Vitamin D–binding protein modifies the vitamin D–bone mineral density relationship

Powe, Camille E.; Ricciardi, Catherine; Berg, Anders H.; Erdenesanaa, Delger; Collerone, Gina; Ankers, Elizabeth; Wenger, Julia; Karumanchi, S. Ananth; Thadhani, Ravi; Bhan, Ishir

doi:10.1002/jbmr.387

Cited by 318 publications

(347 citation statements)

References 55 publications

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“…The main result of this study was the higher serum VDBP values in acromegaly patients as compared to control subjects, the difference being more pronounced when only patients with active acromegaly were investigated [20]. Indeed, the entity of VDBP increase was not defined, since the authors did not provide information on the normal reference values in their own laboratory and the assay used in this study seems to be different from those already employed by others [8,9]. However, looking at the distribution of VDBP values in patients and control subjects, one could argue that most of the acromegaly patients of Altinova study had elevated VDBP levels, since the median value reported in the patients was above the upper limit of range of control subjects [20].…”

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confidence: 81%

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Vitamin D-binding protein: one more piece in the puzzle of acromegalic osteopathy?

2016

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In only 5 years, more than 20,000 papers (more than 300 in the last month) dealing with vitamin D have been published, reflecting the deep interest of the scientific community for the role of this hormone in health and disease. There is an agreement that adequate vitamin D status should be defined by concentrations of serum that is the immediate precursor of the active hormone 1,25 dihydroxy-vitamin D3 [7]. However, in some conditions such parameter may not represent a reliable marker of vitamin D activity due to modifications of free hormone levels independently of total hormone storage and amount [8][9][10]. Consistently with the free hormone hypothesis, only hormone not bound to protein vectors can exert biological actions [11]. More than 80 % of circulating vitamin D (i.e., both 25(OH)-vitamin D and 1,25-dihydroxy-vitamin

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mentioning

confidence: 81%

“…However, in some conditions such parameter may not represent a reliable marker of vitamin D activity due to modifications of free hormone levels independently of total hormone storage and amount [8][9][10]. Consistently with the free hormone hypothesis, only hormone not bound to protein vectors can exert biological actions [11].…”

mentioning

confidence: 89%

Vitamin D-binding protein: one more piece in the puzzle of acromegalic osteopathy?

2016

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“…The same group found free 25(OH)D concentrations to be better correlated with bone mineral density than the total 25(OH)D concentrations in young adults (10) . Prospective cohort studies have provided evidence that indicates that low concentrations of total 25(OH)D are associated with an increased risk of CVD (11,12) .…”

Section: Al Found That Black Americans Had Lower Total 25(oh)d Concementioning

confidence: 92%

Vitamin D and risk of CVD: a review of the evidence

Fry

Sanders

2015

Proc. Nutr. Soc.

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This review summarises evidence for an association between vitamin D status and CVD and the mechanisms involved. Vitamin D 3 is predominantly provided by the action of UVB from sunlight on skin. Average UK diets supply 2-3 μg/d vitamin D but diets containing at least one portion of oily fish per week supply about 7 μg/d. Pharmacological doses of vitamin D 2 (bolus injection of 7500 μg or intakes >50 μg/d) result in a smaller increase in plasma 25 (OH)D than those of D 3 but physiological doses 5-25 μg/d seem equivalent. Plasma 25 (OH)D concentrations are also influenced by clothing, obesity and skin pigmentation. Up to 40 % of the population have plasma 25(OH)D concentrations <25 nmol/l in the winter compared with <10 % in the summer. The relative risk of CVD death is 1·41 (95 % CI 1·18, 1·68) greater in the lowest quintile of plasma 25(OH)D according to meta-analysis of prospective cohort studies. Acute deficiency may inhibit insulin secretion and promote inflammation thus increasing the risk of plaque rupture and arterial thrombosis. Chronic insufficiency may increase arterial stiffness. There is no evidence to support claims of reduced CVD from existing trials with bone-related health outcomes where vitamin D was usually co-administered with calcium. Although several trials with cardiovascular endpoints are in progress, these are using pharmacological doses. In view of the potential toxicity of pharmacological doses, there remains a need for long-term trials of physiological doses of D 2 and D 3 with CVD incidence as the primary outcome. Ergocalciferol: Cholecalciferol: Cardiovascular riskVitamin D deficiency causes rickets in children and osteomalacia in adults and may contribute to the causation of CVD. Cholecalciferol (vitamin D 3 ) is made by the action of UVB light on the skin but is also provided in the diet from foods of animal origin (eggs, oily fish and meat). Ergocalciferol (vitamin D 2 ) is present in fungi that have been exposed to UVB irradiation. Both forms of vitamin D undergo 25-hydroxylation in the liver to form 25(OH) metabolites, most of which circulate in plasma bound to the vitamin D binding protein (VDBP). In the kidney, 25 hydroxyvitamin D (25(OH)D) is converted to the biologically active metabolite 1,25 dihydroxyvitamin D (1,25 (OH) 2 D) by the action of 1α-hydroxylase (Fig. 1). This then binds to the vitamin D receptor, which is a highaffinity nuclear hormone receptor that regulates gene expression (1) . Measurement of serum 25(OH)D to assess vitamin D status has predominantly used immunoassays, which show lower sensitivity (about 30 %) to D 2 metabolites than gold-standard methods such as HPLC/tandem MS. Formerly, a lack of standardisation of methods and appropriate quality control made comparisons between studies difficult (2) . The situation has been remedied by the availability (3) of standard reference serum (SRM 972, National Institute of Standards and Technology) and a quality control programme in the UK organised by the Vitamin D External Quality Assessment Scheme (4) . It has...

