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1.
BMJ Case Rep ; 14(2)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542026

RESUMO

Osteogenesis imperfecta (OI) consists of a group of genetically and phenotypically heterogeneous diseases characterised by bone fragility. Recent improvement in gene sequencing methods has helped us identify rare forms of OI that are inherited in an autosomal recessive manner. Paediatric endocrinology was consulted on a newborn girl with multiple fractures and wavy thin ribs noted on X-rays. In addition to the bone phenotype, she also has short stature and recurrent acute liver failure (ALF) episodes triggered by intercurrent illness. Whole exome sequencing revealed two novel compound heterozygous variants in neuroblastoma amplified sequence (NBAS) gene. NBAS gene codes for a protein that is involved in nonsense-mediated decay pathway and retrograde transport of proteins from Golgi to endoplasmic reticulum. Recognition of pathogenic variants in this gene as a rare cause of autosomal recessive OI and recurrent ALF has important therapeutic implications.


Assuntos
Heterozigoto , Falência Hepática Aguda/genética , Proteínas de Neoplasias/genética , Osteogênese Imperfeita/genética , Conservadores da Densidade Óssea/uso terapêutico , Nanismo/genética , Feminino , Humanos , Lactente , Recém-Nascido , Osteogênese Imperfeita/tratamento farmacológico , Pamidronato/uso terapêutico , Fenótipo , Recidiva , Sequenciamento Completo do Exoma
2.
BMJ Case Rep ; 13(12)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33318265

RESUMO

We present a 9-year-old male child having history of fractures on trivial trauma with a family history of the same. He was treated for osteogenesis imperfecta (OI; zolendronate, calcium and vitamin D) and showed clinical improvement. On evaluating his bone health using dual energy X-ray absorptiometry and peripheral quantitative CT, we found that the child had bone density within the reference range but a smaller bone mass for his height, low muscle mass and thin bones with a lower strength strain index in comparison with healthy children. Our case suggests that treatment with bisphosphonates results in increase in bone density; however, bones remain thin and the lean body mass in these children may also be low. Controlled physical activity to improve muscle health and newer approaches to improve bone geometry would result in better bone health in children with OI.


Assuntos
Absorciometria de Fóton , Densidade Óssea , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/fisiopatologia , Tomografia Computadorizada por Raios X , Conservadores da Densidade Óssea/uso terapêutico , Cálcio/uso terapêutico , Criança , Difosfonatos/uso terapêutico , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Humanos , Masculino , Osteogênese Imperfeita/tratamento farmacológico , Tomografia Computadorizada por Raios X/métodos , Vitamina D/uso terapêutico , Ácido Zoledrônico/uso terapêutico
3.
Med. clín (Ed. impr.) ; 154(12): 512-518, jun. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-195679

RESUMO

INTRODUCCIÓN: La osteogénesis imperfecta (OI) es una enfermedad genética heterogénea manifestada como fragilidad ósea y fracturas. PACIENTES Y MÉTODOS: Estudio descriptivo retrospectivo analizando características clínicas, genéticas y tratamiento de pacientes diagnosticados de OI (1989-2017) en el Hospital Universitario Miguel Servet, Zaragoza (Endocrinología Pediátrica y Reumatología). RESULTADOS: Incluidos 40 pacientes; 32,5% varones, 67,5% mujeres; 29 niños, 11 adultos. Media de fracturas al diagnóstico en OI leve 4,6±6,4 (edad media al diagnóstico 7,8±12,8años), en OI moderada 1,7±2,4 (edad media al diagnóstico 0,04±0,3años), en OI grave 3,7±2,1 y en OI muy grave 12,5±7,8, ambos grupos diagnosticados al nacimiento. Estudio genético en 32 pacientes, 25 con variante patogénica/probablemente patogénica, siendo COL1A1 el gen más frecuentemente afectado. En 7 pacientes no fue encontrada la variante responsable, 5 con confirmación diagnóstica (estudio bioquímico colágenoI). Tratamiento con bifosfonatos 19 pacientes; 7 asociando hormona de crecimiento. Los tratados con bifosfonatos han presentado mejoría clínica (reducción de dolor óseo y/o irritabilidad) y reducción del número de fracturas. CONCLUSIONES: El gen COL1A1 es el más frecuentemente afectado en nuestros pacientes. El tratamiento debe ser multidisciplinar y el uso de bifosfonatos proporciona mejoría


