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1.
J Immunol ; 201(11): 3175-3183, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30381479

RESUMO

A major manifestation of autoimmune polyendocrine syndrome type 1 (APS1) is hypoparathyroidism, which is suggested to result from aberrant immune responses against the parathyroid glands. The calcium-sensing receptor (CaSR), which plays a pivotal role in maintaining calcium homeostasis by sensing blood calcium levels and regulating release of parathyroid hormone (PTH), is an autoantibody target in APS1. In this study, the aim was to characterize the binding sites, specificity, functional affinity, IgG subclass, and functional effects of CaSR autoantibodies using phage-display technology, ELISA, and bioassays. The results indicated that CaSR autoantibody binding sites were at aa 41-69, 114-126, 171-195, and 260-340 in the extracellular domain of the receptor. Autoantibodies against CaSR epitopes 41-69, 171-195, and 260-340 were exclusively of the IgG1 subclass. Autoantibody responses against CaSR epitope 114-126 were predominantly of the IgG1 with a minority of the IgG3 subclass. Only autoantibodies recognizing CaSR epitopes 114-126 and 171-195 affected receptor activity; inositol-phosphate accumulation was increased significantly in HEK293-CaSR cells, and PTH secretion from PTH-C1 cells was reduced significantly when either were incubated with purified Ab and Ca2+ compared with Ca2+ alone. In conclusion, although the majority of APS1 patients do not have CaSR-stimulating autoantibodies, the hypoparathyroid state in a small minority of patients is the result of functional suppression of the parathyroid glands.

2.
Minerva Endocrinol ; 43(2): 156-167, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29125274

RESUMO

The term pseudohypoparathyroidism (PHP) refers to a spectrum of rare disorders of mineral metabolism, characterized by features due to end-organ resistance to PTH. The phenotypes of Albright hereditary osteodystrophy (AHO), originally described as associated to the disease, and progressive osseous heteroplasia, can be associated to the endocrine manifestations of hormonal resistance. Genetic or epigenetic alterations in the complex imprinted GNAS locus, encoding the alpha-subunit of the stimulatory G protein (GSα) and several other transcripts, give rise to the different forms oh PHP, which can be differentiated according to the phenotype, the response to PTH infusion and in vitro assays testing Gsα activity. Since PHP-related phenotypes are overlapping and other non GNAS-dependent disorders mimicking AHO, such as acrodysostosis, have been genetically characterized, the term PHP is today considered obsolete and better referred to the more comprehensive "inactivating PTH/PTHrP signaling disorder (iPPSD)" as proposed in a recent classification. This broad term include all the congenital rare disorders due to impaired PTH/PTHrP cAMP pathway. Genetic and epigenetic analyses, although not necessary for diagnosis made on the basis of major and minor criteria according to clinical and biochemical signs, will let to differentiate among the different forms for proper therapeutic planning, counseling and follow-up.


Assuntos
Pseudo-Hipoparatireoidismo/terapia , Humanos , Hipocalcemia/etiologia , Hormônio Paratireóideo/fisiologia , Pseudo-Hipoparatireoidismo/sangue , Pseudo-Hipoparatireoidismo/complicações
3.
Br J Health Psychol ; 23(2): 296-310, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29265563

RESUMO

OBJECTIVES: The randomized controlled trial examined factors that might be responsible for individual differences in physical activity change among men and women who participated in a lifestyle intervention. The main purpose of the analyses regarded the role of psychological mechanisms involving motivation, planning, self-monitoring, and habit strength. DESIGN: A two-arm digital intervention was conducted in Italy, Spain, and Greece to improve physical activity levels, with follow-ups at 3 and 6 months after baseline assessment. METHODS: Participants were 1,564 adults at baseline, n = 638 at 6-month follow-up. Linear mixed models examined the intervention effects, and a two-group longitudinal structural equation model explored which psychological constructs (motivation, planning, self-monitoring, habit strength) were associated with changes in physical activity. RESULTS: In addition to an overall increase in self-reported activity, there were interactions between time and sex and between time and experimental groups, and a triple interaction between time, sex, and experimental groups, indicating that men reported an increase in activity independent of groups, whereas women in the active control group did not benefit from the intervention. Planning, self-monitoring, and habit strength mediated sequentially between initial motivation and follow-up physical activity. CONCLUSIONS: Although the intervention produced overall improvements in physical activity, the time-by-treatment interaction emerged only for women. The mechanism included a sequence leading from motivation via planning, self-monitoring, and habit strength towards physical activity. Statement of contribution What is already known on this subject? Digital lifestyle interventions can be effective in terms of physical activity performance gains. Men are on average more physically active than women. Long-term adherence rates to digital interventions are usually low. What does this study add? Giving users of an online platform more interactive options did not make a difference. Women gained more than men from adaptive, dynamic online platform content. Individual characteristics (motivation, planning, self-monitoring, habit) were more important than online treatment features.

