[Show abstract][Hide abstract] ABSTRACT: The prevalence of lower limb deformities physiologically decreases after 5 years of age. It remains high in some tropical and subtropical regions where it has been associated with severe vitamin D deficiency, low calcium/milk intakes, malnutrition, and/or fluoride overexposure. Very little data is available in apparently healthy Caucasian children and adolescents.
We evaluated the prevalence of genu varum/valgum and other clinical symptoms, and assessed vitamin D status and markers of calcium metabolism in 226 apparently healthy European full-time boarders (7-16 years) seen during winter-spring and fed a cereal-based diet with little access to meat, milk, and dairy products. A cohort of 71 white children and adolescents hospitalized for acute illness served as age-matched controls.
Association studies showed a high prevalence of lower limb deformities (36%) and higher alkaline phosphate activities in the 21% of children and adolescent full-time boarders with serum 25-(OH)D levels ≤ 30 nmol/l, and low serum calcium in the 74% of boarders with 25-(OH)D levels ≤ 50 nmol/l, compared with boarders with higher vitamin D status. No such anomalies were found in the control cohort despite lower serum 25-(OH)D levels.
Low 25-(OH)D levels, at least during winter-spring, combined with additional risk factors such as very low calcium/milk intakes and possibly digestive disorders, are associated with an increased risk of genu varum/valgum in European children and adolescents. Thus, dietary fortification, or supplementation with vitamin D, may be recommended, at least during the winter, to European children and adolescents with either none or insufficient calcium/dairy product intakes.
European Journal of Endocrinology 11/2010; 163(5):811-7. · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
The Journal of steroid biochemistry and molecular biology 07/2010; 121(1-2):117-20. · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2010; 25(11):2392-8. · 6.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Human Genetics 03/2009; 125(4):401-11. · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment of X-linked hypophosphatemic rickets improves bone mineralization and bone deformities, but its effect on skeletal growth is highly variable.
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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Low calcium intake hampers bone mineral acquisition in adolescent girls. This study explores dietary calcium sources and nutrients possibly associated with vertebral mass. Milk intake is not influenced by genetic variants of the lactase gene and is positively associated with serum IGF-1 and with lumbar vertebrae mineral content and density.
Low calcium intake hampers bone mineral acquisition during adolescence. We identified calcium sources and nutrients possibly associated with lumbar bone mineralization and calcium metabolism in adolescent girls and evaluated the possible influence of a genetic polymorphic trait associated with adult-type hypolactasia.
Lumbar bone mineral content (BMC), bone mineral density (BMD), and area, circulating IGF-1, markers of bone metabolism, and -13910 LCT (lactase gene) polymorphism; and intakes of milk, dairy products, calcium, phosphorus, magnesium, proteins, and energy were evaluated in 192 healthy adolescent girls.
After menarche, BMC, BMD, serum IGF-1, and serum PTH were tightly associated with milk consumption, but not with other calcium sources. All four parameters were also associated with phosphorus, magnesium, protein, and energy from milk, but not from other sources. Girls with milk intakes below 55 mL/day have significantly lower BMD, BMC, and IGF-1 and higher PTH compared to girls consuming over 260 mL/day. Neither BMC, BMD, calcium intakes, nor milk consumption were associated with -13910 LCT polymorphism.
Milk consumption, preferably to other calcium sources, is associated with lumbar BMC and BMD in postmenarcheal girls. Aside from being a major source of calcium, milk provides phosphates, magnesium, proteins, and as yet unidentified nutrients likely to favor bone health.
Osteoporosis International 09/2008; 20(4):567-75. · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Evaluate vitamin D supplementation and vitamin D status during normal pregnancy in Martinique, a Caribbean region with sufficient sunshine for endogenous vitamin D production all year around; and "to validate" or not the necessity of supplementing pregnant women with vitamin D in Martinique.
A prospective evaluation of their vitamin D status was performed over a winter four-month period on 63 healthy women seen at term delivery. Maternal blood sampling for assays of serum 25 (OH)D, calcium, phosphates and alkaline phosphatase activity was realized in working room. All included women answered a questionnaire allowing to know various parameters known to influence vitamin D and calcium status, as their origin, their food habits, their exposure to sunshine, their supplementation or not with vitamin D during pregnancy.
The sample represented 15% of the pregnant women seen in the department over the study period; 16% of the women had received vitamin D supplementation during pregnancy; at delivery, mean 25-(OH)D serum level in the total cohort was 32.6+/-10.7 ng/ml, with no value below 13 ng/ml; serum calcium and phosphates levels were in the normal range.
These data suggest that, during normal pregnancy, and in the absence of any particular risk factor, systematic vitamin D supplementation is not required in the Martinique region.
