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1.
J Bone Miner Res ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32176830

RESUMO

OBJECTIVES: Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB) but little is known about the clinical characteristics of those with early disease. METHODS: Radionuclide bone scans, biochemical markers of bone turnover and clinical characteristics were analysed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. RESULTS: We studied 222 individuals of whom 54.9% were female with average (± sem) age of 50.1± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu which was present in 141/222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%) of which 9 (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 vs. 49.8 ± 8.9, p=0.07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years vs. 59 years, p=0.25). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalised to the upper limit of normal in each centre were higher in those with lesions (0.75 ± 0.69 vs 0.42 ± 0.29; p<0.0001). Similar findings were observed for other biochemical markers of bone turnover but the sensitivity of ALP and other markers in detecting lesions was poor. CONCLUSIONS: Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow up of this cohort will provide important information on the natural history of early PDB and its response to treatment. This article is protected by copyright. All rights reserved.

2.
BMJ Open ; 9(9): e030689, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31488492

RESUMO

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

4.
BMJ Open ; 7(7): e016486, 2017 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-28706103

RESUMO

INTRODUCTION: Acute kidney injury (AKI) affects more than 50% of critically ill patients. The formation of calcitriol, the active vitamin D metabolite, from the main inactive circulating form, 25-hydroxyvitamin D (25(OH)D), occurs primarily in the proximal renal tubules. This results in a theoretical basis for reduction in levels of calcitriol over the course of an AKI. Vitamin D deficiency is highly prevalent in critically ill adults, and has been associated with increased rates of sepsis, longer hospital stays and increased mortality. The primary objective of this study is to perform serial measurements of 25(OH)D and calcitriol (1,25(OH)2D), as well as parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels, in critically ill adult patients with and without AKI, and to determine whether patients with AKI have significantly lower vitamin D metabolite concentrations. The secondary objectives are to describe dynamic changes in vitamin D metabolites, PTH and FGF23 during critical illness; to compare vitamin D metabolite concentrations in patients with AKI with and without renal replacement therapy; and to investigate whether there is an association between vitamin D status and outcomes. METHODS AND ANALYSIS: 230 general adult intensive care patients will be recruited. The AKI arm will include 115 critically ill patients with AKI Kidney Disease Improving Global Outcome stage II or stage III. The comparison group will include 115 patients who require cardiovascular or respiratory support, but who do not have AKI. Serial measurements of vitamin D metabolites and associated hormones will be taken on prespecified days. Patients will be recruited from two large teaching Trusts in England. Data will be analysed using standard statistical methods. ETHICS AND DISSEMINATION: Ethical approval was obtained. Upon completion, the study team will submit the study report for publication in a peer-reviewed scientific journal and for conference presentation. TRIAL REGISTRATION NUMBER: NCT02869919; Pre-results.


Assuntos
Lesão Renal Aguda/sangue , Vitamina D/sangue , Lesão Renal Aguda/metabolismo , Estudos de Coortes , Estado Terminal , Humanos , Estudos Prospectivos , Projetos de Pesquisa , Vitamina D/metabolismo
5.
Trials ; 16: 326, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26231610

RESUMO

BACKGROUND: Metabolic acidosis is more common with advancing chronic kidney disease, and has been associated with impaired physical function, impaired bone health, accelerated decline in kidney function and increased vascular risk. Although oral sodium bicarbonate is widely used to correct metabolic acidosis, there exist potential risks of therapy including worsening hypertension and fluid overload. Little trial evidence exists to decide whether oral bicarbonate therapy is of net benefit in advanced chronic kidney disease, particularly in older people who are most commonly affected, and in whom physical function, quality of life and vascular health are at least as important outcomes as decline in renal function. METHODS/DESIGN: BiCARB is a multi-centre, double-blind, placebo controlled, randomised trial evaluating the clinical and cost-effectiveness of oral sodium bicarbonate in the management of older people with chronic kidney disease and severely reduced glomerular filtration rate (GFR) who have a mild degree of metabolic acidosis. The trial will recruit 380 patients from renal, Medicine for the Elderly, and primary care services across centres in the United Kingdom. Male and female patients aged 60 years and older with an estimated glomerular filtration rate of <30 mL/min/1.73 m(2), not on dialysis, and with serum bicarbonate concentrations <22 mmol/L will be eligible for participation. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at 12 months. Secondary outcomes include muscle strength, quality of life measured using the EQ-5D score and KDQoL tools, cost effectiveness, renal function, presence of albuminuria and blood pressure. Markers of bone turnover (25-hydroxyvitamin D, 1,25-hydroxyvitamin D, tartrate-resistant acid phosphatase-5b and bone-specific alkaline phosphatase) and vascular health (B-type natriuretic peptide) will be measured. Participants will receive a total of 24 months of either bicarbonate or placebo. The results will provide the first robust test of the overall clinical and cost-effectiveness of this commonly used therapy in older patients with severely reduced kidney function. TRIAL REGISTRATION: www.isrctn.com; ISRCTN09486651, registered 17 February 2012.


Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Acidose/tratamento farmacológico , Qualidade de Vida , Insuficiência Renal Crônica/complicações , Bicarbonato de Sódio/administração & dosagem , Acidose/complicações , Acidose/diagnóstico , Acidose/economia , Acidose/fisiopatologia , Acidose/psicologia , Administração Oral , Fatores Etários , Biomarcadores/sangue , Protocolos Clínicos , Análise Custo-Benefício , Método Duplo-Cego , Custos de Medicamentos , Feminino , Taxa de Filtração Glomerular , Nível de Saúde , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Força Muscular , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/economia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/psicologia , Projetos de Pesquisa , Índice de Gravidade de Doença , Bicarbonato de Sódio/efeitos adversos , Bicarbonato de Sódio/economia , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Reino Unido
6.
PLoS One ; 9(3): e91363, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24646518

RESUMO

BACKGROUND: Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease (CKD). We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function, endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [25(OH)D] is unknown, which this study investigated. METHODS: We assessed non-diabetic patients with CKD stage 3/4, age 17-80 years and serum 25(OH)D <75 nmol/L. Brachial artery Flow Mediated Dilation (FMD), Pulse Wave Velocity (PWV), Augmentation Index (AI) and circulating blood biomarkers were evaluated at baseline and at 16 weeks. Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks. RESULTS: Clinical characteristics of 26 patients were: age 50±14 (mean±1SD) years, eGFR 41±11 ml/min/1.73 m2, males 73%, dyslipidaemia 36%, smokers 23% and hypertensives 87%. At 16-week serum 25(OH)D and calcium increased (43±16 to 84±29 nmol/L, p<0.001 and 2.37±0.09 to 2.42±0.09 mmol/L; p = 0.004, respectively) and parathyroid hormone decreased (10.8±8.6 to 7.4±4.4; p = 0.001). FMD improved from 3.1±3.3% to 6.1±3.7%, p = 0.001. Endothelial biomarker concentrations decreased: E-Selectin from 5666±2123 to 5256±2058 pg/mL; p = 0.032, ICAM-1, 3.45±0.01 to 3.10±1.04 ng/mL; p = 0.038 and VCAM-1, 54±33 to 42±33 ng/mL; p = 0.006. eGFR, BP, PWV, AI, hsCRP, von Willebrand factor and Fibroblast Growth Factor-23, remained unchanged. CONCLUSION: This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness, serum calcium or FGF-23. TRIAL REGISTRATION: ClinicalTrials.gov NCT02005718.


Assuntos
Suplementos Nutricionais , Insuficiência Renal Crônica/dietoterapia , Deficiência de Vitamina D/dietoterapia , Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cálcio/sangue , Selectina E/sangue , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Análise de Onda de Pulso , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Molécula 1 de Adesão de Célula Vascular/sangue , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vitamina D/administração & dosagem , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/fisiopatologia
7.
Int Immunopharmacol ; 17(3): 693-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24007780

