Vitamin D Metabolite Ratio Research Articles

Vitamin D and vitamin K status in postmenopausal women with normal and low bone mineral density.

Vitamin D and K are believed to promote bone health, but existing evidence is controversial. This study aimed to measure several metabolites of both vitamins by liquid chromatography tandem mass spectrometry (LC-MS/MS) in a cohort of postmenopausal women with low and normal bone mineral density (BMD). Vitamin metabolites (25-hydroxyvitamin D (25[OH]D), 24,25-dihydroxyvitamin D (24,25(OH)2D), phylloquinone (K1), menaquinone-4 (MK-4) and MK-7) were measured in 131 serum samples by LC-MS/MS. The vitamin D metabolite ratio (VMR) was calculated. Parathyroid hormone (PTH), type I procollagen-N-terminal-peptide (PINP) and C-terminal telopeptides of type I collagen (CTX-I) were measured by immunoassay. Dual X-ray absorptiometry was performed to identify participants with normal (T-score>-1) and low (T-score<-1) BMD. Mean age was 58.2±8.5 years. BMD was normal in 68 and low in 63 women. Median (interquartile range) for25(OH)D and total vitamin K concentrations were 53.5 (39.6-65.9) nmol/L and 1.33 (0.99-2.39) nmol/L. All vitamin metabolites were comparable in individuals with normal and low BMD. Furthermore, BMD and trabecular bone score were comparable in participants with adequate and inadequate vitamin status (at least one criterion was met: 25(OH)D <50 nmol/L, 24,25(OH)2D <3 nmol/L, VMR <4 %, total vitamin K <0.91 nmol/L). PTH, but not PINP or CTX-I, was inversely correlated with 25(OH)D, 24,25(OH)2D and VMR. Synergistic effects between vitamin D and K were not observed. Vitamin D and K status is not related to BMD and trabecular bone quality in postmenopausal women. Inverse associations were only seen between vitamin D metabolites and PTH.

Vitamin D Status in Bipolar Disorder.

Vitamin D status may impact acute affective symptomatology and the severity of symptoms in patients with bipolar disorder (BD). Therefore, this cross-sectional study analyzed 25(OH)D, 24,25(OH)2D, and the vitamin D metabolite ratio (VMR) in BD and correlated the results with clinical affective symptomatology and functionality. The inactive precursor 25(OH)D, and its principal catabolite 24,25(OH)2D, were measured simultaneously with a validated liquid chromatography-tandem mass spectrometry method in 170 BD outpatients and 138 healthy controls. VMR was calculated as follows: VMR = 100×(24,25(OH)2D/25(OH)D). The psychometric assessment comprised: Beck Depression Inventory-II, Hamilton Depression Rating Scale, Young Mania Rating Scale, Global Assessment of Functioning, and number of suicide attempts. We did not find a significant difference between patients and controls in the concentrations of 25(OH)D and 24,25(OH)2D. Additionally, the VMR was comparable in both groups. The calculations for the clinical parameters showed a negative correlation between the Young Mania Rating Scale and 24,25(OH)2D (r = -0.154, p = 0.040), as well as the Young Mania Rating Scale and the VMR (r = -0.238, p = 0.015). Based on the small effect size and the predominantly euthymic sample, further exploration in individuals with manic symptoms would be needed to confirm this association. In addition, long-term clinical markers and an assessment in different phases of the disease may provide additional insights.

Functional Assessment of Vitamin D Status by a Novel Metabolic Approach: The Low Vitamin D Profile Concept.