INTRODUCTION: Osteogenesis imperfecta (OI) is a heterogeneous genetic disease manifesting as bone fragility and fractures. PATIENTS AND METHODS: Retrospective descriptive study analysing clinical and genetic features, and treatment of patients with OI. RESULTS: Forty patients were included; 32.5% males, 67.5% females; 29 children, 11 adults. Number of fractures at diagnosis with mild OI was 4.6±6.4 (average age at diagnosis 7.8±12.8years), with moderate OI 1.7±2.4 (age at diagnosis .04±.3years), in severe OI 3.7±2.1 and in extremely severe forms 12.5±7.8, both groups diagnosed at birth. Genetic study in 32 patients, 25 with a positive genetic study (pathogenic/probably pathogenic variant). COL1A1 gene was the most frequently affected. In 7 patients, no pathogenic or probably pathogenic variant was found (5 diagnosed by biochemical study of typeI collagen). Nineteen patients were treated with bisphosphonates; 7 combined with growth hormone. The patients treated with bisphosphonates showed clinical improvement (reduction of bone pain and/or irritability) and reduction of fractures. CONCLUSIONS: The COL1A1 gene is the most frequently affected. OI patients should receive multidisciplinary management and bisphosphonates can improve their quality of life


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Adulto , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Difosfonatos/administração & dosagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/complicações , Estudos Retrospectivos , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/tratamento farmacológico
4.
Reumatol. clín. (Barc.) ; 16(2,pt.2): 165-168, mar.-abr. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-194341

RESUMO

La osteogénesis imperfecta (OI) es un trastorno hereditario del tejido conectivo generalmente relacionado con mutaciones de los genes del colágeno tipoI. El diagnóstico se basa en los hallazgos clínicos y radiológicos. El manejo clínico de la OI en adultos no está del todo establecido y comprende desde la rehabilitación física y los procedimientos quirúrgicos hasta el uso de tratamientos antirresortivos y osteoformadores. El objetivo del presente trabajo ha sido analizar las características clínicas y analíticas de estos pacientes en la edad adulta, así como evaluar los diferentes tratamientos administrados. Se han revisado los casos de OI diagnosticados en nuestro centro en los últimos 12 años (2005-2017). Se describen 15 pacientes adultos con OI


Osteogenesis imperfecta (OI) is an inherited connective tissue disease. The disease has been linked to mutations in one of the type I collagen genes. The diagnosis is based on clinical and radiologic findings. The management of OI in adults is not well-established and includes physical rehabilitation, surgical procedures, the use of antiresorptive therapy and anabolic agents. The aim of the present work was to analyze the clinical and analytical characteristics of these patients in adulthood, as well as to evaluate the different treatments administered. We reviewed the cases of OI diagnosed in our center over the last 12 years (2005-2017). We describe 15 adult patients with OI


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Difosfonatos/administração & dosagem , Densitometria/métodos , Osteogênese Imperfeita/fisiopatologia , Pró-Colágeno/uso terapêutico , Estudos Retrospectivos , Esclerose/complicações , Dentinogênese , Osteoporose/complicações , Doenças Ósseas Metabólicas/complicações
5.
Acta Ortop Mex ; 33(2): 63-66, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31480105