Journal de Gynécologie Obstétrique et Biologie de la Reproduction 06/2008; 38(2):161-7. · 0.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Numerous association studies have dealt with single-nucleotide polymorphisms (SNPs) in coding and intronic regions of the human vitamin D receptor (hVDR) gene. We have hypothesized that phenotypic traits may also be associated with variations in VDR expression due to the presence of SNPs in promoter regions. In this work, we have studied two SNPs located 1521 bp (G/C) and 1012 bp (A/G) upstream of the transcriptional start site of the main human VDR gene promoter. One base-change in any of the two variant sites led to a dramatic change in protein-DNA complex formation using nuclear extracts from HEK293, Caco-2 and COS-7 cells. Genetic analysis of 185 healthy adolescent girls evidenced two major haplotypes: 1521G/1012A and 1521C/1012G and three main genotypes: homozygous for 1521G/1012A (21.1%), homozygous for 1521C/1012G (17.3%) and heterozygous 1521CG/1012GA (57.3%). On the basis of transfection data, promoter activity was nearly 2-fold higher with the 1521G/1012A haplotype, when compared with the 1521C/1012G haplotype. Clinical and biological association study in the adolescent cohort showed that girls with a CC/GG genotype had (i) lower circulating levels of 25-dihydroxyvitamin D, with no detectable consequence on calcium metabolism, (ii) lower serum IGF-1 levels and (iii) smaller height from 11 years of age up to adult height.
Human Molecular Genetics 12/2005; 14(22):3539-48. · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rickets can still be observed among children and adolescents living in Europe, and a significant proportion of healthy children and adolescents presents serum 25-hydroxyvitamin D (25-(OH)D) values below the threshold indicating an insufficient vitamin D status. We have previously proposed detecting at risk individuals with a decision-making abacus based on questionnaires assessing calcium and vitamin D intakes and vitamin D production via sun exposure.
We tested the validity of this detection by receiver operating characteristic (ROC) analysis, using, as the main outcome measure, the serum 25-(OH)D values measured at the time of questionnaires presentation. In addition, the original questionnaires have been simplified by limiting the items to those significantly associated with 25-(OH)D values. The study group included 116 children and adolescents aged 6 to 17 years, seen at the end of the winter, and randomized in 2 groups: "test", for the development of the tool (n =75), and "validation" (n =41).
The present analysis shows that the proposed decision-making abacus has a sufficient ability to detect children at risk of vitamin D deficiency (with 25-(OH)D values below 10 ng/ml): area under the curve 0.748/0.895, sensibility 0.71/0.83, and specificity 0.62/0.80, in the test and validation groups, respectively.
These questionnaire and abacus may offer a substantial help to detect children and adolescents at risk of vitamin D deficiency in both a private office or hospital environment.
Archives de Pédiatrie 05/2005; 12(4):410-9. · 0.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Clinical Investigation 02/2005; 115(1):177-86. · 13.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examines the influence of chronic retroviral infection of mice with a LPBM5 virus mixture on the paracrine system involving immune cells and 1,25-(OH)2D3 in the spleen. Plasma ionized calcium, 25-(OH)D and 1,25-(OH)2D of infected mice were unchanged. In contrast, the specific binding of 1,25-(OH)2D3 to spleen cytosol and the number of monocyte/macrophages expressing 1,25-(OH)2D3 receptors (VDR) were markedly increased. The retroviral infection also influenced the local production of 1,25-(OH)2D3 in the spleen. It did not alter this production in monocyte/macrophages but increased that in isolated T cells. Isolated B cells in control mice did not produce 1,25-(OH)2D3, but they increased the ability of isolated T cells to produce this metabolite during coculture incubations. Infection altered this cell interaction as 1,25-(OH)2D3 production in infected T cells decreased when these cells were cocultured with infected B cells. Thus, chronic retroviral infection alters both the local vitamin D metabolism and VDR expression by immune cells in mice. These findings suggest close local interactions between 1,25-(OH)2D3 and immune system activation during retroviral infection.
[Show abstract][Hide abstract] ABSTRACT: To determine the biological criteria for neonatal vitamin D deficiency, serum 25-hydroxyvitamin D (calcidiol), parathyroid hormone (PTH), calcium, phosphates, and alkaline phosphatase (ALP) activity were measured during the winter-spring period in 80 healthy neonates and their mothers 3-6 d after delivery. A longitudinal 3-mo survey of the serum biology of 52 of these neonates consuming formula was also performed to test the influence of their neonatal vitamin D status on the effects of two oral ergocalciferol supplements (500 and 1000 IU or 12.5 and 25 micrograms/d). At birth, 63.7% of the infants had calcidiol concentrations < or = 30 nmol/L. Most of them had no other biological sign evocative of vitamin D deficiency, but 14 neonates had low calcidiol concentrations and serum PTH concentrations > 60 ng/L, the upper limit of the adult normal range. They also had a significantly lower mean serum calcium concentration than did neonates with calcidiol concentrations > 30 nmol/L. On the basis of the association of low calcidiol concentrations (< or = 30 nmol/L) and high PTH concentrations (> 60 ng/L) as criteria for vitamin D deficiency, 24% of the neonates born to unsupplemented mothers were found to be vitamin D-deficient. Neonatal vitamin D status influenced the response of the infants to vitamin D supplements. Neonates with no sign of vitamin D deficiency showed similar changes in their serum calcidiol, calcium, phosphate, and PTH concentrations and ALP activity and no toxic effect (hypercalcemia or highly elevated calcidiol concentration) was observed whatever their vitamin D intake. In contrast, neonates with subclinical vitamin D deficiency had normalized serum PTH within 1 mo only when they were given 1000 IU ergocalciferol (25 micrograms)/d in addition to their formula.