Determining serum 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D [24,25(OH)2D] and the vitamin D metabolite ratio (VMR) allows the identification of individuals with a low vitamin D metabolite profile. Here, we evaluated if such a functional approach provides superior diagnostic information to serum 25(OH)D alone. 25(OH)D, 24,25(OH)2D, and the VMR were determined in participants of the DESIRE (Desirable Vitamin D Concentrations, n = 2010) and the LURIC (Ludwigshafen Risk and Cardiovascular Health, n = 2456) studies. A low vitamin D metabolite profile (vitamin D insufficiency) was defined by a 24,25(OH)2D concentration <1.2 ng/mL (<3 nmol/L) and a VMR <4%. Parathyroid hormone (PTH) and bone turnover markers were measured in both cohorts, whereas 10-year mortality data was recorded in LURIC only. The median age in DESIRE and LURIC was 43.3 and 63.8 years, respectively. Median 25(OH)D concentrations were 27.2 ng/mL (68.0 nmol/L) and 15.5 ng/mL (38.8 nmol/L), respectively. Serum 25(OH)D deficiency, defined as <20.2 ng/mL (<50 nmol/L), was present in 483 (24.0%) and 1701 (69.3%) participants of DESIRE and LURIC, respectively. In contrast, only 77 (3.8%) and 521 (21.2%) participants had a low vitamin D metabolite profile. Regardless of the serum 25(OH)D concentration, a low vitamin D metabolite profile was associated with a significantly higher PTH, accelerated bone metabolism, and higher all-cause mortality than an unremarkable vitamin D metabolite profile. The personalized assessment of vitamin D status using a functional approach better identifies patients with accelerated bone metabolism and increased mortality than the use of a fixed 25(OH)D cutoff of 20 ng/mL (50 nmol/L).

The Influence of Vitamin D Status on Cognitive Ability in Patients with Bipolar Disorder and Healthy Controls.

Recent evidence on the association between vitamin D and cognition in mentally healthy individuals is inconsistent. Furthermore, the link between vitamin D and cognitive ability in individuals with bipolar disorder has not been studied yet. Thus, we aimed to investigate the association between 25-hydroxyvitamin D (25(OH)D), 24,25 dihydroxyvitamin D (24,25(OH)2D, the vitamin D metabolite ratio (VMR) and cognition in a cohort of euthymic patients with bipolar disorder. Vitamin D metabolites were measured simultaneously by liquid-chromatography tandem mass-spectrometry in serum samples from 86 outpatients with bipolar disorder and 93 healthy controls. Neither the inactive precursor 25(OH)D, nor the primary vitamin D catabolite 24,25(OH)2D, or the vitamin D metabolite ratio were significantly associated with the domains "attention", "memory", or "executive function" in individuals with bipolar disorder and healthy controls. Further, no vitamin D deficiency effect or interaction group × vitamin D deficiency was found in the cognitive domain scores. In summary, the present study does not support vitamin D metabolism as a modulating factor of cognitive function in euthymic BD patients. Considering the current study's cross-sectional design, future research should expand these results in a longitudinal setting and include additional aspects of mental health, such as manic or depressive symptoms, long-term illness course and psychopharmacological treatment.

#4405 CHANGES OF VITAMIN D BIOMARKERS ACCORDING TO CAUSE-GLOMERULAR FILTRATION RATE-ALBUMINURIA (CGA) CLASSIFICATION OF CKD PATIENTS

Abstract Background and Aims The monitoring of vitamin D status is important to manage metabolic bone disease in patients with chronic kidney disease (CKD). 25(OH)D is used as the vitamin D marker in CKD patients, but vitamin D metabolite ratio (VMR) is also becoming useful as the marker, too. The classification of CKD is based on the cause-glomerular filtration rate (GFR)-albuminuria (CGA) in the KDIGO guidelines. This classification is importantly used in the management decision of CKD and predicts well the prognosis related to CKD. However, there are no study on the changes in various vitamin D markers according to CGA classification. We aimed to investigate the changes of vitamin D biomarkers according to classification by cause of CKD, estimated GFR (eGFR), and proteinuria of CKD patients. Method We prospectively analyzed blood and urine samples from a total of 206 patients who received informed consent with CKD class G2-G5. After classifying each group according to the presence or absence of diabetes, eGFR degree, and proteinuria amount, the differences in various vitamin D biomarkers in each group were compared. VMR was the ratio of 24,25(OH)2D to 25(OH)D. Results The mean age of the 206 patients was 64.14±12.72 years old. The patients with DM were 46.6% and the most common cause of CKD was glomerular disease (51.4%) including diabetic nephropathy (DN). There was no significant difference in all vitamin D markers we measured in the comparison between the DKD group and the non-DKD group. Among DKD patients, the DN group had significantly lower levels of 24,25(OH)2D (p=0.012) and bioavailable 25(OH)D (p=0.044) than the no DN group. When divided into three groups according to the degree of eGFR, the mean value of 24,25(OH)2D (p=0.003) and VMR (p&amp;lt;0.001) were significantly lower as the eGFR decreased but all 25(OH)D markers showed no significant decrease with the change in eGFR. In the diabetic patients, when divided into four groups according to the amount of proteinuria, the group with high proteinuria had significantly lower levels of total 25(OH)D (p=0.001), bioavailable 25(OH)D (p&amp;lt;0.001), free 25(OH)D (p=0.001), and 24,25(OH)2D (p=0.029) compared to the group with low proteinuria but there was no significant difference in VMR. In the non-diabetic patients, when divided into three groups according to the amount of proteinuria, the group with high proteinuria had significantly lower levels of total 25(OH)D (p=0.032), bioavailable 25(OH)D (p=0.010), and free 25(OH)D (p=0.035) compared to the group with low proteinuria but there was no significant difference in 24,25(OH)2D and VMR levels. In these CKD patients, there was no significant difference in the level of VDBP despite the presence or absence of diabetes, the degree of eGFR, and the amount of proteinuria. Conclusion As eGFR decreased, the levels of 24,25(OH)2D and VMR significantly decreased. All vitamin D markers we measured showed no significant difference depending on the presence or absence of diabetes except for the low 24,25(OH)2D and bioavailable 25(OH)D levels in DN patients. Regardless of the presence or absence of diabetes, all 25(OH)D markers decreased significantly as proteinuria increased. Although we showed that significant changes in vitamin D markers differed according to CGA classification, large-scale study and long-term follow-up are necessary for meaningful use in diagnosis and treatment.