RESUMO

INTRODUCTION: Osteogenesis imperfeta (OI) is defined as a heterogeneous group of hereditary diseases, which present with the presence of bone fragility, frequent fractures, bone deformities and short stature. Treatment with biphosfonates in patients with diagnosis of OI has shown a decrease in the frecuency of fractures, as well as an improvement in vertebral bone density. There is little evidence on quality of life in patients diagnosed with OI treated with bisphosphonates, Therefore this study evaluated the quality of life of patients diagnosed with OI after treatment with bisphosphonates. MATERIAL AND METHODS: It is a prospective, deliberate intervention, self-controlled clinical trial. Nine patients with ages between two and thirteen ages and diagnosed with OI were treated with Zolendronic, a quality of life measurement was performed in the patients before and after the application. For measuring the quality of life in the patients we used the PedsQL 4.0 quality of life survey that was applied to both children and parents. RESULTS: In the quality of life survey performed on the parents, an increase was observed in the four dimensions evaluated. In the survey made on the children two dimensions showed a significant increase. The number of fractures decreased after the treatment. CONCLUSIONS: There is a correlation between the decrease in the number of fractures and the perception that both parents and children have in the quality of life after treatment with bisphosphonates.


Assuntos
Conservadores da Densidade Óssea , Difosfonatos , Osteogênese Imperfeita , Qualidade de Vida , Adolescente , Conservadores da Densidade Óssea/uso terapêutico , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Humanos , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/tratamento farmacológico , Estudos Prospectivos
6.
Orphanet J Rare Dis ; 14(1): 219, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533771

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually. METHODS: Ten patients (age range: 6.16-12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting. RESULTS: During follow-up mean relative change of lumbar aBMD was - 6.4%. Lumbar spine aBMD z-Scores decreased from - 1.01 ± 2.61 (mean ± SD) to - 1.91 ± 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 ± 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks. CONCLUSIONS: On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.


Assuntos
Denosumab/uso terapêutico , Osteogênese Imperfeita/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Criança , Colágeno Tipo I/genética , Difosfonatos/uso terapêutico , Feminino , Seguimentos , Humanos , Hipercalciúria/tratamento farmacológico , Masculino , Mutação/genética , Estudos Retrospectivos
8.
J Bone Miner Res ; 34(12): 2198-2204, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31356699

RESUMO

Intravenous cyclical bisphosphonates are widely used to treat children with moderate to severe osteogenesis imperfecta (OI). Bisphosphonates are often discontinued when growth is completed, but subsequent skeletal changes have not been studied in detail. We assessed 31 patients (22 females) with OI who had started intravenous bisphosphonates (either pamidronate or zoledronic acid) before 13 years of age, were treated for at least 2 years (range 4.7-15.7 years), and discontinued treatment after completion of growth, when their age ranged from 13.4 to 20.0 years (mean 16.4 years). At 4 years after treatment discontinuation, lumbar spine areal bone mineral density (BMD) had increased by 4% (p < 0.05). Peripheral quantitative computed tomography of the radius showed a decrease in trabecular volumetric BMD at the distal metaphysis of 19% but an increase in cortical volumetric BMD of 4% (p < 0.05 for both). None of the patients sustained a new vertebral compression fracture during follow-up. The proportion of patients with new long-bone fractures was higher in the 2 years before treatment discontinuation than in the last 2 years of follow-up (42% and 16%, respectively; p < 0.05). © 2019 American Society for Bone and Mineral Research.


