RESUMO
Severe dental troubles are associated with X-linked hypophosphatemic rickets and are mainly related to impaired dentin mineralization. In dentin matrix, matrix extracellular phosphoglycoprotein (MEPE) may be protected from proteolysis by a specific interaction with PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome). The objective of our work was to determine whether PHEX impairment induces MEPE cleavage in dentin and the subsequent release of the C-terminal acidic serine- and aspartate-rich motif (ASARM) peptide, which is known to inhibit mineralization. By Western blot analysis, we explored dentin extracts from seven hypophosphatemic patients with mutations of the PHEX gene. A proteomic approach combining immunoprecipitation, surface-enhanced laser desorption/ionization-time of flight-mass spectrometry and matrix-assisted laser desorption ionization-time of flight analysis of the samples completed this exploration. This study shows a 4.1-kDa peptide containing the MEPE-derived ASARM peptide in hypophosphatemic samples. The presence of ASARM was less marked in patients treated with 1-hydroxylated vitamin D and phosphate during growth. Moreover, recombinant ASARM implanted in a rat pulp injury model disturbed the formation of the reparative dentin bridge. These results suggest that abnormal MEPE cleavage occurs when PHEX activity is deficient in humans, the ASARM peptide may be involved in the mineralization defects and the PHEX-MEPE interaction may be indirect, as ensuring a better phosphate and vitamin D environment to the mineralizing dentin prevents MEPE cleavage.
Assuntos
Dentina/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Raquitismo Hipofosfatêmico Familiar/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X , Glicoproteínas/metabolismo , Peptídeos/metabolismo , Fosfoproteínas/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Calcificação Fisiológica , Criança , Pré-Escolar , Colecalciferol/uso terapêutico , Dentina/química , Proteínas da Matriz Extracelular/genética , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Feminino , Glicoproteínas/genética , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Endopeptidase Neutra Reguladora de Fosfato PHEX/metabolismo , Peptídeos/genética , Fosfoproteínas/genética , Ratos , Vitaminas/uso terapêuticoRESUMO
OBJECTIVE: To analyze vitamin D metabolism and response to ketoconazole, an imidazole derivative that inhibits the vitamin D-1-hydroxylase, in infants with idiopathic hypercalcemia, and hypercalciuria. STUDY DESIGN: Twenty infants (4 days-17 months) with hypercalcemia, severe hypercalciuria, and low parathyroid hormone level, (10 had nephrocalcinosis), including 10 treated with ketoconazole (3-9 mg/kg/day), were followed to the age of 2 to 51 months. Vitamin D receptor expression (VDR), 24-hydroxylase activity, and functional gene polymorphisms of vitamin D metabolism regulators VDR(rs4516035), 1-hydroxylase(rs10877012), 24-hydroxylase(rs2248359), FGF23(rs7955866), Klotho(rs9536314, rs564481, rs648202), were evaluated. RESULTS: Serum calcium levels, which occurred faster in the ketoconazole group (0.7 +/- 0.2 versus 2.4 +/- 0.6 months; P = .0076), and urinary calcium excretion (2.5 +/- 0.5 versus 4.2 +/- 1.7 months) normalized in all patients. Serum 1,25-(OH)2D levels were high normal and positively correlated to 25-(OH)D levels. Serum 24,25-(OH)2D levels were low normal, and skin fibroblasts from 1 patient showed defective up-regulation of the 24-hydroxylase by 1,25-(OH)2D despite normal VDR binding ability. An abnormally low prevalence of haplotype CC/CC for H589H/A749A in Klotho gene was found in patients and family members. CONCLUSIONS: Ketoconazole is a potentially useful and safe agent for treatment of infantile hypercalcemia. Abnormal vitamin D metabolism is suggested as the mechanism, possibly involving defective up-regulation of the 24-hydroxylase by 1,25-(OH)2D3, and the klotho-FGF23 axis.