American Journal of Clinical Nutrition 04/1997; 65(3):771-8. · 6.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Administration of oral vitamin D supplements has been the usual strategy used in France for the prevention of rickets. But this strategy needs reevaluation since the fortification of infant formulas with vitamin D is authorized in this country. We report the effects of oral daily supplements of vitamin D on the calcium metabolism and vitamin D status of infants receiving or not fortified milk during the first trimester of life.
Circulating levels of 25-hydroxyvitamin D (25-(OH)D) were measured: 1) in 64 infants aged 1 to 4 months, seen as outpatients between February and October, given oral vitamin D2 (theoretically 1,000 IU/d) and fed infant formulas, fortified or not with vitamin D; 2) in healthy neonates born to unsupplemented (n = 48) or supplemented vitamin D mothers (n = 22), between April and July, followed from birth (n = 70) to 3 months of age (n = 52), fed fortified milk, and given either 500 or 1,000 IU/D of vitamin D2. Serum calcium, phosphate, intact parathyroid hormone levels and alkaline phosphatase activities were simultaneously measured in this second study.
In the first study, the infants who had been seen during the summer and fed fortified milk had 25-(OH)D levels higher than those seen during the winter and fed the unfortified formulas (37.0 +/- 11.2 ng/mL vs 29.1 +/- 9.7 ng/mL, P = 0.013). But when daily supplements of vitamin D2 were strictly controlled (second study), all infants fed the fortified milk had 25-(OH)D levels within the adult range (10 to 37 ng/mL) at 1 and 3 months of age, whatever their vitamin D status at birth and although these infants were seen during the summer. No difference was found between infants given 500 or 1,000 IU/d as regards their mean serum calcium, phosphate and alkaline phosphatase activities. In addition, the percentage of infants with calcemia above 2.60 mM/L was even lower with the 1,000 IU/d vitamin D dosage than with the 500 IU/d dosage.
Daily supplements of vitamin D2 (500 to 1,000 IU/d) during the first trimester of life do not appear to induce a significant vitamin D overload when fortified milk is given to the infants. These supplementations may thus be maintained, especially when neonates are at risk of vitamin D deficiency.
Archives de Pédiatrie 03/1997; 4(2):126-32. · 0.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. — Administration of oral vitamin D supplements has been the usual strategy used in France for the prevention of rickets. But this strategy needs reevaluation since the fortification of infant formulas with vitamin D is authorized in this country. We report the effects of oral daily supplements of vitamin D on the calcium metabolism and vitamin D status of infants receiving or not fortified milk during the first trimester of life.Population and methods. — Circulating levels of 25-hydroxyvitamin D (25-(OH)D) were measured: 1) in 64 infants aged 1 to 4 months, seen as outpatients between February and October, given oral vitamin D2 (theorically 1,000 IU/d) and fed infant formulas, fortified or not with vitamin D; 2) in healthy neonates born to unsupplemented (n = 48) or supplemented vitamin D mothers (n = 22), between April and July, followed from birth (n = 70) to 3 months of age (n = 52), fed fortified milk, and given either 500 or 1,000 IU/d of vitamin D2. Serum calcium, phosphate, intact parathyroid hormone levels and alkaline phosphatase activities were simultaneously measured in this second study.Results. — In the first study, the infants who had been seen during the summer and fed fortified milk had 25-(OH)D levels higher than those seen during the winter and fed the unfortified formulas (37.0 ± 11.2 ng/mL vs 29.1 ± 9.7 ng/mL, P = 0.013). But when daily supplements of vitamin D2 were strictly controlled (second study), all infants fed the fortified milk had 25·(OH)D levels within the adult normal range (10 to 37 ng/mL) at 1 and 3 months of age, whatever their vitamin D status at birth and although these infants were seen during the summer. No difference was found between infants given 500 or 1,000 IU/d as regards their mean serum calcium, phosphate and alkaline phosphatase activities. In addition, the percentage of infants with calcemia above 2.60 mM/L was even lower with the 1,000 IU/d vitamin D dosage than with the 500 IU/d dosage.Conclusions. — Daily supplements of vitamin D2 (500 to 1,000 IU/d) during the first trimester of life do not appear to induce a significant vitamin D overload when fortified milk is given to the infants. These supplementations may thus be maintained, especially when neonates are at risk of vitamin D deficiency.
Archives de Pédiatrie 02/1997; 4(2):126-132. · 0.41 Impact Factor