The Vitamin D Metabolite Ratio (VMR) is a Biomarker of Vitamin D Status That is Not Affected by Acute Changes in Vitamin D Binding Protein.

25-hydroxyvitamin D[25(OH)D] may be a poor marker of vitamin D status due to variability in levels of vitamin D binding protein (VDBP). The vitamin D metabolite ratio (VMR) is the ratio of 24,25-dihydroxyvitamin D[24,25(OH)2D3] to 25(OH)D3 and has been postulated to reflect vitamin D sufficiency independent of variability in VDBP. Therapeutic plasma exchange (TPE) is a procedure that removes plasma, including VDBP, and may lower bound vitamin D metabolite concentrations. Effects of TPE on the VMR are unknown. We measured 25(OH)D, free 25(OH)D, 1,25-dihydroxyvitamin D[1,25(OH)2D], 24,25(OH)2D3, and VDBP in persons undergoing TPE, before and after treatment. We used paired t-tests to assess changes in these biomarkers during a TPE procedure. Study participants (n = 45) had a mean age of 55 ± 16 years; 67% were female; and 76% were white. Compared to pretreatment concentrations, TPE caused a significant decrease in total VDBP by 65% (95%CI 60,70%), as well as all the vitamin D metabolites-25(OH)D by 66% (60%,74%), free 25(OH)D by 31% (24%,39%), 24,25(OH)2D3 by 66% (55%,78%) and 1,25(OH)2D by 68% (60%,76%). In contrast, there was no significant change in the VMR before and after a single TPE treatment, with an observed mean 7% (-3%, 17%) change in VMR. Changes in VDBP concentration across TPE parallel changes in 25(OH)D, 1,25(OH)2D, and 24,25(OH)2D3, suggesting that concentrations of these metabolites reflect underlying VDBP concentrations. The VMR is stable across a TPE session despite a 65% reduction in VDBP. These findings suggest that the VMR is a marker of vitamin D status independent of VDBP levels.

24,25-Dihydroxy Vitamin D and Vitamin D Metabolite Ratio as Biomarkers of Vitamin D in Chronic Kidney Disease.

The appropriate management of vitamin D deficiency and hyperparathyroidism is essential to prevent metabolic bone disorder (MBD) and cardiovascular diseases in chronic kidney disease (CKD). Recently, the 24,25-dihydroxyvitamin D [24,25(OH)2D] and vitamin D metabolite ratio (VMR), i.e., the ratio of 24,25(OH)2D to 25-hydroxyvitamin D [25(OH)D], have emerged as biomarkers of vitamin D level. We analyzed the usefulness of vitamin D biomarkers for the evaluation of MBD in patients with CKD. We analyzed blood and urine samples from 208 outpatients with CKD stage G2-G5. 25(OH)D showed a poor correlation with the estimated glomerular filtration rate (eGFR). Conversely, the 24,25(OH)2D level and VMR were significantly correlated with eGFR and the intact parathyroid hormone level. In conclusion, 24,25(OH)2D and VMR have the potential to be vitamin D biomarkers for the detection of MBD in CKD patients.