Assuntos
Hipercalcemia/tratamento farmacológico , Hipercalcemia/etiologia , Hipercalciúria/tratamento farmacológico , Hipercalciúria/etiologia , Cetoconazol/uso terapêutico , Vitamina D/metabolismo , Cálcio/sangue , Feminino , Fator de Crescimento de Fibroblastos 23 , Haplótipos , Humanos , Lactente , Recém-Nascido , Masculino , Hormônio Paratireóideo/metabolismo , Polimorfismo Genético , Receptores de Calcitriol/biossíntese , Esteroide Hidroxilases/antagonistas & inibidores , Esteroide Hidroxilases/biossíntese , Vitamina D3 24-HidroxilaseRESUMO
Familial hypophosphatemic rickets is a rare disease, which is mostly transmitted as an X-linked dominant trait, and mutations on the phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) gene are responsible for the disease in most familial cases. In this study we analyzed PHEX in a large cohort of 118 pedigrees representing 56 familial cases and 62 sporadic cases. The high-resolution melting curves technique was tested as a screening method, along with classical sequencing. PHEX mutations have been found in 87% of familial cases but also in 72% of sporadic cases. Missense mutations were found in 16 probands, two of which being associated with other PHEX mutations resulting into truncated proteins. By plotting missense mutations described so far on a 3D model of PHEX we observed that these mutations focus on two regions located in the inner part of the PHEX protein. Family members of 13 sporadic cases were analyzed and a PHEX mutation was detected in one of the apparently healthy mother. These results highlight the major role of PHEX in X-linked dominant hypophosphatemic rickets, and give new clues regarding the genetic analysis of the disease. A screening of the different family members should be mandatory when a PHEX mutation is assessed in a sporadic case and the search for another PHEX mutation should be systematically proceed when facing a missense mutation.
Assuntos
Raquitismo Hipofosfatêmico Familiar/enzimologia , Raquitismo Hipofosfatêmico Familiar/genética , Doenças Genéticas Ligadas ao Cromossomo X , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Regiões 5' não Traduzidas , Sequência de Bases , Códon sem Sentido , Estudos de Coortes , DNA/genética , Análise Mutacional de DNA , Primers do DNA/genética , Feminino , Mutação da Fase de Leitura , Humanos , Íntrons , Masculino , Modelos Moleculares , Mutagênese Insercional , Mutação de Sentido Incorreto , Endopeptidase Neutra Reguladora de Fosfato PHEX/química , Linhagem , Conformação Proteica , Sítios de Splice de RNA , Deleção de SequênciaRESUMO
Familial hypophosphatemic rickets is transmitted in most cases as an X-linked dominant trait and results from the mutation of the PHEX gene predominantly expressed in osteoblast and odontoblast. Patients with rickets have been reported to display important dentin defects. Our purpose was to explore the structure, composition and distribution of noncollagenous proteins (NCPs) of hypophosphatemic dentin. We collected teeth from 10 hypophosphatemic patients whose mineralization occurred either in a hypophosphatemic environment or in a corrected phosphate and vitamin environment. Teeth were examined by scanning electron microscopy, immunohistochemistry and Western blot analysis. An abnormal distribution (accumulation in interglobular spaces) and cleavage of the NCPs and particularly of matrix extracellular phosphoglycoprotein were observed in deciduous dentin. In contrast, it was close to normal in permanent dentin mineralized under corrected conditions. In conclusion, dentin mineralization in a corrected phosphate and vitamin D environment compensates the adverse effect of PHEX mutation.