RESUMO

Inflammatory/pro-resorptive cytokines and chemokines form part of a complex inter-dependent network and may be influenced by vitamin D. We investigated their inter-relationship and the effect of a loading dose of vitamin D. We measured plasma concentrations of an array of cytokines including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, IL-17, IL-8, granulocyte macrophage colony stimulating factor (GM-CSF), and the chemokine monocyte chemoattractant protein-1 (MCP-1). Cytokines, 25 (OH) vitamin D, 1,25 (OH)2 vitamin D, the Wnt inhibitor, DKK1 concentrations and bone turnover markers were measured at baseline and 3 months following a bolus dose (300,000 IU) of vitamin D2 in 39 subjects with vitamin D insufficiency. We observed strong correlations between TNF-α with GM-CSF (r=0.628, p<0.001), IL-17 (r=0.7, p<0.001) and MCP-1 (r=0.5, p=0.001), between IL-1ß with IL-17 (r=0.45, p=0.004) and between the 2 chemokines, IL-8 and MCP-1 (r=0.45, p=0.004). A positive correlation was seen between DKK1 and IL-1ß (r=0.35, p=-0.029). Following vitamin D loading at 3 months, the relationships between some of the cytokines changed (TNF-α and MCP-1: r=0.38, p=0.017, IL-1ß and IL-17: r=0.3, p=0.06). 1,25 (OH)2 vitamin D increased markedly following supplementation. Significant correlations were seen between 25 (OH) vitamin D (r=0.4 p=0.016) and 1,25 (OH)2 vitamin D (r=0.39 p=0.02) with plasma CTX (marker of bone resorption) at 3 months. TNF-α and IL-1ß increased significantly at 3 months (p<0.05). The close association between several cytokines is influenced by vitamin D status. Acute increases in 1,25 (OH)2 vitamin D, achieved with loading doses of vitamin D, lead to increases in pro-resorptive cytokines.


Assuntos
Citocinas/sangue , Deficiência de Vitamina D/sangue , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem , Idoso , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vitamina D/sangue , Vitamina D/farmacocinética , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas/sangue , Vitaminas/farmacocinética
8.
Bone ; 56(1): 42-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23702386

RESUMO

Epidemiological studies have shown an association between bone loss/osteoporosis and vascular calcification (VC). Recent studies have implicated the Wnt signalling pathway in the pathogenesis of VC. We investigated the association between circulating concentrations of Wnt inhibitors; DKK1 and sclerostin with bone mineral density (BMD), abdominal aortic calcification (AAC) and arterial stiffness in post-menopausal women. One hundred and forty six post-menopausal women aged (mean [SD]) 61.5[6.5] years were studied. Sclerostin and DKK1 were measured in serum. BMD was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH). AAC was detected by Vertebral Fracture Assessment (VFA) imaging and quantified using an 8- and 24- point scoring methods. Arterial stiffness was determined by aortic pulse wave velocity (PWV). A significant positive correlation was observed between sclerostin and BMD at the FN (r = 0.166, p = 0.043) and TH (r = 0.165, p = 0.044). The association remained significant at the FN (p = 0.045) and TH (p = 0.026) following adjustment for confounders. No significant correlation was observed between DKK1 and BMD. In contrast, there was a significant negative correlation between log DKK1 and AAC (24-point score: r = -0.25, p = 0.008 and 8-point score: r = -0.21, p = 0.024). Subjects with AAC score of 1 or less had significantly higher DKK1 (p = 0.01). The association between DKK1 and AAC remained significant following correction for age, blood pressure, cholesterol (24-point score: p = 0.017, 8-point score: p = 0.044). In adjusted linear regression analysis, sclerostin was positively associated with AAC (24-point score: p = 0.048, 8-point score: p = 0.031). Subjects with a PWV>9 m/s had significantly higher sclerostin than those with PWV <9 m/s: 23.8[12.3], vs 29.7 [14] pmol/l, p = 0.03). No association was observed between DKK1 and PWV. The opposite association between AAC and the 2 Wnt signaling inhibitors is of interest and merits further investigations. Future longitudinal studies are needed to establish the precise role of sclerostin and DKK1 in the pathogenesis of VC.


Assuntos
Densidade Óssea , Proteínas Morfogenéticas Ósseas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pós-Menopausa/fisiologia , Calcificação Vascular/fisiopatologia , Rigidez Vascular , Via de Sinalização Wnt , Aorta Abdominal/patologia , Aorta Abdominal/fisiopatologia , Pressão Sanguínea , Feminino , Marcadores Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Modelos Lineares , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Análise de Onda de Pulso , Calcificação Vascular/sangue
9.
Ital J Anat Embryol ; 118(1 Suppl): 34-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24640568