Lower bone mineral density is associated with primary hyperparathyroidism patients with abnormal vitamin D metabolite ratio (VMR): A case-control study

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Vitamin D Metabolite Ratio in Pregnant Women with Low Blood Vitamin D Concentrations Is Associated with Neonatal Anthropometric Data.

Existing evidence on the correlation between maternal vitamin D concentrations and birth outcomes is conflicting. Investigation of these associations requires accurate assessment of vitamin D status, especially in individuals with low 25-hydroxyvitamin D (25(OH)D) concentrations. This study examined the correlations between birth outcomes and the maternal vitamin D metabolite ratio (VMR) 1 (defined as the ratio of 24,25(OH)2D3 to 25(OH)D) and VMR2 (defined as the ratio of 3-epi-25(OH)D3 to 25(OH)D) using data from the Japan Environment and Children’s Study at Chiba Regional Center. A total of 297 mother–neonate pairs were analyzed. Using liquid chromatography–tandem mass spectrometry, we measured 25(OH)D2, 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3 concentrations in maternal serum samples. These data were analyzed in relation to birth anthropometric data using multivariable linear regression. Of the study participants, 85.2% showed insufficient vitamin D concentrations. VMR1 was strongly correlated with 25(OH)D concentrations, whereas VMR2 showed a weak correlation. Only VMR2 was associated with all anthropometric data. VMR2 in pregnant women with low vitamin D blood concentrations is a useful marker for neonatal anthropometric data and is independent of 25(OH)D. Accurate measurement of vitamin D metabolites could help better understand the effects of vitamin D on birth outcomes.

100 YEARS OF VITAMIN D: Combined hormonal contraceptives and vitamin D metabolism in adolescent girls.

ObjectiveCombined hormonal contraceptive (CHC) use has been associated with higher total 25-hydroxyvitamin D (25(OH)D) levels. Here, we investigate the relation between CHC use and vitamin D metabolism to elucidate its clinical interpretation.MethodsThe cross-sectional Fit Futures 1 included 1038 adolescents. Here, a subgroup of 182 girls with available 25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D), vitamin D-binding protein (DBP) and measured free 25(OH)D levels, in addition to parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), was investigated. Vitamin D metabolites were compared between girls using (CHC+) and not using CHC (CHC−). Further, the predictability of CHC on 25(OH)D levels was assessed in a multiple regression model including lifestyle factors. The ratios 1,25(OH)2D/25(OH)D and 24,25(OH)2D/25(OH)D (vitamin D metabolite ratio (VMR)) in relation to 25(OH)D were presented in scatterplots.ResultsCHC+ (n = 64; 35% of the girls) had higher 25(OH)D levels (mean ± s.d., 60.3 ± 22.2) nmol/L) than CHC- (n = 118; 41.8 ± 19.3 nmol/L), P -values <0.01. The differences in 25(OH)D levels between CHC+ and CHC− were attenuated but remained significant after the adjustment of lifestyle factors. CHC+ also had higher levels of 1,25(OH)2D, 24,25(OH)2D, DBP and calcium than CHC−, whereas 1,25(OH)2D/25(OH)D, PTH, FGF23 and albumin were significantly lower. Free 25(OH)D and VMR did not statistically differ, and both ratios appeared similar in relation to 25(OH)D, irrespective of CHC status.ConclusionThis confirms a clinical impact of CHC on vitamin D levels in adolescents. Our observations are likely due to an increased DBP-concentration, whereas the free 25(OH)D appears unaltered.

