A has been reported in all kindreds with FEO, whereas a 12-bp duplication was found in the young man with PEBD complicated by a massive jaw tumor. We report the clinical course and successful treatment with bisphosphonates of a girl with the 12-bp duplication yet a skeletal phenotype seemingly milder than PEBD. CASE PRESENTATION AND DISCUSSION: This 10-year-old girl presented for dental and orthodontic treatment and was found to have progressive external tooth root resorption. Speech delay was identified at age 18 months, and audiological evaluation showed both conductive and sensorineural hearing loss subsequently treated with a cochlear implant at age 3 years. Biochemical studies indicated increased bone turnover with elevated urinary N-telopeptide levels and serum alkaline phosphatase in the upper normal range. Low lumbar spine bone mineral density (BMD) was revealed by dual-energy X-ray absorptiometry, but whole-body Technetium-99 m bone scintigraphy was normal. Genetic testing identified the identical de novo 12-bp duplication within exon 1 of TNFRSF11A harbored by the young man with PEBD and massive jaw tumor. Bisphosphonate treatment, initiated with one dose of intravenous zoledronic acid that caused prolonged hypocalcemia, then comprised weekly oral alendronate that decreased bone turnover markers and normalized her BMD. CONCLUSION: Constitutive activation of RANK signaling should be considered a possible cause in any young person with rapid bone turnover, particularly in the context of early-onset deafness and/or root resorption of permanent teeth. Early diagnosis and anti-resorptive treatment, given judiciously to avoid sudden and prolonged hypocalcemia, may prevent further skeletal disease.
Assuntos
Doenças Ósseas Metabólicas , Surdez , Hipocalcemia , Osteíte Deformante , Reabsorção da Raiz , Feminino , Humanos , Doenças Ósseas Metabólicas/genética , Difosfonatos , NF-kappa B , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , CriançaRESUMO
The prevalence of Paget's disease of bone (PDB) reaches 1-2% of all adults aged ≥55 years old. However, reports describing PDB among HIV positive patients are extremely rare. We report here the case of a HIV positive person receiving tenofovir disoproxil fumarate (DF)-based antiretroviral therapy and who had persistently elevated alkaline phosphatase (AP) revealing PDB. It is well established that tenofovir-DF use is associated with reversible increases in serum AP levels. Clinicians should bear in mind that persistently elevated AP in a person receiving tenofovir DF-based cART could be related to PDB, in particular in person older than 50 years with no other notable biological abnormalities related to kidney tubular dysfunction.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , Osteíte Deformante , Adulto , Humanos , Pessoa de Meia-Idade , Adenina/efeitos adversos , Fosfatase Alcalina/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , Osteíte Deformante/tratamento farmacológico , Tenofovir/efeitos adversosRESUMO
Paget's 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. Increasing serum alkaline phosphatase or unique radiographic lesions may serve as the diagnostic indicators. Common symptoms include bone pain, bowing of the long bones, an enlarged skull, and hearing loss. The diagnosis is frequently confirmed by radiographic and nuclear scintigraphy of the bone. Further, bisphosphonates such as zoledronic acid and pamidronate are effective for its treatment. Moreover, biochemical monitoring is superior to the symptoms as a recurrence indicator. This article discusses the updates of Paget's disease of bone with a clinical case.
Assuntos
Reabsorção Óssea , Osteíte Deformante , Humanos , Osteíte Deformante/diagnóstico , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/etiologia , Difosfonatos/uso terapêutico , Pamidronato/uso terapêutico , Osso e Ossos/diagnóstico por imagem , Reabsorção Óssea/complicações , Reabsorção Óssea/tratamento farmacológicoRESUMO
Bone science has over the last decades unraveled many important pathways in bone and mineral metabolism and the interplay between genetic factors and the environment. Some of these discoveries have led to the development of pharmacological treatments of osteoporosis and rare bone diseases. Other scientific avenues have uncovered a role for the gut microbiome in regulating bone mass, which have led to investigations on the possible therapeutic role of probiotics in the prevention of osteoporosis. Huge advances have been made in identifying the genes that cause rare bone diseases, which in some cases have led to therapeutic interventions. Advances have also been made in understanding the genetic basis of the more common polygenic bone diseases, including osteoporosis and Paget's disease of bone (PDB). Polygenic profiles are used for establishing genetic risk scores aiming at early diagnosis and intervention, but also in Mendelian randomization (MR) studies to investigate both desired and undesired effects of targets for drug design.