Assuntos
Dentina/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Raquitismo Hipofosfatêmico Familiar/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X , Adolescente , Adulto , Calcificação Fisiológica , Criança , Pré-Escolar , Dentina/ultraestrutura , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Humanos , Imuno-Histoquímica , Dente Molar/metabolismo , Dente Decíduo/metabolismoRESUMO
CONTEXT: Treatment of X-linked hypophosphatemic rickets improves bone mineralization and bone deformities, but its effect on skeletal growth is highly variable. OBJECTIVE: Genetic variants in the promoter region of the vitamin D receptor (VDR) gene may explain the response to treatment because this receptor mediates vitamin D action. DESIGN: We studied the VDR promoter haplotype structure in a large cohort of 91 patients with hypophosphatemic rickets including 62 patients receiving 1alpha-hydroxyvitamin D3 derivatives and phosphates from early childhood on. RESULTS: Treatment improved bone deformities and final height, but 39% of treated patients still had short stature at the end of growth (-2 sd score or below). Height was closely associated with VDR promoter Hap1 genotype. Hap1(-) patients (35% of the cohort) had severe growth defects. This disadvantageous association of Hap1(-) status with height was visible before treatment, under treatment, and on to adulthood. Gender and age at initiation of treatment could not account for the Hap1 effect. No association with growth was found with a polymorphism of the PTH receptor gene otherwise found to be associated with adult height. Compared with Hap1(+) patients, those who were Hap1(-) had a higher urinary calcium response to 1alpha-hydroxyvitamin D3 and had significantly lower circulating FGF23 levels (C-terminal assay), taking into account their phosphate and 1alpha-hydroxyvitamin D3 intakes. CONCLUSIONS: The present work identifies the VDR promoter genotype as a key predictor of growth under treatment with 1alpha-hydroxyvitamin D3 derivatives in patients with hypophosphatemic rickets, including those with established PHEX alterations. The VDR promoter genotype appears to provide valuable information for adjusting treatment and for deciding upon the utility of early GH therapy.
Assuntos
Raquitismo Hipofosfatêmico Familiar/genética , Doenças Genéticas Ligadas ao Cromossomo X , Receptores de Calcitriol/genética , Adolescente , Adulto , Envelhecimento/fisiologia , Calcitriol/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , DNA/biossíntese , DNA/genética , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfatos/uso terapêutico , Valor Preditivo dos Testes , Regiões Promotoras Genéticas/genética , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Caracteres Sexuais , Adulto JovemRESUMO
Vitamin D controls calcium homeostasis and the development and maintenance of bones through vitamin D receptor activation. Prolonged therapy with rifampicin or phenobarbital has been shown to cause vitamin D deficiency or osteomalacia, particularly in patients with marginal vitamin D stores. However, the molecular mechanism of this process is unknown. Here we show that these drugs lead to the upregulation of 25-hydroxyvitamin D(3)-24-hydroxylase (CYP24) gene expression through the activation of the nuclear receptor pregnane X receptor (PXR; NR1I2). CYP24 is a mitochondrial enzyme responsible for inactivating vitamin D metabolites. CYP24 mRNA is upregulated in vivo in mice by pregnenolone 16alpha-carbonitrile and dexamethasone, 2 murine PXR agonists, and in vitro in human hepatocytes by rifampicin and hyperforin, 2 human PXR agonists. Moreover, rifampicin increased 24-hydroxylase activity in these cells, while, in vivo in mice, pregnenolone 16alpha-carbonitrile increased the plasma concentration of 24,25-dihydroxyvitamin D(3). Transfection of PXR in human embryonic kidney cells resulted in rifampicin-mediated induction of CYP24 mRNA. Analysis of the human CYP24 promoter showed that PXR transactivates the sequence between -326 and -142. We demonstrated that PXR binds to and transactivates the 2 proximal vitamin D-responsive elements of the human CYP24 promoter. These data suggest that xenobiotics and drugs can modulate CYP24 gene expression and alter vitamin D(3) hormonal activity and calcium homeostasis through the activation of PXR.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Regulação da Expressão Gênica , Osteomalacia/induzido quimicamente , Osteomalacia/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Esteroide Hidroxilases/genética , Animais , Células Cultivadas , Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/sangue , Sistema Enzimático do Citocromo P-450/química , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Mutação/genética , Osteomalacia/metabolismo , Receptor de Pregnano X , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores de Esteroides/agonistas , Rifampina/farmacologia , Esteroide Hidroxilases/biossíntese , Esteroide Hidroxilases/sangue , Esteroide Hidroxilases/química , Ativação Transcricional/genética , Elemento de Resposta à Vitamina D/genética , Vitamina D3 24-HidroxilaseRESUMO
The human vitamin D receptor (hVDR) gene encompasses eight exons (2-9) in the so-called coding region and six more exons (1a-1f) in the so-called regulatory region, which contains several reported promoters. Evolutionary comparison performed on the VDR promoter sequences of a dozen of mammalian species shows a very high conservation of numerous regions around and in the 1a promoter, including exons 1e, 1a and 1d, and the Sp1 site region. This suggests that the so-called 1a promoter is well conserved among mammals. Homology among mammals also concerns three functional SNP site regions of the hVDR 1a promoter, the 1e-G-1739A SNP region (a Cdx-2 binding site), and both 1a-G-1521C and 1a-A-1012G sites, the 1a-1012A being located within a GATA site. Interestingly, the 1521G and 1012A nucleotides are being evolutionary conserved, suggesting that the 1521C/1012G haplotype, which is found in human chromosomes (43% of Caucasians), is a human specificity.