Longitudinal changes in vitamin D and its metabolites in pregnant South Africans

BackgroundVitamin D deficiency (VDD) has been associated with adverse maternal and foetal outcomes and is determined by measuring 25 hydroxyvitamin D (25(OH)D). The 25(OH)D is catabolized to 24, 25-(OH) 2D and the ratio of 25(OH) D to 24, 25-(OH)2D, the vitamin D metabolite ratio (VMR), is thought to be a superior marker of VDD, being elevated in such states. The aims of this study were to assess the longitudinal vitamin D status of pregnant women by measuring cholecalciferol, 25(OH)D, 24, 25-(OH)2D and VMR at two time points and also to determine any association of vitamin D and metabolites with gestational age at birth, birth length and weight. MethodsWe recruited 400 pregnant black African women in their first trimester (V1) and measured weights and heights. Ultrasound scans were performed for gestational age. Blood was drawn at V1 and at about 26 weeks (V2) of gestation for cholecalciferol, 25(OH)D, 24, 25-(OH)2D, VMR and parathyroid hormone (PTH). An OGTT was performed at V2 where fasting glucose, insulin and 30-minute glucose were measured. At birth, we measured birth weight, length and gestational age. Maternal insulin, PTH and vitamin D binding protein (VDBP) were measured by immunoassay. Maternal albumin was measured colorimetrically. Maternal cholecalciferol, 25(OH)D and 24, 25-(OH)2D, were measured by mass spectrometry and free and bioavailable vitamin D were calculated. Initial gestation was determined by ultrasound. We compared analytes by visit as well as by 25(OH)D status. Vitamin D deficiency (<30 nmol/L) was defined according to the National Academy of Medicine guidelines. Linear regression analysis was used to determine associations of vitamin D molecules with maternal blood pressure, fasting and 30-minute insulin and blood glucose and neonatal parameters. ResultsResults are presented for participants for whom we had complete data (n = 330–346 depending on variable). The prevalence of vitamin D deficiency (VDD) was 35.8 % at V1 and 32.4 % at V2. Levels of 25(OH)D did not change significantly between visits. Levels of 24, 25(OH)2D dropped from the first to the second visit (17.64 ± 12.64 to 9.39 ± 9.07 nmol/L; p < 0.0001) while VMR increased ((3.15 (1.31; 7.67) to 7.90 (2.44; 25.98); p < 0.0001). The proportion of women with the lowest cholecalciferol concentrations increased at V2 compared to the V1 (36.1–42.8 %; p = 0.02). In multivariable regression models 25(OH)D was negatively associated with 30-minute glucose concentrations (p = 0.038) whilst 24, 25-(OH)2D was positively associated with fasting insulin (p = 0.017) and HOM A-I R (p = 0.023). There was no correlation of 25(OH)D or metabolites with infant birth weight, birth length or gestational age. ConclusionsMaternal VDD is common in pregnant black South African women. Decreased VMR suggest that catabolism of 25(OH)D is reduced in pregnancy to maintain adequate free vitamin D levels.

Vitamin D Metabolites and Clinical Outcome in Hospitalized COVID-19 Patients.

(1) Background: Vitamin D, a well-established regulator of calcium and phosphate metabolism, also has immune-modulatory functions. An uncontrolled immune response and cytokine storm are tightly linked to fatal courses of COVID-19. The present retrospective study aimed to inves-tigate vitamin D status markers and vitamin D degradation products in a mixed cohort of 148 hospitalized COVID-19 patients with various clinical courses of COVID-19. (2) Methods: The serum concentrations of 25(OH)D3, 25(OH)D2, 24,25(OH)2D3, and 25,26(OH)2D3 were determined by a validated liquid-chromatography tandem mass-spectrometry method in leftover serum samples from 148 COVID-19 patients that were admitted to the University Hospital of the Medical Uni-versity of Graz between April and November 2020. Anthropometric and clinical data, as well as outcomes were obtained from the laboratory and hospital information systems. (3) Results: From the 148 patients, 34 (23%) died within 30 days after admission. The frequency of fatal outcomes did not differ between males and females. Non-survivors were significantly older than survivors, had higher peak concentrations of IL-6 and CRP, and required mechanical ventilation more frequently. The serum concentrations of all vitamin D metabolites and the vitamin D metabolite ratio (VMR) did not differ significantly between survivors and non-survivors. Additionally, the need for res-piratory support was unrelated to the serum concentrations of 25(OH)D vitamin D and the two vitamin D catabolites, as well as the VMR. (4) Conclusion: The present results do not support a relevant role of vitamin D for the course and outcome of COVID-19.

Association of vitamin D metabolites with cognitive function and brain atrophy in elderly individuals - the Austrian stroke prevention study.