Assuntos
Estatura , Osso e Ossos/patologia , Difosfonatos/uso terapêutico , Osteogênese Imperfeita/tratamento farmacológico , Suspensão de Tratamento , Absorciometria de Fóton , Adolescente , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Criança , Pré-Escolar , Difosfonatos/farmacologia , Feminino , Fraturas Ósseas/diagnóstico por imagem , Humanos , Lactente , Vértebras Lombares/diagnóstico por imagem , Masculino , Osteogênese Imperfeita/diagnóstico por imagem , Tomografia Computadorizada por Raios X
9.
Bone ; 127: 164-171, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31216496

RESUMO

Vertebral compression fracture (VCF) is a common and severe complication of osteogenesis imperfecta (OI). We prospectively observe the changes of vertebral shape during zoledronic acid (ZOL) treatment and assess influence factors of VCF in OI children. 32 children with VCF and 10 children without VCF (NVCF) were included and given ZOL treatment for 2 years, who were matched in age and gender. Control group included 17 treatment naïve OI patients with VCF who were matched in age, gender and clinical severity to 17 patients in VCF group received ZOL treatment for 1 year (as ZOL treated group). We performed quantitative vertebral morphometry and calculated concavity index (mh/ph), height-length ratio (ah/LL, mh/LL, ph/LL) and projection area (PA) of vertebrae from T4 to L4 before and after treatment. At baseline, patients in VCF group had significantly lower PA, mh/ph, ah/LL, mh/LL and ph/LL than patients in NVCF group (P < 0.01). PA, mh/ph, ah/LL, mh/ LL and ph/LL of patients with VCF were raised by (35.2 ±â€¯19.5)%, (22.9 ±â€¯15.1)%, (19.6 ±â€¯13.9)%, (33.6 ±â€¯25.5)%, and (8.1 ±â€¯8.8)% (P < 0.01) after 1-year treatment of ZOL, and were increased by (71.8 ±â€¯28.2)%, (42.8 ±â€¯21.8)%, (35.1 ±â€¯20.6)%, (65.4 ±â€¯43.2)%, and (12.5 ±â€¯11.4)% after 2-year treatment of ZOL (P < 0.01). Compared to control group, mh/ph, ah/LL and mh/LL were significantly higher (P < 0.01) in ZOL treated group. LS-BMD and its increase were positively correlated to vertebral height and PA at baseline and the improvement of vertebral height and PA after ZOL treatment, respectively. In conclusion, the compressive vertebrae of OI children could be effectively reshaped during ZOL treatment. Low LS-BMD was an independent risk factor for VCF and its increase was positively correlated to the improvement in vertebral shape after ZOL treatment.


Assuntos
Osteogênese Imperfeita/tratamento farmacológico , Coluna Vertebral/patologia , Ácido Zoledrônico/uso terapêutico , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Humanos , Estudos Longitudinais , Osteogênese Imperfeita/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Ácido Zoledrônico/efeitos adversos , Ácido Zoledrônico/farmacologia
10.
J Food Sci ; 84(6): 1646-1650, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31116433

RESUMO

Pepino (Solanum muricatum), which is an evergreen plant native to South America, is well-known for its effects in antioxidation, antidiabetic activity, anti-inflammation, and antitumor activity. A previous study in our lab indicated that Solanum muricatum (SM) extract promoted osteogenic differentiation by upregulating Wnt and BMP signaling pathway in rat bone marrow stromal cells. The osteogenesis imperfecta (OI) mouse model was used in order to further discover the osteogenic properties of SM extract in the present research. We utilized microCT analysis to collect bone mass and microarchitectural parameters at vertebrae and at femur metaphysis in OI mice. Raman spectrometry was applied to identify change of bone mineral and matrix composition during SM treatment. Finally, collagen synthesis marker PINP and collagen degradation marker CTX were detected using enzyme immunoassay. SM extract could improve the bone mass and microarchitectural parameters both at vertebrae and at femur metaphysis. It also significantly increased the collagen content by promoting its biosynthesis and inhibiting its degradation. By using heterozygous Col1a1Jrt /+ mice as a model of OI, 6 weeks treatment of SM extract could significantly ameliorate the symptoms in OI mice. Thus, SM holds potential for developing new drugs of bone formation and bone remodeling.