RESUMO

Insulin-like factor 3 (INSL3) is a peptide hormone produced in leydig cells of the testes. Its role in the adult male is unknown but INSL3 and its receptor RXFP2 have been linked to bone cell differentiation. It is speculated that low levels of INSL3 could be responsible for low bone mineral density in patients with primary osteoporosis and Klinefelter's Syndrome. The aim of this study was to assess plasma INSL3 in patients with osteoporosis and Klinefelter's Syndrome compared to healthy males. Fourteen healthy males, 21 males with osteoporosis (4 primary and 17 secondary) and 4 patients with Klinefelter's Syndrome were studied. Plasma INSL3, testosterone, LH, FSH and Sex hormone-binding globulin were evaluated. Plasma INSL3 concentrations were similar in osteoporosis patients compared to healthy controls (0.72 vs. 0.69 ng/mL, p = 0.26). INSL3 was significantly higher in patients with primary osteoporosis (n = 4) compared to age-matched healthy controls (n = 8) (0.845 vs. 0.665 ng/mL, p = 0.021). INSL3 levels in Klinefelter's Syndrome patients were significantly lower compared to healthy controls (0.39 vs. 0.69 ng/mL, p = 0.01). Plasma INSL3 levels were lower in Klinefelter's Syndrome reflecting testicular failure. INSL3 levels were not lower in men with osteoporosis. The relationship between INSL3, its receptor and bone metabolism requires further study.


Assuntos
Hipogonadismo/fisiopatologia , Insulina/fisiologia , Síndrome de Klinefelter/fisiopatologia , Osteoporose/fisiopatologia , Proteínas/fisiologia , Adulto , Humanos , Masculino
10.
Clin Transplant ; 26(6): E617-23, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23083399

RESUMO

In this study, we explored the determinants of vitamin D status in a large cohort of stable, Long-term renal transplant (RTx) patients. Serum 25(OH)D concentrations, and bone biochemistry parameters, were retrospectively analyzed from 266 RTx patients (>10 yr post-engraftment) presenting to clinic over the course of a year. Forty-five percent of the cohort were vitamin D deficient (<37.5 nM), 38% insufficient (37.5 75-nM), and 17% sufficient (>75 nM). Serum 25(OH)D concentrations were higher in patients presenting in summer (p<0.001) and in more active patients (p<0.05). RTx patients with non-melanoma skin cancer (NMSC) (n=45) had higher 25(OH)D concentrations than patients without NMSC (n=221; p<0.05) despite these patients being older, having worse eGFR, transplanted for longer, and less active physically (p<0.05). Lower 25(OH)D concentrations were associated with higher PTH concentrations (p<0.05) which, in the setting of widespread hypovitaminosis, suggests that secondary hyperparathyroidism was common in this cohort. In conclusion, season and activity status are important determinants of vitamin D status. We report, for the first time, that NMSC is associated with higher 25(OH)D, probably through increased UV radiation exposure. Long-term RTx patients may benefit from oral vitamin D supplementation, but this requires a randomized controlled trial to confirm.


Assuntos
Nefropatias/cirurgia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Deficiência de Vitamina D/diagnóstico , Vitamina D/sangue , Densidade Óssea , Estudos Transversais , Suplementos Nutricionais , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/etiologia
11.
Int J Womens Health ; 4: 455-69, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23071416

RESUMO

Bisphosphonates (BPs) are synthetic analogues of pyrophosphate. They inhibit bone resorption and are therefore widely used in disorders where there are increases or disruptions in bone resorption. This includes postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease of bone, and malignancy-related bone loss. To best understand the clinical application of BPs, an understanding of their pharmacokinetics and pharmacodynamics is important. This review describes the structure, pharmacology and mode of action of BPs, focusing on their role in clinical practice. Controversies and side effects surrounding their use will also be discussed.

12.
Calcif Tissue Int ; 90(6): 473-80, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22527202

RESUMO

Abnormalities of bone metabolism and increased vascular calcification are common in chronic kidney disease (CKD) and important causes of morbidity and mortality. The Wnt signaling pathway may play a role in the bone and vascular disturbances seen in CKD, termed collectively "CKD-MBD." The aim of the study was to investigate the possible association of circulating concentrations of the secreted Wnt signaling inhibitors DKK1 and sclerostin with BMD and arterial stiffness in predialysis CKD. Seventy-seven patients (48 M, 29 F), mean age 57 (SD = 14) years with CKD stages 3B (n = 32) and 4 (n = 45) were studied. Sclerostin, DKK1, PTH, and 1,25(OH)(2)D were analyzed. BMD was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH), and forearm (FARM). Arterial stiffness index was determined by contour analysis of digital volume pulse (SI(DVP)). There was a positive correlation between sclerostin and age (r = 0.47, p < 0.000). Sclerostin was higher in men than women (p = 0.013). Following correction for age and gender, there was a negative association between GFR and sclerostin (p = 0.002). We observed a positive association between sclerostin and BMD at the LS (p = 0.0001), FN (p = 0.004), and TH (p = 0.002). In contrast, DKK1 was negatively associated with BMD at the FN (p = 0.038). A negative association was seen between DKK1 and SI(DVP) (p = 0.027). Our data suggest that the Wnt pathway may play a role in CKD-MBD. Prospective studies are required to establish the clinical relevance of sclerostin and DKK1 as serological markers in CKD.