Background: Vitamin D is a well-established regulator of calcium and phosphate metabolism that has neurotrophic and neuroprotective properties. Deficiency of vitamin D has been proposed to promote cognitive dysfunction and brain atrophy. However, existing studies provide inconsistent results. Here we aimed to investigate the association between vitamin D metabolites, cognitive function and brain atrophy in a cohort of well-characterized community-dwelling elderly individuals with normal neurological status and without history of stroke and dementia.Methods: 25(OH)D3, 25(OH)D2 and 24,25(OH)2D3 were measured by liquid-chromatography tandem mass-spectrometry in serum samples from 390 community-dwelling elderly individuals. All participants underwent thorough neuropsychiatric tests capturing memory, executive function and visuopractical skills. In 139 of these individuals, MRI of the brain was performed in order to capture neurodegenerative and vascular changes.Results: Total 25(OH)D (ß=0.003, 0.037), 24,25(OH)2D3 (ß=0.0456, p=0.010) and vitamin D metabolite ratio (VMR) (ß=0.0467, p=0.012) were significantly related to memory function. Adjustment for multiple testing weakened these relationships, but trends (p≤0.10) remained. 24,25(OH)2D3 and VMR showed similar trends also for visuopractical skills and global cognitive function. No significant relationships existed between vitamin D metabolites and MRI derived indices of neurodegeneration and vascular changes. Sub-group analyses of individuals with low concentrations of 25(OH)D and 24,25(OH)2D3 showed significantly worse memory function compared to individuals with normal or high concentrations.Conclusions: Vitamin D deficient individuals appear to have a modest reduction of memory function without structural brain atrophy. Future studies should explore if vitamin D supplementation can improve cognitive function.

Multiplex LC–MS/MS for simultaneous determination of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D3, albumin, and vitamin D-binding protein with its isoforms: One-step estimation of bioavailable vitamin D and vitamin D metabolite ratio

Bioavailable vitamin D and vitamin D metabolite ratio (VMR) have emerged as potential novel vitamin D markers. We developed a multiplex liquid chromatography-tandem mass spectrometry (LC–MS/MS) method to determine all elements necessary for the calculation of bioavailable vitamin D and VMR, including 25-hydroxyvitamin D [25-(OH)D] and 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], VDBP and its isoforms, and albumin. Following separate reactions of hexane extraction and trypsin digestion, serum samples were analyzed using LC–MS/MS to measure 25-(OH)D3, 25-(OH)D2, 24,25-(OH)2D3, VDBP and its isoforms, and albumin. Analytical performances were assessed. Korean (n = 229), Arab (n = 98), White (n = 99) and Black American (n = 99) samples were analyzed. Bioavailable vitamin D and VMR were calculated. All target molecules were clearly separated and accurately quantified by LC–MS/MS. Analytical performances, including imprecision, accuracy, ion suppression, limit of quantification, linearity, and comparison with existing methods were within acceptable levels. The allele frequencies of VDBP isoforms in various races resulted similar to previously known values. The levels of bioavailable vitamin D were highest in White Americans and lowest in Black Americans. We have successfully developed a multiplex LC–MS/MS-based assay method that can simultaneously perform the measurement of all parameters needed to calculate bioavailable vitamin D and VMR. Our devised method was robust and reliable in terms of analytical performances and could be applied to routine clinical samples in the future to more accurately assess vitamin D status.

Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications

BackgroundVitamin D deficiency is diagnosed by total serum 25-hydroxyvitamin D (25(OH)D) concentration and is associated with poor health and increased mortality; however, some populations have low 25(OH) D concentrations without manifestations of vitamin D deficiency. The Vitamin D Metabolite Ratio (VMR) has been suggested as a superior indicator of vitamin D status. Therefore, VMR was determined in a population with type 2 diabetes at high risk for vitamin D deficiency and correlated with diabetic complications.Research design and methodsFour hundred sisty patients with type 2 diabetes (T2D) were recruited, all were vitamin D3 supplement naive. Plasma concentration of 25-hydroxyvitamin D3 (25(OH)D3) and its metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and its epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), were measured by LC-MS/MS analysis. VMR-1 was calculated as a ratio of 24,25(OH)2D3:25(OH)D3; VMR-2 as a ratio of 1,25(OH)2D3:25(OH)D3; VMR-3 was calculated as a ratio of 3-epi-25(OH)D3: 25(OH)D3.ResultsAn association means that there were significant differences between the ratios found for those with versus those without the various diabetic complications studied. VMR-1 was associated with diabetic retinopathy (p = 0.001) and peripheral artery disease (p = 0.012); VMR-2 associated with hypertension (p < 0.001), dyslipidemia (p < 0.001), diabetic retinopathy (p < 0.001), diabetic neuropathy (p < 0.001), coronary artery disease (p = 0.001) and stroke (p < 0.05). VMR-3 associated with hypertension (p < 0.05), dyslipidemia (p < 0.001) and coronary artery disease (p < 0.05).ConclusionsIn this cross sectional study, whilst not causal, VMR-2 was shown to be the superior predictor of diabetic and cardiovascular complications though not demonstrative of causality in this cross-sectional study population over VMR-1, VMR-3 and the individual vitamin D concentration measurements; VMR-2 associated with both microvascular and cardiovascular indices and therefore may have utility in predicting the development of diabetic complications.