Assuntos
Osteogênese Imperfeita/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Solanum/química , Animais , Densidade Óssea/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteogênese/efeitos dos fármacos , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/fisiopatologia , Microtomografia por Raio-X
11.
Orthop Clin North Am ; 50(2): 193-209, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850078

RESUMO

Osteogenesis imperfecta is a genetically and phenotypically heterogeneous disorder related to a defect or deficiency in the production of type I collagen. It is characterized by brittle bones, fractures, spine and extremity deformity, and a host of extraskeletal manifestations. Type I collagen is present in bone, tendons, ligaments, skin, dentin, and the sclera of the eye and other connective tissues. Osteogenesis imperfecta includes a multitude of disease manifestations that may be present at birth or develop over time and vary depending on the severity of the disease. This article describes the disease presentation and management considerations from a pediatric orthopedic perspective.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Deformidades Congênitas dos Membros/diagnóstico , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cálcio/administração & dosagem , Cálcio/uso terapêutico , Criança , Pré-Escolar , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Exercício Físico/fisiologia , Feminino , Órtoses do Pé/normas , Fraturas Ósseas/complicações , Fraturas Ósseas/terapia , Humanos , Lactente , Comunicação Interdisciplinar , Deformidades Congênitas dos Membros/etiologia , Deformidades Congênitas dos Membros/cirurgia , Deformidades Congênitas dos Membros/terapia , Masculino , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/patologia , Escoliose/patologia , Escoliose/cirurgia , Coluna Vertebral/anormalidades , Coluna Vertebral/patologia , Vitamina D/uso terapêutico
12.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(2): 108-116, feb. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-175802

RESUMO

La osteogénesis imperfecta (OI) es una enfermedad genética que cursa con baja densidad mineral y fragilidad ósea. Varios trabajos han demostrado la eficacia de los bisfosfonatos para mejorar la densidad mineral ósea (DMO). El objetivo de este estudio es evaluar la evolución de la DMO y parámetros bioquímicos de metabolismo óseo, en pacientes adultos con OI tratados con ácido zoledrónico intravenoso (iv) durante un periodo medio de 5 años, así como valorar la seguridad de dicho tratamiento. Pacientes y métodos: Estudio prospectivo, observacional en pacientes adultos con OI con osteoporosis u osteopenia, con T-score<-2, a los que se administró ácido zoledrónico (4mg iv) cada 6 meses durante 3 años y posteriormente de forma anual. Se registraron a las 24 y 48 h los cambios agudos en calcio, fósforo, creatinina y hemograma así como los efectos secundarios tras la infusión. Se realizó densitometría basal y cada año. Se determinaron basal y anualmente calcio, fósforo, paratohormona (PTHi), 25OH-vitamina D y marcadores de remodelado óseo (fosfatasa alcalina ósea, ß-cross-lap y deoxipiridolina en orina). Se registraron las nuevas fracturas. Resultados: Se trataron 20 pacientes, 6 hombres y 14 mujeres con una mediana de seguimiento de 5 años. Los niveles de calcio y las plaquetas disminuyeron significativamente a las 24 y 48 h tras la primera infusión. El recuento de hematíes disminuyó a las 24h. Estos cambios no fueron clínicamente relevantes. Siete pacientes presentaron un cuadro pseudogripal tras la primera dosis. La DMO medida en columna lumbar mostró un aumento significativo (6,7%) a los 12 meses de seguimiento (0,741±0,178 vs. 0,791±0,140g/cm2; p=0,003) así como a los tres (5,7%) y 5 años (9%) de seguimento. En cuello femoral se evidenció incremento significativo de la DMO a los 3 años (11,1%): 0,648±0,148 vs. 0,720±0,138g/cm2; p=0,01. En cadera total el incremento (10,1%) resultó significativo a los 3 años de tratamiento (0,706±0,118 vs. 0,720±0,138; p=0,01). No se evidenciaron diferencias significativas en los niveles de calcio y 25OH-vitamina D largo del seguimiento, el fósforo disminuyó significativamente al año y PTHi aumentó a los 3 años. ß-cross-lap disminuyó al año de tratamiento. Solo un paciente ha presentado nuevas fracturas. Conclusiones: El ácido zoledrónico es un tratamiento cómodo, seguro y eficaz para mejorar la DMO en pacientes adultos con OI