4.
Psychol Health ; 33(5): 652-668, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28990404

RESUMO

OBJECTIVE: An online intervention to improve fruit and vegetable (FV) intake examines the role of planning, outcome expectancies, self-efficacy and gender. Women are not only expected to eat more FV than men, but they are also expected to be more responsive to nutritional advice and benefit more from treatment. METHOD: A two-arm digital intervention with 269 men and 395 women (Mage = 41.2, SDage = 11.45; range: 19-66 years) was conducted in Italy, Spain and Greece, followed up at three and six months, comparing a static with a dynamic, feedback-intensive platform. RESULTS: Linear mixed models yielded an increase in FV consumption in both the dynamic and the static intervention arms. In men, outcome expectancies were positively related to follow-up FV intake. Dietary planning interacted with self-efficacy on behavioural outcomes. CONCLUSION: FV intake increased overall, and being a woman and involvement in planning facilitated behaviour change. Women seemed to be more engaged in the dynamic platform resulting in a higher amount of planning. Initial motivation, as indicated by outcome expectancies, seemed to be beneficial for men. Self-efficacious individuals benefitted from their engagement in planning, but self-efficacy did not compensate for failing to plan.

5.
Lancet Diabetes Endocrinol ; 5(7): 513-523, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28546097

RESUMO

BACKGROUND: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. FINDINGS: Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. INTERPRETATION: Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. FUNDING: Amgen.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Denosumab/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Fatores de Tempo
6.
Public Health Nutr ; 20(5): 938-947, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27829475

RESUMO

OBJECTIVE: The traditional Mediterranean diet includes high consumption of fruits, vegetables, olive oil, legumes, cereals and nuts, moderate to high intake of fish and dairy products, and low consumption of meat products. Intervention effects to improve adoption of this diet may vary in terms of individuals' motivational or volitional prerequisites. In the context of a three-country research collaboration, intervention effects on these psychological constructs for increasing adoption of the Mediterranean diet were examined. DESIGN: An intervention was conducted to improve Mediterranean diet consumption with a two-month follow-up. Linear multiple-level models examined which psychological constructs (outcome expectancies, planning, action control and stage of change) were associated with changes in diet scores. SETTING: Web-based intervention in Italy, Spain and Greece. SUBJECTS: Adults (n 454; mean age 42·2 (sd 10·4) years, range 18-65 years; n 112 at follow-up). RESULTS: Analyses yielded an overall increase in the Mediterranean diet scores. Moreover, there were interactions between time and all four psychological constructs on these changes. Participants with lower levels of baseline outcome expectancies, planning, action control and stage of change were found to show steeper slopes, thus greater behavioural adoption, than those who started out with higher levels. CONCLUSIONS: The intervention produced overall improvements in Mediterranean diet consumption, with outcome expectancies, planning, action control and stage of change operating as moderators, indicating that those with lower motivational or volitional prerequisites gained more from the online intervention. Individual differences in participants' readiness for change need to be taken into account to gauge who would benefit most from the given treatment.


Assuntos
Dieta Mediterrânea , Medicina Baseada em Evidências , Internet , Cooperação do Paciente , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Grécia , Comportamentos Relacionados com a Saúde , Humanos , Itália , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Avaliação Nutricional , Projetos Piloto , Estudos Prospectivos , Reprodutibilidade dos Testes , Espanha , Resultado do Tratamento , Adulto Jovem
7.
Br J Health Psychol ; 20(4): 824-41, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26112344