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“…Bioavailable 25(OH)D (the free plus albumin bound portions) has been proposed as a better indicator of vitamin D activity (32)(33)(34), possibly explaining discrepancies between findings of vitamin D effect on health outcomes in studies relying on total 25(OH)D. Several studies have identified a strong relationship between bioavailable vitamin D and indicators of vitamin D status such as bone mineral density and parathyroid hormone (32,33). Bioavailable 25(OH)D can be calculated using several equations and a mathematical model, which incorporate 25(OH)D, VDBP, albumin levels, and VDBP binding affinity by haplotype to varying degrees (32)(33)(34). Recently, an assay of free 25(OH)D has become commercially available, and a comparison of the calculated to measured free 25(OH)D showed that a calculation that does not incorporate VDBP binding affinity overestimates the measured levels (35).…”

Section: Low Serum Concentrations Of Total 25-hydroxyvitamin D (25[oh]d)mentioning

confidence: 99%

“…In addition, certain disease states, including diffuse inflammation and critical illness, have been shown to be associated with lower VDBP levels (44,46). VDBP concentration and haplotype influence the proportion of bioavailable vitamin D (32)(33)(34)47), meaning that the biologic activity of vitamin D could be similar in patients with widely different total 25(OH)D levels. We sought to determine VDBP levels and to identify patient-related factors, including genotype, that may influence these levels in critically ill children.…”

Section: Low Serum Concentrations Of Total 25-hydroxyvitamin D (25[oh]d)mentioning

confidence: 99%

Critically Ill Children Have Low Vitamin D Binding Protein, Influencing Bioavailability of Vitamin D

Madden¹,

Feldman²,

Chun³

et al. 2015

Annals ATS

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Rationale: Vitamin D deficiency, often defined by total serum 25-hydroxyvitamin D (25[OH]D) ,20 ng/ml, is common in critically ill patients, with associations with increased mortality and morbidity in the intensive care unit. Correction of vitamin D deficiency in critical illness has been recommended, and ongoing clinical trials are investigating the effect of repletion on patient outcome. The biologically active amount of 25(OH)D depends on the concentration and protein isoform of vitamin D-binding protein (VDBP), which is also an acutephase reactant affected by inflammation and injury.Objectives: We performed a secondary analysis of a cohort of critically ill children in which we reported a high rate of vitamin D deficiency, to examine how VDBP level and genotype would impact vitamin D status. Methods:We prospectively enrolled 511 children admitted to the pediatric intensive care unit over a 12-month period. Measurements and Main Results:We measured serum VDBP in 479 children. We genotyped single nucleotide polymorphisms rs7041 and rs4588 in the VDBP gene (GC) to determine haplotypes GC1F, GC1S, and GC2 in 178 subjects who consented, then calculated bioavailable 25(OH)D from serum 25(OH)D, VDBP, albumin, and GC haplotype. The median serum VDBP level was 159 mg/ml (interquartile range, 108-221), lower than has been reported in healthy children. Factors predicting lower levels in multivariate analysis included age ,1 year, nonwhite race, being previously healthy, 25(OH)D ,20 ng/ml and greater illness severity. In the subgroup that was genotyped, GC haplotype had the strongest association with VDBP level; carriage of one additional copy of GC1S was associated with a 37.5% higher level (95% confidence interval, 31.9-44.8; P , 0.001). Bioavailable 25(OH)D was also inversely associated with illness severity (r = 20.24, P , 0.001), and ratio to measured total 25(OH)D was variable and related to haplotype.Conclusions: Physiologic deficiency of 25(OH)D in critical illness may be more difficult to diagnose, given that lower VDBP levels increase bioavailability. Treatment studies conducted on the basis of total 25(OH)D level, without consideration of VDBP concentration and genotype, may increase the risk of falsely negative results.

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Vitamin D–binding protein modifies the vitamin D–bone mineral density relationship

Cited by 318 publications

References 55 publications

Vitamin D-binding protein: one more piece in the puzzle of acromegalic osteopathy?

Vitamin D-binding protein: one more piece in the puzzle of acromegalic osteopathy?

Vitamin D and risk of CVD: a review of the evidence

Critically Ill Children Have Low Vitamin D Binding Protein, Influencing Bioavailability of Vitamin D

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