Assuntos
Proteínas Morfogenéticas Ósseas/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Falência Renal Crônica/complicações , Rigidez Vascular , Densidade Óssea , Proteínas Morfogenéticas Ósseas/metabolismo , Remodelação Óssea , Diálise , Feminino , Marcadores Genéticos , Taxa de Filtração Glomerular , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Calcificação Vascular/patologia , Via de Sinalização Wnt
13.
J Clin Pathol ; 64(12): 1042-50, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21896577

RESUMO

With an increasingly ageing population, osteoporosis and osteoporosis-related fractures is fast becoming an important public health problem placing a considerable economic burden on health service resources. This does not account for the substantial pain, disability and indeed mortality incurred after a fracture, particularly a hip fracture. Osteoporosis is a systemic skeletal disorder which results from an imbalance in bone remodeling. This leads to a reduction in bone strength and increased susceptibility to fracture. It affects up to 1 in 2 women and 1 in 5 men. In the past 2 decades, there have been significant advances in bone biology which have helped in the understanding of the pathogenesis of osteoporosis and have led to improved therapies. In developing strategies for fracture prevention, it is important to identify those individuals with the highest fracture risk who will require pharmacological intervention. Treatment is aimed at fracture prevention and includes modification of general lifestyle factors which have been linked to fractures in epidemiological studies and ensuring optimum calcium and vitamin D intake as adjunct to active anti-fracture therapy. A number of drugs are now approved for the treatment of osteoporosis. This review article will describe the pathogenesis of osteoporosis and focus on the methods currently in use for the identification of patients at high fracture risk and will highlight their usefulness and limitations. The existing anti-fracture pharmacotherapies and those in development will be reviewed. Assessment of their effectiveness including the use of biochemical markers of bone turnover in this clinical context will be reviewed.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Absorciometria de Fóton , Biomarcadores/sangue , Densidade Óssea/fisiologia , Remodelação Óssea/fisiologia , Cálcio/metabolismo , Dieta , Feminino , Fraturas Ósseas/prevenção & controle , Humanos , Estilo de Vida , Masculino , Osteogênese/fisiologia , Osteoporose/diagnóstico , Osteoporose/etiologia , Medição de Risco , Deficiência de Vitamina D/complicações
14.
Cytokine ; 46(3): 376-81, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19394248

RESUMO

Vascular endothelial growth factor (VEGF) plays an important role in bone health. We investigated the factors which influence circulating VEGF and their association with bone mineral density (BMD). Two hundred and fifty two post-menopausal women aged 64.5 [9.2] years were studied. BMD was determined at the lumbar spine (LS), femoral neck (FN) and total hip (TH). Serum oestradiol and VEGF were measured. Subjects were genotyped for two polymorphic variants in the 5' untranslated region of the VEGF gene; G(634)C and C(936)T. Positive correlations were seen between circulating VEGF and BMI (r=0.2, p<0.02) and oestradiol (r=0.25, p<0.001). Following multi-linear regression analysis, serum VEGF was associated with the G(634) polymorphism (p=0.08) and dietary calcium intake (p=0.02). The association with calcium intake may be mediated by PTH as suggested by the in vitro studies. Following correction for confounders, there was no association between circulating VEGF and BMD at any site. Both VEGF polymorphisms were significant predictors of LS BMD G(634)C: p=0.017 and C(936)T: p=0.05. Circulating VEGF may be influenced by genetic, environmental and endocrine factors. Polymorphic variants in the VEGF gene are associated with spine BMD. Further larger studies are needed.