Assuntos
Éxons/genética , Regiões Promotoras Genéticas/genética , Receptores de Calcitriol/genética , Animais , Sequência de Bases , Sequência Conservada , Evolução Molecular , Humanos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
During preeclampsia several alterations of calcium metabolism have been described, the most common of them is hypocalciuria, which pathophysiology is still unclear. In order to assess the contribution of calciotropic hormones to urinary calcium excretion, a cross-sectional study was done including 26 preeclamptic Mexican women (PE group) and 26 normotensive control pregnant women (NT group). Total and fractional urinary calcium excretion were significantly lower (P<0.0001) in the PE group than in the NT group (82+/-7 versus 171+/-7 mg/24h and 0.62+/-0.38 versus 1.38+/-0.71%, respectively), without significant differences in creatinine clearance, urinary sodium excretion and phosphate tubular reabsorption. In addition, serum 1,25-(OH)(2)D and IGF-I levels were significantly (P<0.05) lower in the PE than in NT group (43+/-9 versus 50+/-9 pg/mL and 195+/-67 versus 293+/-105 ng/mL, respectively), without significant differences in serum PTH levels. In the NT group, association analysis showed that total and fractional urinary calcium excretions positively correlated with serum levels of 1,25-(OH)(2)D (P<0.01) and IGF-I (P<0.001). In the PE group, total urinary calcium excretion positively correlated only with serum 1,25-(OH)(2)D (P<0.05). In conclusion, the results obtained in this study confirm that PE is associated with hypocalciuria and suggest that 1,25-(OH)(2)D and/or IGF-I may be involved in the regulation of urinary calcium excretion.
Assuntos
Calcitriol/sangue , Cálcio/urina , Fator de Crescimento Insulin-Like I/metabolismo , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/urina , Adulto , Feminino , Humanos , GravidezRESUMO
UNLABELLED: We report here the first association between vitamin D-resistant rickets, alopecia, and type 1 diabetes in a child with compound heterozygous mutations in the VDR gene. Transfection studies suggest dissociated effects of VDR gene mutations on the regulation of genes involved in vitamin D metabolism and dendritic cell maturation. INTRODUCTION: Whereas vitamin D may play a role in the immune tolerance process, no patient has been reported to associate hereditary vitamin D-resistant rickets (HVDRR) and an autoimmune disease, and no attempt has been made to delineate the outcome of mutations of the vitamin D receptor (VDR) on the transcription of genes controlling immune tolerance. MATERIALS AND METHODS: The VDR gene was analyzed in a child with vitamin D-resistant rickets, total alopecia, and early childhood-onset type 1 diabetes. Patient's fibroblasts and COS-7 cells transfected with wildtype or mutant VDRs were studied for ligand-binding capacity, transactivation activity using two gene promoters [CYP-24, a classical 1,25(OH)2D3-responsive gene, and relB, a critical NF-kappaB component for regulation of dendritic cell differentiation], VDR-RXR heterodimers association to CYP 24 VDREs by gel mobility shift assays, and co-activator binding by Glutathione-S-transferase pull-down assays. RESULTS: Two novel compound heterozygous mutations (L263R and R391S) were identified in the VDR ligand-binding domain in this child. Both mutations significantly impaired VDR ligand-binding capacity but had dissociated effects on CYP-24 and RelB promoter responses to vitamin D. CYP 24 response binding to SRC-1 and RXR-heterodimer binding to CYP24 VDREs were abolished in L263R mutants but normal or partially altered in R391S mutants. In the opposite, RelB responses to vitamin D were close to normal in L263R mutants but abolished in R391S mutants. CONCLUSIONS: We report the first clinical association between HVDRR, total alopecia, and early childhood-onset type 1 diabetes. Mutations in the VDR ligand-binding domain may hamper the 1,25(OH)2D3-mediated relB responses, an effect that depends on the site of the VDR mutation and cannot be anticipated from VDR ligand-binding ability or CYP-24 response. Based on these results, we propose to survey the immune function in patients with HVDRR, including those with moderate features of rickets.