RESUMO

OBJECTIVES: Commonly, health behaviour theories have been applied to single behaviours, giving insights into specific behaviours but providing little knowledge on how individuals pursue an overall healthy lifestyle. In the context of diet and physical activity, we investigated the extent to which cross-behaviour cognitions, namely transfer cognitions and compensatory health beliefs, contribute to single behaviour theory. DESIGN: A total of 767 participants from two European regions (i.e., Germany n = 351, southern Europe n = 416) completed online questionnaires on physical activity and healthy dietary behaviour, behaviour-specific cognitions (i.e., self-efficacy, outcome expectancies, risk perception, intention, action planning, action control), as well as cross-behaviour cognitions, namely transfer cognitions and compensatory health beliefs. METHODS: Nested path models were specified to investigate the importance of cross-behaviour cognitions over and above behaviour-specific predictors of physical activity and healthy nutrition. RESULTS: Across both health behaviours, transfer cognitions were positively associated with intention and self-regulatory strategies. Compensatory health beliefs were negatively associated with intention. Action planning and action control mediated the effect of intentions on behaviour. CONCLUSIONS: Cross-behaviour cognitions contribute to single behaviour theory and may explain how individuals regulate more than one health behaviour. Statement of contribution What is already known on this subject? Cross-behaviour cognitions are related to a healthy lifestyle. Compensatory health beliefs hinder the adoption of a healthy lifestyle. Transfer cognitions encourage the engagement in a healthy lifestyle. What does this study add? Transfer cognitions were positively associated with intentions, action planning, and action control over and above behaviour-specific cognitions. Compensatory health beliefs were related to intentions only. Both facilitating and debilitating cross-behaviour cognitions need to be studied within a unified multiple behaviour research framework.


Assuntos
Comportamentos Relacionados com a Saúde , Teoria Psicológica , Adulto , Atitude Frente a Saúde , Cognição , Dieta/psicologia , Feminino , Humanos , Masculino , Atividade Motora , Assunção de Riscos , Autoeficácia , Inquéritos e Questionários
8.
J Rheumatol ; 41(9): 1884-92, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25086083

RESUMO

OBJECTIVE: Deficiency of 25-hydroxyvitamin D [25(OH)D] is reported to be common in patients with rheumatoid arthritis (RA); data in patients with juvenile idiopathic arthritis (JIA) are inconsistent. We assessed serum 25(OH)D in children, adolescents and young adults with JIA, in order to identify the risk factors for vitamin D deficiency in patients with JIA. METHODS: We evaluated 152 patients with JIA: 115 female, 37 male, mean age 16.2 ± 7.4 yrs; evaluated by onset type, 96 had oligoarticular, 35 polyarticular, 7 systemic, and 14 enthesitis-related arthritis (ERA). Patients were compared with a control group matched for sex and age. All patients and controls underwent laboratory tests of plasma 25(OH)D, parathyroid hormone (PTH), calcium, phosphorus, and bone alkaline phosphatase levels, and dual-energy x-ray absorptiometry examination. RESULTS: Patients with JIA showed significantly reduced 25(OH)D levels compared to controls (p < 0.001), even divided into subtypes (oligoarticular, p < 0.05; polyarticular, p < 0.005; systemic, p < 0.001; ERA, p < 0.005). Patients with active disease and/or frequent relapses had significantly reduced 25(OH)D levels compared to patients with no active disease and no frequent flares (p < 0.005, respectively). Nevertheless, JIA patients had significantly higher PTH levels compared to controls (p < 0.0001). JIA patients with 25(OH)D deficiency showed a significantly lower bone mineral apparent density than those with normal 25(OH)D levels (p < 0.001). CONCLUSION: JIA patients have reduced 25(OH)D and higher PTH values. This may explain at least in part why JIA patients, despite more effective current drugs, do not achieve bone-normal condition over time. JIA patients with more severe disease could require higher supplementation of vitamin D to maintain normal 25(OH)D serum levels. Longterm studies are needed to investigate the relationship between serum 25(OH)D levels and disease activity in JIA.