Osteogenesis imperfecta (OI) is an inherited disorder that causes low mineral density and bone fragility. Previous studies have shown the efficacy of bisphosphonates to increase bone mineral density (BMD). This study assessed changes over time in BMD and biochemical markers of bone metabolism in adult patients with osteogenesis imperfecta treated with intravenous zoledronic acid and the safety of this treatment. Patients and methods: A prospective, observational study in patients with OI, osteoporosis or osteopenia (T score <-2) who were administered zoledronic acid infusions (4mg IV) every 6 months for three years and annually thereafter. Densitometry was performed annually. Acute changes in complete blood count and calcium, phosphate, and creatinine levels, as well as side effects of the infusion, were recorded 24 and 48h after treatment. Calcium, phosphate, parathyroid hormone (iPTH), 25OH-vitamin D and bone turnover markers (bone alkaline phosphatase, ß-crosslaps and urinary deoxypyridinoline) were measured at baseline and every 12 months. Adverse events and new fractures were recorded. Results: Twenty patients (6 men and 14 women) were treated. Median follow-up time was five years. Calcium levels and platelet counts significantly decreased 24 and 48hours after the first infusion, and the red blood cell count decreased at 24hours. These changes were not clinically relevant. Seven patients experienced a flu-like episode after the first dose. Treatment induced significant increases in BMD in the lumbar spine (6.7%) after 12 months of follow-up (0.791±0.178 vs. 0.791±0.140g/cm2, p=.003) and at three (5.7%) and five years (9%) of follow-up. Femoral neck BMD significantly increased after 3 years (11.1%): 0.648±0.148 vs. 0.720±0.138g/cm2; p=.01. In total hip, increase in BMD (10.1%) was significant after three years of treatment (0.706±0.118 vs. 0.720±0.138, p=.01). There were no significant differences in calcium and 25OH-vitamin D levels during follow-up, phosphorus significantly decreased after one year, and iPTH increased at three years. ß-crosslaps decreased after one year of treatment. Only one patient sustained new fractures. Conclusions: Zoledronic acid is a convenient, safe, and effective treatment that increases BMD in adult patients with OI


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Osteogênese Imperfeita/tratamento farmacológico , Efeitos Adversos de Longa Duração , Densidade Óssea , Osso e Ossos/metabolismo , Difosfonatos/efeitos adversos , Adulto , Difosfonatos/metabolismo , Difosfonatos/uso terapêutico , Estudo Observacional , Estudos Prospectivos , Densitometria
13.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
14.
J Cell Mol Med ; 23(3): 1735-1745, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30597759

RESUMO

Osteogenesis imperfecta (OI) is commonly caused by heterozygous type I collagen structural mutations that disturb triple helix folding and integrity. This mutant-containing misfolded collagen accumulates in the endoplasmic reticulum (ER) and induces a form of ER stress associated with negative effects on osteoblast differentiation and maturation. Therapeutic induction of autophagy to degrade the mutant collagens could therefore be useful in ameliorating the ER stress and deleterious downstream consequences. To test this, we treated a mouse model of mild to moderate OI (α2(I) G610C) with dietary rapamycin from 3 to 8 weeks of age and effects on bone mass and mechanical properties were determined. OI bone mass and mechanics were, as previously reported, compromised compared to WT. While rapamycin treatment improved the trabecular parameters of WT and OI bones, the biomechanical deficits of OI bones were not rescued. Importantly, we show that rapamycin treatment suppressed the longitudinal and transverse growth of OI, but not WT, long bones. Our work demonstrates that dietary rapamycin offers no clinical benefit in this OI model and furthermore, the impact of rapamycin on OI bone growth could exacerbate the clinical consequences during periods of active bone growth in patients with OI caused by collagen misfolding mutations.