Low Prenatal Vitamin D Metabolite Ratio and Subsequent Postpartum Depression Risk.

Background: Depression is a common complication of pregnancy and vitamin D deficiency is one biological risk factor for postpartum depression (PPD). Materials and Methods: We evaluated the ratio of 24,25(OH)2D and 25(OH)D serum concentrations referred to as the Vitamin D Metabolite Ratio (VMR), a new candidate biomarker during pregnancyand its relationship with PPD. Women were enrolled in the first trimester of pregnancy and followed through four timepoints. Results: A total of 89 women had complete depression, biomarker and demographic data and 34% were at risk for PPD (CES-D≥16). Stepwise multiple logistic regression models for PPD risk were carried out with eight predictors. Results showed that only lower VMR, OR = 1.43, 95% CI 1.10-1.86, p = 0.007, and Hispanic/Latina identification, OR = 3.83, 95% CI 1.44-10.92, p = 0.007 were significantly associated with higher PPD risk. Conclusion: Routine prenatal screening for vitamin D metabolites, particularly in Hispanic/Latina women, may identify women at risk for PPD.

Differential effects of phosphate binders on vitamin D metabolism in chronic kidney disease.

Phosphate binders are commonly used in the treatment of patients with hyperphosphatemia. While phosphate binders are used to lower phosphate, the effects of specific phosphate binder types on vitamin D metabolism are unknown. We performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D. Compared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI -0.9, -0.1) and 11.8 pg/ng (95% CI -20, -3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites. Administration of different phosphate binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.

Simultaneous measurement of 25(OH)-vitamin D and 24,25(OH)2-vitamin D to define cut-offs for CYP24A1 mutation and vitamin D deficiency in a population of 1200 young subjects.

Background Simultaneous measurement of 25(OH)D and 24,25(OH)2D is a new tool for predicting vitamin D deficiency and allows evaluating CYP24A1 lack of function. Interpretation of 24,25(OH)2D should be performed according to 25(OH)D levels and a ratio, called the vitamin D metabolite ratio (VMR) has been proposed for such a purpose. Unfortunately, the VMR can be expressed in different ways and cannot be used if 24,25(OH)2D concentrations are undetectable. Here, we propose evaluating the enzyme activity taking into consideration the probability that a normal population presents undetectable 24,25(OH)2D concentrations according to 25(OH)D levels. We thus retrospectively measured 25(OH)D and 24,25(OH)2D in a population of 1200 young subjects to evaluate the 25(OH)D threshold above which the enzyme was induced. Methods Serum samples from 1200 infants, children, adolescent and young adults were used to simultaneously quantify 25(OH)D and 24,25(OH)2D by LCMS/MS. Results Median (interquartile range [IQR]) levels were 20.6 (14.4-27.2) ng/mL for 25(OH)D. 172 subjects (14.3%) presented 24,25(OH)2D values below the LOQ. When 25(OH)D values were <11 ng/mL, 63.1% of subjects presented undetectable 24,25(OH)2D concentrations. Percentage decreased with increasing 25(OH)D values to become 19.7% for 25(OH)D comprised between 12 and 15 ng/mL, 5.1% for 25(OH)D between 16 and 20 and 0.7% for 25(OH)D >21 ng/mL. Conclusions We suggest using a statistical approach to evaluate CYP24A1 function according to 25(OH)D concentrations. Our results also show that vitamin D deficiency, as defined biochemically, could be around 20 ng/mL in infants, children, adolescent and young adults and that vitamin D deficiency could be evaluated on a more individual basis.