Assuntos
Doenças Ósseas , Osteíte Deformante , Osteoporose , Humanos , Osteíte Deformante/tratamento farmacológico , Osso e Ossos , Densidade Óssea/genética , Osteoporose/genéticaRESUMO
The epidemiology of Paget's disease of bone (PDB) has changed in the last years but there is no update data on its clinical presentation, diagnosis and management in Latin America. Our aim was to describe its clinical features, diagnostic evaluation and responses to treatment in a group of PDB patients treated between June 2012 and December 2019 in an institution specialized in bone diseases, in Buenos Aires, Argentina. The frequency of PDB (180/10 714) was 1.68%. Median age was 67 (range 39-97) years and 59.5% were women. Most patients were asymptomatic (58.6%) and had monostotic disease (54.3%). Favorable responses were obtained in all patients who were treated with zoledronate (n = 36), in 10 out of 14 treated with pamidronate, in 9 out of 10 who received intravenous ibandronate and in 12 out of 13 who received oral bisphosphonates. The response rates were not significantly different when we compared monostotic vs. polyostotic disease. Among the biochemical parameters, mean values of bone specific and total alkaline phosphatase, and C-terminal crosslinked telopeptide of type I collagen decreased significantly after treatment with bisphosphonates. It seems that our results reflect the change in PDB epidemiology towards a more indolent disease. In the future, this would probably allow physicians to use lower doses of bisphosphonates than the ones historically recommended for these patients.
La epidemiología de la enfermedad de Paget ósea (EPO) ha cambiado en los últimos años. Son necesarios datos actualizados sobre su forma de presentación clínica, diagnóstico y tratamiento en nuestra región. Nuestro objetivo fue describir las características clínicas, evaluación diagnóstica y respuestas al tratamiento de un grupo de pacientes con EPO en un centro especializado en salud ósea de Buenos Aires, Argentina. Se evaluaron todos los pacientes que fueron atendidos en nuestra institución por enfermedades óseas entre junio de 2012 y diciembre de 2019. La frecuencia de EPO (180/10 714) fue de 1.68%. La mediana de edad fue de 67 (rango 39-97) años. El 59.5% eran mujeres. La mayoría se encontraba asintomático (58.6%) y tenían enfermedad monostótica (54.3%). Se objetivaron respuestas favorables en todos los que recibieron zoledronato (n = 36), en 10 de 14 pacientes que recibieron pamidronato, en 9 de 10 que utilizaron ibandronato endovenoso y en 12 de 13 con bifosfonatos orales. Los porcentajes de respuesta no variaron significativamente entre pacientes con formas monostóticas y poliostóticas. Entre los parámetros bioquímicos, los valores de fosfatasa alcalina total y ósea y de Β cross-laps disminuyeron significativamente luego del tratamiento con bifosfonatos. Nuestros resultados reflejarían un cambio en la epidemiología de la EPO hacia una forma de presentación más indolente. Esto permitiría probablemente el uso de dosis más bajas de bifosfonatos que las históricamente recomendadas para estos pacientes.