Assuntos
Calcitriol/farmacologia , Diabetes Mellitus Tipo 1/complicações , Fibroblastos/enzimologia , Hipofosfatemia Familiar/complicações , Receptores de Calcitriol/genética , Esteroide Hidroxilases/genética , Fator de Transcrição RelB/genética , Animais , Células Cultivadas , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Fibroblastos/efeitos dos fármacos , França , Amplificação de Genes , Genoma , Humanos , Hipofosfatemia Familiar/genética , Masculino , Mutação , Regiões Promotoras Genéticas/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Análise de Sequência de DNA , Vitamina D3 24-Hidroxilase , População Branca/genéticaRESUMO
We conducted clinical and biological studies including screening for mutations in the gene encoding the alpha subunit of G(s) (GNAS1) in 30 subjects (21 unrelated families) with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte G(s) activity (PHP-Ia; n = 19); AHO and decreased erythrocyte G(s) activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte G(s) activity (PHP-Ic; n = 1). A heterozygous GNAS1 gene lesion was found in 14 of 17 PHP-Ia index cases (82%), including 11 new mutations and a mutational hot-spot involving codons 189-190 (21%). These lesions lead to a truncated protein in all but three cases with missense mutations R280K, V159M, and D156N. In the patient diagnosed with PHP-Ic, G(s)alpha protein was shortened by just four amino acids, a finding consistent with the conservation of G(s) activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in individuals with isolated AHO that were not relatives to PHP-Ia patients (n = 5). Intrafamilial segregation analyses of the mutated GNAS1 allele in nine PHP-Ia patients established that the mutation had either occurred de novo on the maternal allele (n = 4) or had been transmitted by a mother with a mild phenotype (n = 5). This finding is consistent with an imprinting of GNAS1 playing a role in the clinical phenotype of loss of function mutations and with a functional maternal GNAS1 allele having a predominant role in preventing the hormonal resistance of PHP-Ia.
Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/deficiência , Genótipo , Humanos , Hipocalcemia/genética , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Pseudo-Hipoparatireoidismo/sangueRESUMO
The aim of this study was to determine whether early changes in bone markers could predict long-term response in bone mineral density (BMD) after calcium (500 mg) and vitamin D (400 IU) supplementation twice daily in ambulatory elderly women with vitamin D insufficiency (25-hydroxyvitamin D, <12 ng/ml). One hundred and ninety-two women (mean age, 75 +/- 7 yr) were randomized to receive either the supplementation (n = 95) or a placebo (n = 97) in a double-blind, controlled clinical trial for 1 yr. In comparison with the placebo group, supplementation significantly increased BMD, normalized 25-hydroxyvitamin D and significantly decreased intact PTH and bone remodeling markers. The initial values of telopeptide cross-links were correlated with improvement in total body BMD [urinary N-telopeptides (NTX), r = 0.38; C-telopeptides (CTX), r = 0.32; serum CTX, r = 0.28], and the 3-month changes in the same markers were correlated with improvement in total body (urinary N-telopeptides, r = -0.29; serum CTX, r = -0.26) and vertebral BMD (CTX, r = -0.26; all P < 0.05). We concluded that short-term changes in bone resorption markers can predict long-term variations in BMD in elderly women with vitamin D insufficiency receiving calcium and vitamin D supplementation.