Assuntos
Densidade Óssea/efeitos dos fármacos , Colágeno Tipo I/fisiologia , Modelos Animais de Doenças , Imunossupressores/farmacologia , Osteoblastos/efeitos dos fármacos , Osteogênese Imperfeita/tratamento farmacológico , Sirolimo/farmacologia , Animais , Apoptose , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Osteoblastos/citologia , Osteogênese , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia
15.
Genet Med ; 21(2): 275-283, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29970925

RESUMO

PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. METHODS: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. RESULTS: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). CONCLUSION: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.


Assuntos
Estatura/fisiologia , Peso Corporal/fisiologia , Osteogênese Imperfeita/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Feminino , Humanos , Masculino , América do Norte , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/uso terapêutico , Adulto Jovem
17.
Eur J Pediatr ; 178(3): 323-329, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30499050

RESUMO

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal-recessive disorder, characterized by severe osteoporosis and early-onset blindness. Loss of function mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5) have been established as the genetic defect of the disease. We report the clinical and genetic evaluation of ten OPPG cases in eight related nuclear families and their close relatives. Bone mineral density (BMD) in OPPG patients was assessed by dual-energy X-ray absorptiometry (DXA). Genotyping of LRP5 gene and targeted detection of index mutation were performed by DNA direct sequencing. Four patients were introduced to bisphosphonates. Mutational screening of LRP5 gene revealed the c.2409_2503+79del deletion in homozygous state, expected to result in a truncated protein. Among 44 members of the pedigree, 10 (22%) were identified homozygous and 34 (59%) heterozygous for this mutation. All patients had congenital blindness and 7 of them had also impaired bone mineral density. Four of them received bisphosphonates and responded with decreased bone pain and improvement in BMD; however, 3 patients presented with one fracture during treatment.Conclusion: The current study presents the molecular and clinical profiles of 10 new OPPG cases, being part of an extended pedigree. Patients who received bisphosphonate treatment responded well with increase in their BMD, though fractures occurred during therapy. What is known: • OPPG syndrome is a rare genetic disorder characterized by congenital blindness and juvenile osteoporosis. • Loss of function mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5) is the genetic defect of the disease. What is new: • Genetic and clinical phenotype of 10 new OPPG patients. • The ten new OPPG patients presented with phenotypical variability in osseous manifestations.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Osteogênese Imperfeita , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Seguimentos , Marcadores Genéticos , Técnicas de Genotipagem , Grécia , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/prevenção & controle , Linhagem , Fenótipo , Deleção de Sequência , Resultado do Tratamento
18.
Gynecol Obstet Invest ; 84(2): 204-208, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30408804

RESUMO

BACKGROUND: We discuss the ethical decision points in a case report that describes a novel COL1A1 mutation associated to Osteogenesis Imperfecta type II, but with a non-lethal outcome. CASE: A 33-year-old female underwent a 21-week ultrasound that revealed short bowed femurs and humeri with old fractures and bowed tibias and fibulas. Amniotic fluid testing revealed a novel COL1A1 mutation (c.1840G>A; p.Gly614Arg). OI Type II diagnosis was made. A previously reported mutation of the same gene but different locus (c.1840G>C; p.Gly614Arg) led to a lethal form of OI type II. The newborn was delivered via a cesarean delivery and intravenous bisphosphonates (Zaledronic acid) was administered every 3 months. Currently the infant is 22 months old, is growing, with mild bilateral conductive hearing loss. CONCLUSION: The unexpected clinical outcome should serve as a reminder that phenotypic variability can occur with genetic mutations. Our case shows that the diagnosis of the type of OI should be based not only on clinical findings and genetic investigations but also on the clinical course over time.