Assuntos
Osteíte Deformante , Adulto , Idoso , Idoso de 80 Anos ou mais , Argentina/epidemiologia , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteíte Deformante/diagnóstico , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/epidemiologia , Ácido Zoledrônico/uso terapêuticoRESUMO
Paget's disease of bone (PDB) is a rare metabolic bone disorder, which is extremely rare in Asian population. This study aimed to investigate the phenotypes and the pathogenic mutations of woman with early-onset PDB. The clinical features, bone mineral density, x-ray, radionuclide bone scan, and serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and ß-carboxy-terminal cross-linked telopeptide of type 1 collagen (ß-CTX) were measured in detail. The pathogenic mutations were identified by whole-exon sequencing and confirmed by Sanger sequencing. We also evaluated the effects of intravenous infusion of zoledronic acid on the bones of the patient and summarized the phenotypic characteristics of reported patients with mutation at position 155 of the valosin-containing protein (VCP). The patient only exhibited bone pain as the initial manifestation with vertebral compression fracture and extremely elevated ALP, P1NP, and ß-CTX levels; she had no inclusion body myopathy and frontotemporal dementia. The missense mutation in exon 5 of the VCP gene (p.Arg155His) was identified by whole-exome sequencing and further confirmed by Sanger sequencing. No mutation in candidate genes of PDB, such as SQSTM1, CSF1, TM7SF4, OPTN, PFN1, and TNFRSF11A, were identified in the patient by Sanger sequencing. Rapid relief of bone pain and a marked decline in ALP, P1NP, and ß-CTX levels were observed after zoledronic acid treatment. Previously reported patients with VCP missense mutation at position 155 (R155H) always had myopathy, frontotemporal dementia, and PDB, but the patient in this study exhibited only PDB. This was the first report of R155H mutation-induced early-onset in the VCP gene in Asian population. PDB was the only manifestation having a favorable response to zoledronic acid treatment. We broadened the genetic and clinical phenotype spectra of the VCP mutation.
Assuntos
Fraturas por Compressão , Demência Frontotemporal , Doenças Musculares , Osteíte Deformante , Fraturas da Coluna Vertebral , Feminino , Demência Frontotemporal/genética , Humanos , Mutação/genética , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/genética , Dor , Profilinas/genética , Proteína com Valosina/genética , Ácido ZoledrônicoRESUMO
In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height z-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.
Assuntos
Denosumab/administração & dosagem , Fêmur , Lâmina de Crescimento , Úmero , Osteíte Deformante , Pamidronato/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Fêmur/crescimento & desenvolvimento , Fêmur/metabolismo , Fêmur/fisiopatologia , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/fisiopatologia , Humanos , Úmero/crescimento & desenvolvimento , Úmero/fisiopatologia , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/metabolismo , Osteíte Deformante/fisiopatologia , Osteoprotegerina/metabolismoRESUMO
INTRODUCTION: Juvenile Paget's Disease (JPD) is an ultra-rare inherited osteopathy featuring markedly accelerated bone turnover. Several clinical characteristics have been reported, including bone deformities developing in childhood and hearing loss. CASE REPORT: We report the case of a 2 ¾-year-old girl that presented with progressive bowing of both legs since the age of 2, lower limb pain and frequent falls with one consequent femur fracture. Plain radiographs revealed osteoectasia of the long bone's diaphysis, and laboratory tests showed extremely high serum total alkaline phosphatase levels. A missense mutation on the gene TNFRSF11B was identified in homozygosity, and the diagnosis of JPD was made. Treatment with bisphosphonates was initiated early and markedly improved lower limb bowing and pain. The patient reached adulthood with normal height, minor bone deformities, and no functional impairment. Despite the good skeletal symptom's response, bisphosphonates failed to prevent or improve sensorineural hearing loss. CONCLUSIONS: In this clinical case, early treatment with bisphosphonates was effective for the treatment of JPD skeletal deformities. New therapeutic strategies need to be developed to better control the extraskeletal manifestations of JPD.