Assuntos
Densidade Óssea/fisiologia , Osteoporose Pós-Menopausa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/genética , Linhagem Celular , Estradiol/metabolismo , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoporose Pós-Menopausa/genética , Hormônio Paratireóideo/farmacologia , Polimorfismo Genético , Fator A de Crescimento do Endotélio Vascular/genética
15.
BMC Nephrol ; 9: 12, 2008 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-18816383

RESUMO

BACKGROUND: Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive disorder of renal calcium and magnesium wasting frequently complicated by progressive chronic renal failure in childhood or adolescence. METHODS: A 7 year old boy was investigated following the findings of marked renal insufficiency and nephrocalcinosis in his 18-month old sister. He too was found to have extensive nephrocalcinosis with increased fractional excretion of magnesium: 12.4% (<4%) and hypercalciuria: 5.7 mmol (< 2.5/24 hours). He had renal impairment, partial distal renal tubular acidosis and defective urinary concentrating ability. Therapy with thiazide diuretics and magnesium supplements failed to halt the progression of the disorder. Both children subsequently underwent renal transplantation. Both children's parents are unaffected and there is one unaffected sibling. RESULTS: Mutation analysis revealed 2 heterozygous mutations in the claudin 16 gene (CLDN16) in both affected siblings; one missense mutation in exon 4: C646T which results in an amino acid change Arg216Cys in the second extracellular loop of CLDN16 and loss of function of the protein and a donor splice site mutation which changes intron 4 consensus splice site from 'GT' to 'TT' resulting in decreased splice efficiency and the formation of a truncated protein with loss of 64 amino acids in the second extracellular loop. CONCLUSION: The mutations in CLDN16 in this kindred affect the second extra-cellular loop of claudin 16. The clinical course and molecular findings suggest complete loss of function of the protein in the 2 affected cases and highlight the case for molecular diagnosis in individuals with FHHNC.


Assuntos
Triagem de Portadores Genéticos , Hipercalciúria/genética , Proteínas de Membrana/genética , Mutação/genética , Nefrocalcinose/genética , Adulto , Claudinas , Espaço Extracelular/genética , Feminino , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/genética , Síndrome de Gitelman/cirurgia , Humanos , Hipercalciúria/diagnóstico , Hipercalciúria/cirurgia , Transplante de Rim , Masculino , Proteínas de Membrana/deficiência , Nefrocalcinose/diagnóstico , Nefrocalcinose/cirurgia , Processamento de RNA/genética
16.
Calcif Tissue Int ; 83(2): 112-20, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18612580

RESUMO

Arterial calcification leading to increased arterial stiffness, a powerful risk factor for cardiovascular disease, may underlie the association of osteoporosis with cardiovascular disease in postmenopausal women. Osteoprotegerin (OPG), an indirect inhibitor of osteoclastogenesis, may be involved in arterial calcification. We examined relationships between calcification of subclinical atherosclerotic plaque and arterial stiffness with bone mineral density (BMD) and OPG in a group of 54 postmenopausal women referred for routine osteoporosis screening by dual-energy X-ray absorptiometric scanning of the lumbar spine and hip. Presence of calcified and noncalcified plaque in carotid and femoral arteries was examined using ultrasonography. Pulse wave velocity (PWV), a measure of arterial stiffness, was determined by sequential tonometry over the carotid and femoral region. Fifty-nine percent of osteoporotic women had calcified (echogenic) plaque at one or more sites compared with 42% and 20% for women with osteopenia and normal BMD, respectively (P = 0.04). There was a significant negative correlation between PWV and hip BMD (r = -0.35, P = 0.01), which remained significant when age, mean arterial pressure, and serum lipids were taken into account (P = 0.05). No significant relationships were observed between serum concentrations of OPG and lumbar spine or total hip BMD or with the number of arterial sites with calcified or noncalcified plaque. However, there was a strong correlation between OPG and PWV (r = 0.44, P = 0.001), which remained significant when adjusted for age (P = 0.01). These findings suggest that decreased BMD is associated with arterial calcification and stiffening and raise the possibility that OPG is a marker of arterial stiffening, independent of any association with BMD.


Assuntos
Aterosclerose/patologia , Densidade Óssea/fisiologia , Calcinose/patologia , Programas de Rastreamento/métodos , Osteoporose Pós-Menopausa/diagnóstico , Osteoprotegerina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/sangue , Aterosclerose/diagnóstico por imagem , Biomarcadores/metabolismo , Calcinose/sangue , Calcinose/diagnóstico por imagem , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Feminino , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/metabolismo , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/metabolismo , Pessoa de Meia-Idade , Radiografia , Ultrassonografia
17.
BMC Musculoskelet Disord ; 8: 3, 2007 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-17214897