Assuntos
Densidade Óssea , Remodelação Óssea/efeitos dos fármacos , Cálcio/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Pós-Menopausa , Valor Preditivo dos Testes , Resultado do TratamentoRESUMO
This study was undertaken to determine the longitudinal changes of serum 1,25-dihydroxyvitamin D (1,25-(OH)(2)D) and insulin like growth factor I (IGF-I) levels at 20.7, 27.6, and 35.5 week periods of gestation in 40 pregnant women who remained normotensive (NT) and in 10 women who developed preeclampsia (PE). As compared with the first period, significant increases (P < 0.01) in maternal serum 1,25-(OH)(2)D and IGF-I were observed in the NT group. In the PE group, a similar increase in serum 1,25-(OH)(2)D was observed. In contrast, significant (P < 0.05) lower IGF-I levels were observed in the PE group at the moment of diagnosis. In addition a high incidence of subjects with low increase in IGF-I levels (Assuntos
Fator de Crescimento Insulin-Like I/metabolismo
, Pré-Eclâmpsia/metabolismo
, Vitamina D/análogos & derivados
, Vitamina D/sangue
, Feminino
, Humanos
, Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo
, Estudos Longitudinais
, Gravidez
RESUMO
OBJECTIVE: Calcium and vitamin D deficiency is common in older individuals, particularly those who live in nursing homes, and increases the risk of osteoporosis and fractures. METHODS: We conducted a randomized double-blind placebo-controlled study of combined supplementation with 500 mg of elemental calcium, as carbonate, and 400 IU of vitamin D bid for 12 months in women older than 65 years of age with vitamin D deficiency, defined as serum 25(OH)D concentrations =12 ng/ml. RESULTS: Mean patient age was 75 +/- 7 years, and median daily dietary intakes of calcium and vitamin D were 697 mg and 66.8 IU in the supplemented group (n = 95) and 671 mg and 61.8 IU in the placebo group (n = 97). The median serum 25(OH)D level was 7.0 ng/ml in both groups, and the medial intact parathyroid hormone (PTHi) levels were 49 and 48 pg/ml in the supplemented and placebo groups, respectively. The median increase in serum 25(OH)D was 22.0 ng/ml in the supplemented group and 4 ng/ml in the placebo group (P < 0.0001), and the median PTHi decrease was 17 and 5 pg/ml, respectively (P < 0.0001). The median bone mineral density increase was significantly greater in the supplemented group than in the placebo group: +2.98% vs. -0.21% at L2-L4 (P = 0.0009), +1.19% and -0.83% at the femoral neck (P = 0.015), +0.86% and -0.56% at the trochanter (P = 0.015), and +0.99% and +0.11% for the whole body (P = 0.01). Similarly, the median decrease in the main bone markers was significantly greater in the treated group than in the placebo group: -1.35 microg/l vs. +0.50 microg/l for bone alkaline phosphatase (P = 0.008), -16.6 nmol/mmol creatinine vs. -2.3 nmol/mmol creatinine for urinary type I amino-terminal telopeptide (P = 0.001), and -896 pmol/l vs. -201 pmol/l for serum type I carboxy-terminal telopeptide (P = 0.003). We found no significant differences between the two groups for serum calcium, although urinary calcium excretion changed more in the supplemented group than in the placebo group. In conclusion, bone mass in older women with vitamin D deficiency increases significantly at the lumbar spine, femur, trochanter, and whole body after calcium and vitamin D supplementation for 1 year, and concomitantly bone markers improved as vitamin D levels returned to normal.