Assuntos
Artrite Juvenil/sangue , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Adolescente , Artrite Juvenil/complicações , Artrite Juvenil/diagnóstico por imagem , Densidade Óssea/fisiologia , Criança , Feminino , Humanos , Masculino , Hormônio Paratireóideo/sangue , Radiografia , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/diagnóstico por imagem , Adulto Jovem
9.
10.
J Bone Miner Res ; 29(1): 158-65, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23794225

RESUMO

In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p < 0.0001) and decreased by -4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Absorciometria de Fóton , Idoso , Fenômenos Biomecânicos/efeitos dos fármacos , Denosumab , Feminino , Análise de Elementos Finitos , Quadril/diagnóstico por imagem , Humanos , Pós-Menopausa , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/efeitos dos fármacos , Tomografia Computadorizada por Raios X
11.
FEBS J ; 280(3): 867-79, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23176170

RESUMO

This study comprised a comprehensive analysis of the glutathione (GSH) redox system during osteogenic differentiation in human osteoblast-like SaOS-2 cells. For the first time, a clear relationship between expression of specific factors involved in bone remodeling and the changes in the GSH/oxidized GSH (GSSG) redox couple induced during the early phases of the differentiation and mineralization process is shown. The findings show that the time course of differentiation is characterized by a decrease in the GSH/GSSG ratio, and this behavior is also related to the expression of osteoclastogenic markers. Maintenance of a high GSH/GSSG ratio due to GSH exposure in the early phase of this process increases mRNA levels of osteogenic differentiation markers and mineralization. Conversely, these events are decreased by a low GSH/GSSG ratio in a reversible manner. Redox regulation of runt-related transcription factor-2 (RUNX-2) activation through phosphorylation is shown. An inverse relationship between RUNX-2 activation and extracellular signal-regulated kinases related to GSH redox potential is observed. The GSH/GSSG redox couple also affects osteoclastogenesis, mainly through osteoprotegerin down-regulation with an increase in the ratio of receptor activator of NF-κB ligand to osteoprotegerin and vice versa. No redox regulation of receptor activator of NF-κB ligand expression was found. These results indicate that the GSH/GSSG redox couple may have a pivotal role in bone remodeling and bone redox-dysregulated diseases. They suggest therapeutic use of compounds that are able to modulate not just the GSH level but the intracellular redox system through the GSH/GSSG redox couple.


Assuntos
Biomarcadores Tumorais/metabolismo , Dissulfeto de Glutationa/metabolismo , Glutationa/metabolismo , Osteoblastos/metabolismo , Acetilcisteína/farmacologia , Western Blotting , Butionina Sulfoximina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glutamato-Cisteína Ligase/antagonistas & inibidores , Glutamato-Cisteína Ligase/metabolismo , Glutationa/farmacologia , Humanos , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Oxirredução , Ligante RANK/genética , Ligante RANK/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
J Bone Miner Res ; 24(4): 632-42, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19049332

RESUMO

Mutations affecting the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) are commonly found in Paget's disease of bone (PDB) and impair SQSTM1's ability to bind ubiquitin, resulting in dysregulated NF-kappaB signaling. In contrast, non-UBA domain mutations are rarer, and little is known about how they manifest their effects. We present the first characterization at the molecular, cellular, and functional level of a non-UBA domain missense mutation (A381V) of SQSTM1. Direct sequencing of exon 7 of the SQSTM1 gene in an Italian PDB patient detected a heterozygous C to T transversion at position 1182, resulting in an alanine to valine substitution at codon 381. Pull-down assays showed the non-UBA region of SQSTM1 that contains A381 is important in mediating ubiquitin-binding affinity and that the A381V mutation exerts weak negative effects on ubiquitin binding. Structural and binding analyses of longer UBA constructs containing A381, using NMR spectroscopy and circular dichroism, showed this region of the protein to be largely unstructured and confirmed its contribution to increased ubiquitin-binding affinity. Co-transfections of U20S cells showed that the A381V mutant SQSTM1 co-localized with ubiquitin with a cellular phenotype indistinguishable from wildtype. Finally, effects of the wildtype and mutant SQSTM1 on NF-kappaB signaling were assessed in HEK293 cells co-transfected with an NF-kappaB luciferase reporter construct. A381V mutant SQSTM1 produced a level of activation of NF-kappaB signaling greater than wildtype and similar to that of UBA domain mutants, indicating that non-UBA and UBA domain mutations may exert their effects through a common mechanism involving dysregulated NF-kappaB signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação de Sentido Incorreto/genética , Osteíte Deformante/genética , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Linhagem Celular , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Proteínas Mutantes/metabolismo , NF-kappa B/metabolismo , Fenótipo , Ligação Proteica , Estrutura Terciária de Proteína , Proteína Sequestossoma-1 , Transdução de Sinais , Transfecção , Ubiquitina/metabolismo
14.
Clin Drug Investig ; 26(2): 63-74, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17163237