Assuntos
Mutação de Sentido Incorreto , Osteíte Deformante , Adulto , Difosfonatos/uso terapêutico , Feminino , Homozigoto , Humanos , Osteíte Deformante/diagnóstico , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/genética , Osteoprotegerina/genética , Osteoprotegerina/uso terapêutico , Adulto JovemRESUMO
Despite the current debate on the best therapeutic approach, i.e. symptomatic vs intensive strategy, one zoledronate (Zol) infusion is effective in most patients with Paget's disease of bone (PDB), whereas few need retreatment, whose predictors are not well established. We aimed to evaluate long-term efficacy of intensive Zol therapy and predictors of retreatment in PDB. Pagetic complications, clinical and biochemical response to Zol together with frequency of retreatment were retrospectively assessed in forty-seven PDB patients (age, mean ± SD: 72.5 ± 8.9 years, M/F: 24/23; symptomatic/asymptomatic: 16/31). Statistical analysis for retreatment prediction were based on Mann-Whitney U test, Pearson's Χ2 and ROC curve analysis. During seven-year follow-up, all patients achieved pain relief and only one underwent arthroplasty. Bone alkaline phosphatase (BAP) detected three non-responder (6%) and six relapsing (13%) patients needing retreatment. Retreated patients had less old age (66.1 ± 11.2 vs 74.0 ± 7.7 years), higher frequency of polyostotic disease (78% vs 40%) and higher baseline (96.5 ± 24.8 vs 44.9 ± 27.7 mcg/l) and post-Zol nadir BAP levels (24.7 ± 24.1 vs 8.1 ± 4.1 mcg/l) than patients treated once (p < 0.05 for all comparisons). In multivariate analysis both serum baseline and post-Zol nadir BAP significantly predicted retreatment (OR 1.09, 95%CI 1.01-1.17 and 1.29, 1.03-1.62, respectively), with ROC curve analysis showing the greatest accuracies for threshold values of 75.6 and 9.9 mcg/l (sensitivity 88 and 90%, specificity 94 and 86%, AUC 0.92 and 0.93, respectively). Our data in mostly asymptomatic, metabolically active PDB patients treated with intensive Zol therapy show a negligible incidence of pagetic complications and long-term optimal disease control, with BAP being the best predictor of retreatment.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Osteíte Deformante , Ácido Zoledrônico/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina , Difosfonatos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteíte Deformante/tratamento farmacológico , Retratamento , Estudos RetrospectivosRESUMO
BACKGROUND: Paget's disease of bone (PDB) is a common destructive condition of bone that affects 1-2% of the population, most typically those over the age of 55 years. It is usually asymptomatic. OBJECTIVE: The aim of this article is to describe the clinical presentation, diagnosis and management of patients with PDB. DISCUSSION: Most cases of PDB are diagnosed incidentally on radiographs or as an isolated elevation of serum alkaline phosphatase. Symptomatic patients present with bone pain, fractures, arthritis and features of compression neuropathy. Diagnosis is made on the basis of typical radiological features on plain films, while a radionuclide bone scan may be used to assess the extent of disease. The mainstay of treatment for PDB is bisphosphonate therapy, with zoledronic acid being the most effective agent. A single infusion of zoledronic acid leads to a sustained reduction in bone pain and markers of bone turnover. However, bisphosphonates should be reserved for symptomatic patients, as treatment with these agents has been associated with an increase in rates of fracture in patients with asymptomatic PDB.
Assuntos
Fraturas Ósseas , Osteíte Deformante , Difosfonatos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/tratamento farmacológico , Radiografia , Ácido ZoledrônicoRESUMO
Autophagy is an evolutionarily conserved intracellular process and is considered one of the main catabolism pathways. In the process of autophagy, cells are digested nonselectively or selectively to recover nutrients and energy, so it is regarded as an antiaging process. In addition to the essential role of autophagy in cellular homeostasis, autophagy is a stress response mechanism for cell survival. Here, we review recent literature describing the pathway of autophagy and its role in different bone cell types, including osteoblasts, osteoclasts, and osteocytes. Also discussed is the mechanism of autophagy in bone diseases associated with bone homeostasis, including osteoporosis and Paget's disease. Finally, we discuss the application of autophagy regulators in bone diseases. This review aims to introduce autophagy, summarize the understanding of its relevance in bone physiology, and discuss its role and therapeutic potential in the pathogenesis of bone diseases such as osteoporosis.