RESUMO

BACKGROUND: It is still unclear whether addition of calcium/vitamin D supplements leads to an incremental benefit in patients taking bisphosphonates and whether achievement of serum level of 25 (OH) vitamin D of at least 70 nmol/L has an impact on the skeletal response to bisphosphonates. Moreover the maintenance of BMD after bisphosphonates withdrawal with the continuation of calcium/vitamin D supplements only, remains uncertain. The aims were to assess the impact of vitamin D status on changes in bone mineral density (BMD) in firstly patients with post-menopausal osteoporosis on bisphosphonates and secondly following discontinuation of bisphosphonates after long-term use. METHODS: Two patient groups were recruited. The first study population comprised of 112 women treated with a bisphosphonate. The second study population consisted of 35 women who had been on bisphosphonates for > 5 years in whom the treatment agent was discontinued. Baseline BMD, changes in BMD following treatment, duration of treatment, serum 25 (OH) vitamin D, parathyroid hormone (PTH), urine C-terminal telopeptides of type 1 collagen (CTX) were obtained on the study participants. RESULTS: In the first study group, subjects with serum vitamin D concentrations (> 70 nmol/L) had a significantly lower serum PTH level (mean [SEM] 41 2 ng/L). PTH concentrations of 41 ng/L or less was associated with a significantly higher increase in BMD at the hip following treatment with bisphosphonates compared to patients with PTH > 41 ng/L (2.5% [0.9] v/s -0.2% [0.9], P = 0.04). In the second study group, discontinuation of bisphosphonate for 15 months after long-term treatment did not result in significant bone loss at the lumbar spine and total hip, although a trend towards gradual decline in BMD at the femoral neck was observed. CONCLUSION: the data suggest that optimal serum 25 (OH) vitamin D concentration may lead to further reduction in bone loss at the hip in patients on bisphosphonates. A prospective controlled trial is needed to evaluate whether the response to bisphosphonates is influenced by vitamin D status. BMD is preserved at the lumbar spine and total hip following discontinuation of bisphosphonate for a short period following long-term treatment, although a gradual loss occurs at the femoral neck.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Difosfonatos/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Vitamina D/uso terapêutico , Idoso , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/administração & dosagem , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/fisiopatologia , Hormônio Paratireóideo/sangue , Síndrome de Abstinência a Substâncias , Tempo , Resultado do Tratamento , Vitamina D/sangue , Suspensão de Tratamento
18.
Clin Endocrinol (Oxf) ; 65(5): 598-605, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17054460

RESUMO

OBJECTIVES: Associations between calcium-sensing receptor (CaSR) polymorphisms and serum calcium, PTH and bone mineral density (BMD) have been reported by six studies. However, three other studies have failed to detect such associations. We therefore further investigated three CaSR coding region polymorphisms (Ala986Ser, Arg990Gly and Gln1011Glu) for associations with indices of calcium homeostasis and BMD and for alterations in receptor function. PATIENTS AND DESIGN: One hundred and ten adult, Caucasian, female, dizygotic twin pairs were investigated for associations between the three CaSR polymorphisms and serum calcium, albumin, PTH, 25-hydroxyvitamin D(3) (25OHD(3)), 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], urinary calcium excretion and BMD. Each polymorphic CaSR was also transfected into HEK293 cells and functionally evaluated. RESULTS: There was a lack of association between each of these three CaSR polymorphisms and serum calcium corrected for albumin, PTH, 25OHD(3), 1,25(OH)(2)D(3), urinary calcium excretion or BMD at the hip, forearm and lumbar spine. These findings were supported by a lack of functional differences in the dose-response curves of the CaSR variants, with the EC(50) values (mean +/- SEM) of the wild-type (Ala986/Arg990/Gln1011), Ser986, Gly990 and Glu1011 CaSR variants being 2.74 +/- 0.29 mm, 3.09 +/- 0.34 mm (P > 0.4), 2.99 +/- 0.23 mm (P > 0.4) and 2.96 +/- 0.30 mm (P > 0.5), respectively. CONCLUSIONS: Our study, which was sufficiently powered to detect effects that would explain up to 5%, but not less than 1%, of the variance has revealed that the three CaSR polymorphisms of the coding region have no major influence on indices of calcium homeostasis in this female population, and that they do not alter receptor function.