The Effect of Vitamin D Supplementation on its Metabolism and the Vitamin D Metabolite Ratio.

25-hydroxyvitamin D (25(OH)D) is commonly measured to assess vitamin D status. Other vitamin D metabolites such as 24,25-dihydroxyvitamin D (24,25(OH)2D) provide additional insights into vitamin D status or metabolism. Earlier studies suggested that the vitamin D metabolite ratio (VMR), calculated as 24,25(OH)2D/25(OH)D, could predict the 25(OH)D increase after vitamin D supplementation. However, the evidence for this additional value is inconclusive. Therefore, our aim was to assess whether the increase in 25(OH)D after supplementation was predicted by the VMR better than baseline 25(OH)D. Plasma samples of 106 individuals (25(OH)D < 75 nmol/L) with hypertension who completed the Styrian Vitamin D Hypertension Trial (NC.T.02136771) were analyzed. Participants received vitamin D (2800 IU daily) or placebo for 8 weeks. The treatment effect (ANCOVA) for 25(OH)D3, 24,25(OH)2D3 and the VMR was 32 nmol/L, 3.3 nmol/L and 0.015 (all p < 0.001), respectively. Baseline 25(OH)D3 and 24,25(OH)2D3 predicted the change in 25(OH)D3 with comparable strength and magnitude. Correlation and regression analysis showed that the VMR did not predict the change in 25(OH)D3. Therefore, our data do not support routine measurement of 24,25(OH)2D3 in order to individually optimize the dosage of vitamin D supplementation. Our data also suggest that activity of 24-hydroxylase increases after vitamin D supplementation.

The Relationship Between Oral Contraceptive Use With Total Hydroxyvitamin D And Its Metabolites In Young Adult Women

Vitamin D deficiency, defined as total hydroxyvitamin D (25(OH)D) <50 nmol/L, is associated with poor bone health, impaired muscle function and increased risk of some diseases. The biologically active form of vitamin D is dihydroxyvitamin D (1,25(OH)2D), but there is emerging evidence that the relative proportion of 1,25(OH)2D to the catabolic metabolite (24,25(OH)2D) determines biological activity. In women, higher 25(OH)D concentrations have been reported in oral contraceptive pill (OCP) users, but the influence of OCP and other hormonal contraceptives (HC) on vitamin D metabolites and their ratio is unknown. PURPOSE: To examine the relationship between vitamin D metabolites, the vitamin D metabolite ratio (VMR) and HC use in young adult women. METHODS: 512 female Army recruits, mean (SD) age 23 (3.2) years, height 1.66 (0.06) m, and body mass 64.8 (7.9) kg, volunteered to provide a venous blood sample at the start of basic military training. Samples were analysed for 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, intact parathyroid hormone (iPTH), and albumin adjusted calcium (aCa). Participants had passed Army selection including medical screening and physical performance testing. Hormonal contraceptive use was assessed by questionnaire, and later verified from medical records. RESULTS: 163 women using vitamin D supplements were excluded from the analysis. Remaining participants were subdivided into groups: no-HC (n=157); OCP (n=95); progesterone-only pill (POP, n=25); injection (n=13); and, implant (n=59). There were no differences in participant characteristics between groups (p>0.05). Compared with no-HC, OCP users had higher 25(OH)D (61 (28) vs 73 (31) nmol/L), 1,25(OH)2D (159 (38) vs 177 (50) pmol/L), 24,25(OH)2D (6 (3) vs 7 (4) nmol/L), and lower iPTH (3.64 (1.04) vs 3.22 (1.05) pmol/L) (p<0.01). There were no differences in the VMR (25(OH)D:24,25(OH)2D and 1,25(OH)2D:24,25(OH)2D), or in aCa, between groups (p>0.05). iPTH and 25(OH)D:24,25(OH)2D VMR were lower, and aCa was higher, in POP than in no-HC users (p<0.05). CONCLUSION: Oral contraceptive pill users have higher 25(OH)D, possibly from the stimulation of vitamin D binding protein and increased bioavailability of 25(OH)D, but the balance between the active and catabolic vitamin D metabolites is not dependent on HC use.