Assuntos
Densidade Óssea/efeitos dos fármacos , Cálcio/administração & dosagem , Deficiência de Vitamina D/dietoterapia , Vitamina D/administração & dosagem , Idoso , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Cálcio/metabolismo , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Osteoporose Pós-Menopausa/dietoterapia , Osteoporose Pós-Menopausa/etiologia , Deficiência de Vitamina D/complicaçõesAssuntos
Falência Renal Crônica/mortalidade , Vitamina D/sangue , Calcifediol/sangue , Cálcio/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Hormônio Paratireóideo/sangue , Fósforo/sangue , Prevalência , Prognóstico , Taxa de Sobrevida , Vitamina D/uso terapêutico , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/mortalidadeRESUMO
BACKGROUND: Intestinal calcium absorption is regulated principally by 1,25-dihydroxyvitamin D, but other regulators are also involved. CASE REPORT: The 3 children studied were born with unaffected bones. Two were referred at 21 months of age, with clinical features of severe vitamin D-resistant rickets. They were treated with intravenous calcium for 12-18 months, following an initial lack of response to oral calcium and vitamin D. The third patient, who was exclusively breast-fed, was diagnosed at 4 months of age, due to alopecia. His condition was successfully managed with high doses of oral calcium and vitamin D. All 3 patients were homozygous for a mutation in the DNA-binding domain of vitamin D receptor. At the most recent evaluation of these patients, currently maintained on oral calcium and vitamin D, clinical findings were normal. CONCLUSION: During gestation, calcium flux across the placenta is normal, preventing bone diseases in affected fetuses. High calcium intake early in life and, perhaps, the maintenance of breastfeeding for several months may constitute an effective approach to ensuring adequate absorption and preventing severe rickets. During childhood, after parenteral calcium treatment to bypass intestinal calcium absorption, it is possible to maintain normal bone through long-term oral calcium supplementation.
Assuntos
Cálcio/administração & dosagem , Cálcio/metabolismo , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Absorção Intestinal , Administração Intravenosa , Administração Oral , Aleitamento Materno , Criança , Pré-Escolar , Consanguinidade , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Humanos , Lactente , Masculino , Receptores de Calcitriol/genética , Vitamina D/administração & dosagem , Vitamina D/análogos & derivadosRESUMO
Patients with cystic fibrosis (CF) are at risk of developing low bone mineral density (BMD) and fragility fractures. This paper presents consensus statements that summarise current knowledge of the epidemiology and pathophysiology of CF-related skeletal deficits and provides guidance on its assessment, prevention and treatment. The statements were validated using a modified Delphi methodology.
Assuntos
Fibrose Cística , Fraturas Ósseas , Guias de Prática Clínica como Assunto , Calcificação Fisiológica/fisiologia , Fibrose Cística/epidemiologia , Fibrose Cística/fisiopatologia , Fibrose Cística/terapia , Técnica Delphi , Europa (Continente)/epidemiologia , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/fisiopatologia , Fraturas Ósseas/prevenção & controle , Humanos , Fatores de RiscoRESUMO
No consensus has been reached on the serum 25-hydroxyvitamin D [25(OH)D] levels required to ensure optimal bone health around menarche. We searched for a possible interaction of 25(OH)D levels and calcium intake on lumbar spine mineralization and on biologic features of bone metabolism in healthy late-pubertal girls. Lumbar spine parameters (ie, area, mineral content, and density) and calcium intake were evaluated in 211 healthy white adolescent girls at pubertal stages IV-V (11 to 16.9 years), together with biologic markers of calcium and bone metabolism and with International External Quality Assessment Scheme for Vitamin D Metabolite (DEQAS)-validated serum 25(OH)D levels. A high prevalence of 25(OH)D levels ≤ 30 nmol/L (41%), ≤ 40 nmol/L (61%), and ≤ 50 nmol/L (70%) was found during winter-spring. Parathyroid hormone (PTH) levels were inversely associated with 25(OH)D levels (p = .0021). In contrast, lumbar spine mineral content and density were not associated with 25(OH)D, excepted when calcium intake was below 600 mg/day (p = .0081). Girls with such low calcium intake and 25(OH)D levels of 40 nmol/L or less (9% of the cohort) had a 0.4 to 0.7 SD lower mean areal bone mineral density Z-score than girls with higher calcium intake and/or higher 25(OH)D status. The adverse association between lumbar spine mineralization and combined calcium deficiency-low 25(OH)D levels remained significant in the 91 girls who could be followed over 4 years after their initial evaluation. We conclude that low 25(OH)D levels (≤40 nmol/L) are observed frequently during winter-spring in late-pubertal European girls, which may exacerbate the negative impact of calcium deficiency on lumbar spine mineralization.