Assuntos
Autofagia , Remodelação Óssea , Osso e Ossos/patologia , Osteíte Deformante/patologia , Osteoartrite/patologia , Osteoporose/patologia , Animais , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Homeostase , Humanos , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/metabolismo , Osteíte Deformante/fisiopatologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/fisiopatologia , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/fisiopatologiaRESUMO
BACKGROUND: Bisphosphonates represent the gold standard treatment for Paget's disease of bone. Neridronate is a potent bisphosphonate, licensed in Italy for this use, but only few clinical trials have investigated the outcomes of this treatment. The aim of our study was to report our long-term experience with intravenous Neridronate. METHODS: This is a 48 months observational, descriptive and prospective study on patients with active Paget's disease of bone treated with intravenous Neridronate. Patients underwent laboratory tests (total alkaline phosphatase (ALP), calcium, phosphate, 25 OH Hydroxivitamin D, serum protein electrophoresis, parathyroid hormone) at the time of diagnosis and every 6 months. In all subjects, mutations in the SQSTM1 and ZNF687 genes were searched. The primary endpoint was the treatment efficacy in term of rate of therapeutic response at 48 months (normalization of ALP levels or a reduction of at least 75% in total ALP excess). RESULTS: Fifteen patients (10 female, mean age 70.3 years) were enrolled at our division from 2016 to 2020. One was positive for the ZNF687 gene mutation. After 48-month follow-up, the therapeutic response was maintained in 80% of patients treated with intravenous neridronate. ALP values were higher at 48 months than at 6 months, but this difference was not clinically relevant because the percentage of subjects who maintained a therapeutic response at 48 months was not significantly different from that observed at 6 months (80% vs. 86.6%, P=0.62). One patient had a biochemical relapse, and was retreated with the same therapeutic regimen, achieving a good response. CONCLUSIONS: Treatment with intravenous neridronate is effective in inducing and maintaining sustained remission in patients with PDB for at least 48 months. Administration in single intravenous infusion may improve long-term compliance compared to oral formulations.
Assuntos
Osteíte Deformante , Idoso , Osso e Ossos , Difosfonatos/uso terapêutico , Feminino , Humanos , Osteíte Deformante/tratamento farmacológico , Estudos ProspectivosRESUMO
Paget's disease is a monostotic or polyostotic progressive skeletal disease with a genetic predisposition. The affected bone areas show osseous swelling and often grotesque deformation, chronic pain and fractures. Many cases are asymptomatic for a long time resulting in a late diagnosis. The pathogenesis is still unknown. In addition to a genetic predisposition, viral factors are also discussed. Laboratory tests and imaging are used for diagnosis. The effective principle of medicinal bisphosphonate treatment is to inhibit osteoclastic bone resorption and should be initiated early to prevent secondary complications. This article presents the current knowledge about this rare osteological disease.
Assuntos
Osteíte Deformante , Reabsorção Óssea , Osso e Ossos , Diagnóstico por Imagem , Difosfonatos/uso terapêutico , Humanos , Osteíte Deformante/diagnóstico , Osteíte Deformante/tratamento farmacológicoRESUMO
The first clinical use of bisphosphonates was in Paget's disease of bone (PDB) when disodium etidronate was found to be effective at suppressing metabolic activity of the disease. Subsequently, PDB became a testing ground for many bisphosphonates using changes in alkaline phosphatase (ALP) as the primary outcome measure in clinical trials. Bisphosphonates are now considered to be the treatment of choice for PDB since they are highly effective at suppressing the elevations in bone turnover that are characteristic of the disease. Short term studies have shown that treatment with alendronate and risedronate can promote formation of lamellar bone in affected sites and improve x-ray appearances in some patients. Bisphosphonates have also been shown to improve bone pain in PDB and within the bisphosphonates, zoledronic acid (ZA) is most likely to give a favourable pain response. Many patients with PDB do not have pain however, even when there is increased metabolic activity and more research is needed to find out why this is the case. The effects of bisphosphonates on complications of PDB such as deformity, pathological fractures and deafness have not been adequately studied since most clinical trials have been short term and have not collected information on these important outcomes. The PRISM and PRISM-EZ studies investigated the long-term effects of bisphosphonates in patients with established PDB using a treat-to-target approach and showed that intensive bisphosphonate therapy aimed at normalising ALP was no more effective than symptom directed treatment with bisphosphonates at preventing complications of PDB. The Zoledronate in the Prevention of Paget's Disease (ZiPP) trial, which is currently in progress, seeks to determine whether early intervention with this potent bisphosphonate might be effective in preventing disease progression. Should the ZiPP study yield positive results, genetic testing coupled to prophylactic bisphosphonate therapy might represent a new indication for these highly effective inhibitors of bone resorption in future years.