Assuntos
Mutação , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Adulto , Colágeno Tipo I/genética , Feminino , Humanos , Lactente , Recém-Nascido , Osteogênese Imperfeita/tratamento farmacológico , Gravidez , Resultado da Gravidez , Ultrassonografia Pré-Natal , Ácido Zoledrônico/uso terapêutico
19.
J Bone Miner Res ; 34(2): 207-214, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30357929

RESUMO

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I encoding genes. Recent studies in mouse models of recessive OI, Crtap-/- mice, and dominant OI, +/G610C mice, found that application of a transforming growth factor beta (TGF-ß) neutralizing antibody 1D11 rescues the bone phenotype. In the present study, we investigated TGF-ß signaling in a mouse model of severe dominant OI with a high incidence of spontaneous fractures, Col1a1Jrt/+ mice, and the effect of TGF-ß neutralizing antibody 1D11 on bone phenotype in 8-week-old mice. Col1a1Jrt/+ mice had elevated TGF-ß signaling in bone tissue. Treatment of Col1a1Jrt/+ mice with 1D11 was associated with increased bone length but had no significant effect on bone mass or bone mechanical properties, and no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity) or resorption (tartrate-resistant acid phosphatase) were found. Our data thus indicate that the TGF-ß neutralizing antibody 1D11 is not effective in a mouse model of dominant OI with a high incidence of spontaneous fractures. © 2018 American Society for Bone and Mineral Research.


Assuntos
Anticorpos Neutralizantes/farmacologia , Osso e Ossos/metabolismo , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Osso e Ossos/patologia , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/deficiência , Proteínas da Matriz Extracelular/metabolismo , Camundongos , Camundongos Knockout , Chaperonas Moleculares/metabolismo , Osteogênese/genética , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
20.
Osteoporos Int ; 30(2): 513-517, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30448959

RESUMO

Atypical femoral fractures (AFFs) are low-energy femoral fractures with characteristic radiological features and a suspected relation to treatment with bisphosphonate (BP) or denosumab. In osteogenesis imperfecta (OI), BP is currently the drug of choice when medical treatment is indicated. Due to bone deformities, the radiologic appearance of femoral fractures may be different in patients with OI and patients with osteoporosis. We investigated the prevalence and appearance of femoral fractures in a cohort of adult patients with confirmed OI (55 patients, age range 19-69 years, 26 women (47%) and 35 patients (64%) had received BP treatment), who attended the outpatient clinic at Aarhus University Hospital. The fractures were evaluated according to major and minor AFF criteria. In our OI cohort, we found that eight out of 55 patients had suffered a femoral fracture in adult year: five women and three men, aged 25 to 54 years. One patient had OI type I, two had OI type III, four had OI type IV, and one had OI type V. All fractures were associated with no or minimal trauma. Four patients had fractures that fulfilled the criteria of AFFs. Two of the four patients had received long-term BP treatment prior to the fracture and three patients had severe deformities of the femur. Femoral fractures in OI imitate AFFs. This suggests that bone deformity, collagen deficiencies, and alterations in mineralization of bone may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment. Bone deformities should be monitored as part of the management of adult patients with OI. Continuous dull or aching pain in the groin or thigh should lead to radiographic examination. The radiologic appearance of femoral fractures may be different in patients with osteogenesis imperfecta (OI) and patients with osteoporosis, thus imitate atypical femoral fractures (AFF). We found that bone deformity, collagen deficiencies, and alterations in bone mineralization may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment.


Assuntos
Fraturas do Fêmur/etiologia , Osteogênese Imperfeita/complicações , Fraturas por Osteoporose/diagnóstico por imagem , Adulto , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Mau Alinhamento Ósseo/complicações , Mau Alinhamento Ósseo/diagnóstico por imagem , Estudos de Coortes , Diagnóstico Diferencial , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Feminino , Fraturas do Fêmur/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Radiografia , Adulto Jovem
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