Assuntos
Calcificação Fisiológica/fisiologia , Cálcio da Dieta/metabolismo , Dieta , Vértebras Lombares/fisiologia , Puberdade/fisiologia , Vitamina D/análogos & derivados , Adolescente , Antropometria , Biomarcadores/sangue , Densidade Óssea/fisiologia , Cálcio/metabolismo , Cálcio da Dieta/administração & dosagem , Criança , Estudos de Coortes , Feminino , França , Humanos , Modelos Lineares , Vértebras Lombares/anatomia & histologia , Análise Multivariada , Tamanho do Órgão/fisiologia , Hormônio Paratireóideo/sangue , Estações do Ano , Vitamina D/sangueRESUMO
Calcium homeostasis and bone metabolism require the vitamin D receptor (VDR) to function properly, as evidenced in patients and transgenic mice with VDR mutations. We have shown that (A/G) polymorphism at the -1012 locus of the VDR promoter (rs4516035) is frequent in European populations, may influence VDR expression, is associated with height in French adolescent girls, and is associated with their lumbar spine mineral density in case of insufficient milk intake. Here, an association study was performed in a cohort of Moldovan children and adolescents, living at latitude similar to the first cohort but receiving a cereal-based diet with very low milk/dairy product intakes. Children and adolescents in this cohort had similar 25-(OH) D levels, but a short stature and low serum calcium levels, compared to the first cohort. Their height remained associated with the A-1012G VDRp genotype. In addition, their serum calcium levels were associated with VDRp polymorphism, excepted when their 25-(OH) D levels were low (below 33 nmol/L). In conclusion, the -1012 VDRp genotype appears to be associated with height in European children whatever their calcium/dairy product intakes, and may modulate their calcium homeostasis in conditions of low calcium/milk intakes when vitamin D status is sufficient.
Assuntos
Cálcio da Dieta/metabolismo , Regiões Promotoras Genéticas , Receptores de Calcitriol/genética , Adolescente , Estatura , Cálcio da Dieta/sangue , Criança , Estudos de Coortes , Europa (Continente) , Feminino , Genótipo , Humanos , Masculino , Modelos Genéticos , Mutação , Polimorfismo GenéticoRESUMO
Bone mass is a key determinant of fracture risk. Maximizing bone mineral mass during childhood and adolescence may contribute to fracture risk reduction during adolescence and possibly in the elderly. Although more than 60% of the variance of peak bone mass (PBM), the amount of bone present in the skeleton at the end of its maturation process, is genetically determined, the remainder is likely influenced by factors amenable to positive intervention, such as adequate dietary intake of dairy products as a natural source of calcium and proteins, vitamin D, and regular weight-bearing physical activity. Low calcium and vitamin D intakes are associated with negative effects on bone, including suboptimal PBM acquisition. As suggested by intervention studies, regular intake of dairy products may have positive and possibly sustained effects on bone mineral mass gain, contributing thereby to fracture risk reduction. Further evidence from intervention studies suggests that weight-bearing physical activities, such as jumping, may contribute to bone mineral mass gain in children. Optimizing PBM acquisition through dietary and physical exercise measures may represent a valuable primary method for the prevention of fractures.