Assuntos
Densidade Óssea/fisiologia , Cálcio/metabolismo , Polimorfismo Genético , Receptores de Detecção de Cálcio/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Calcitriol/sangue , Cálcio/sangue , Cálcio/urina , Linhagem Celular , Análise por Conglomerados , Feminino , Expressão Gênica , Genótipo , Homeostase , Humanos , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Receptores de Detecção de Cálcio/metabolismo , Análise de Regressão , Albumina Sérica/análise , Gêmeos Dizigóticos , Vitamina D/análogos & derivados , Vitamina D/sangue
19.
BMC Genet ; 5: 14, 2004 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-15176972

RESUMO

BACKGROUND: Monozygotic twin pairs who are genetically identical would be potentially useful in gene expression study for specific traits as cases and controls, because there would be much less gene expression variation within pairs compared to two unrelated individuals. However the twin pair has to be discordant for the particular trait or phenotype excluding those resulting from known confounders. Such discordant monozygotic twin pairs are rare and very few studies have explored the potential usefulness of this approach. RESULTS: We studied genome-wide gene expression in primary osteoblast-like culture from marrow aspirates obtained from three pairs of monozygotic twins. We used the latest Affymetrix microchip contains probe sets for more than 20,000 genes. Two pairs were discordant for bone mineral density at the hip by more than one standard deviation, and the third pair was unrelated concordant and used as control. Only 1.5% on average of genes showed variation in expression within pairs as compared to 5% between pairs or over 15% from the literature. Importantly we identified several groups of genes showing variations within the discordant pairs and not within the concordant pair such as chondroitin beta 1,4 N-acetylgalactosaminyltransferase, inhibin beta A, interleukin 1 beta and colony stimulating factor 1 macrophage. These genes are known to have potential roles in bone physiology relating to bone density, osteoporosis and osteoarthritis. CONCLUSION: Using the example of osteoblast-like cells in our monozygotic discordant twins for osteoporosis, we identified genes showing differential expression. Although without further experiment, we cannot confirm or conclude these are genes definitely related to bone physiology, we believe we have shown the potential and cost-effectiveness of further gene expression studies in discordant monozygotic twin pairs. A replication study for confirmation is essential.


Assuntos
Expressão Gênica , Osteoblastos/metabolismo , Osteoporose/genética , Adulto , Densidade Óssea , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Variação Genética , Genoma Humano , Humanos , Osteoporose/diagnóstico , Osteoporose/metabolismo
20.
J Biol Chem ; 279(21): 22624-34, 2004 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-14985365

RESUMO

The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. The C-terminal zinc finger (ZnF2) binds DNA, whereas the N-terminal finger (ZnF1) stabilizes this DNA binding and interacts with other zinc finger proteins, such as the Friends of GATA (FOG). We have investigated seven HDR probands and their families for GATA3 abnormalities and have identified two nonsense mutations (Glu-228 --> Stop and Arg-367 --> Stop); two intragenic deletions that result in frameshifts from codons 201 and 355 with premature terminations at codons 205 and 370, respectively; one acceptor splice site mutation that leads to a frameshift from codon 351 and a premature termination at codon 367; and two missense mutations (Cys-318 --> Arg and Asn-320 --> Lys). The functional effects of these mutations, together with a previously reported GATA3 ZnF1 mutation and seven other engineered ZnF1 mutations, were assessed by electrophoretic mobility shift, dissociation, yeast two-hybrid and glutathione S-transferase pull-down assays. Mutations involving GATA3 ZnF2 or adjacent basic amino acids resulted in a loss of DNA binding, but those of ZnF1 either lead to a loss of interaction with specific FOG2 ZnFs or altered DNA-binding affinity. These findings are consistent with the proposed three-dimensional model of ZnF1, which has separate DNA and protein binding surfaces. Thus, our results, which expand the spectrum of HDR-associated GATA3 mutations and report the first acceptor splice site mutation, help to elucidate the molecular mechanisms that alter the function of this zinc finger transcription factor and its role in causing this developmental anomaly.


Assuntos
Proteínas de Ligação a DNA/genética , Surdez/genética , Hipoparatireoidismo/genética , Nefropatias/patologia , Transativadores/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sítios de Ligação , Núcleo Celular/metabolismo , Criança , Pré-Escolar , Códon , Códon sem Sentido , DNA/química , Éxons , Saúde da Família , Feminino , Mutação da Fase de Leitura , Fator de Transcrição GATA3 , Deleção de Genes , Genes Dominantes , Glutationa Transferase/metabolismo , Proteínas de Fluorescência Verde , Humanos , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Genéticos , Dados de Sequência Molecular , Mutação , Mutação de Sentido Incorreto , Linhagem , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína , Processamento de RNA , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Software , Relação Estrutura-Atividade , Técnicas do Sistema de Duplo-Híbrido , Zinco/química , Dedos de Zinco
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