RESUMO

BACKGROUND: The objective of the study was to evaluate the effects of alendronic acid once weekly relative to risedronic acid once weekly on bone mineral density (BMD), markers of bone turnover and tolerability in the treatment of osteoporosis in postmenopausal women. METHODS: This was a randomised, double-masked, double-dummy multicentre international study (75 centres in 27 countries in Europe, the Americas and Asia-Pacific). A total of 1303 women were screened and 936 with low bone density (T-score < or = -2.0 at the spine, hip trochanter, total hip or femoral neck) were randomised; 91% (n = 854) completed the study. Patients were randomised to treatment with either active alendronic acid 70 mg weekly (Fosamax) and placebo identical to risedronic acid weekly or active risedronic acid 35 mg weekly (Actonel) and placebo identical to alendronic acid weekly for 12 months. The primary efficacy endpoint was the percentage change from baseline in hip trochanter BMD at 12 months. Secondary endpoints included the percentage change from baseline in lumbar spine, total hip and femoral neck BMD; biochemical markers of bone turnover (including serum bone-specific alkaline phosphatase [BSAP] and urinary type I collagen N-telopeptides [NTx]); and safety and tolerability as assessed by reporting of adverse experiences. RESULTS: Alendronic acid produced greater increases in BMD than did risedronic acid at 12 months at all sites measured. Mean percentage increases from baseline in hip trochanter BMD at month 12 were 3.56% and 2.71% in the alendronic acid and risedronic acid groups, respectively (treatment difference [95% CI]: 0.83% [0.22, 1.45; p = 0.008]). Mean percentage increases from baseline were greater with alendronic acid than risedronic acid at the lumbar spine, total hip and femoral neck BMD at month 12 (p = 0.002, p < 0.001, p = 0.039, respectively). Increases in BMD with alendronic acid compared with risedronic acid were also significantly greater at 6 months at the trochanter and total hip. There was a greater reduction in bone turnover with alendronic acid compared with risedronic acid: NTx decreased 58% with alendronic acid compared with 47% with risedronic acid at 12 months (p < 0.001); and BSAP decreased 45% with alendronic acid compared with 34% with risedronic acid at 12 months (p < 0.001). Overall tolerability and upper gastrointestinal tolerability were similar for both agents. CONCLUSIONS: Alendronic acid once weekly produced greater BMD increases at both hip and spine sites and greater reductions in bone turnover relative to risedronic acid once weekly. Both agents were well tolerated with no significant difference in upper gastrointestinal adverse experiences. Clinicians should consider these results when making treatment decisions for postmenopausal women with osteoporosis.


Assuntos
Alendronato/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Ácido Etidrônico/análogos & derivados , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Alendronato/efeitos adversos , Método Duplo-Cego , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Ácido Risedrônico
15.
J Bone Miner Res ; 19(6): 1013-7, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15125799

RESUMO

UNLABELLED: PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder. INTRODUCTION: Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight different human chromosomal loci are correlated with its pathogenesis. Mutations of the sequestosome1 (SQSTM1) gene were identified as responsible for most of the sporadic and familial forms of Paget in patients of French Canadian and British descent. Such mutations were located at exon 7 and 8 levels, encoding for the ubiquitin protein-binding domain (UBA) and representing a mutational hot spot area. MATERIALS AND METHODS: To verify the involvement of this gene in Italian subjects affected by PDB, we performed mutational analysis in 62 sporadic PDB cases. RESULTS: We described three different mutations at exon 8 level: P392L, already described in the French Canadian population and families predominantly of British descendent, and two novel mutations consisting of the amino acid substitutions M404V and G425R. No significant differences in the clinical history of PDB have been observed in patients with SQSTM1 mutations in respect to those without. CONCLUSIONS: Even though our findings suggest a minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget's cases, the identification of different significant mutations within the SQSTM1 gene in unrelated, but clinically similar individuals, offers extremely convincing evidence for a causal relationship between this gene and PDB. Longitudinal studies are needed to assess the penetrance of genotype/phenotype correlations. Our findings confirm the evidence of a clustered mutation area at this level in this disorder.


Assuntos
Éxons , Mutação , Osteíte Deformante/genética , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Primers do DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Sequestossoma-1
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