Determinants of circulating calcitriol in cardiovascular disease.

Circulating calcitriol may contribute to the risk of cardiovascular disease (CVD), but its regulation in patients with CVD is poorly characterized. We therefore aimed to assess determinants of circulating calcitriol in these patients. We analyzed 2183 independent samples from a large cohort of patients scheduled for coronary angiography and 1727 independent samples from different other cohorts from patients with a wide range of CVDs, including heart transplant candidates, to quantify the association of different parameters with circulating calcitriol. We performed univariable and multivariable linear regression analyses using the mathematical function that fitted best with circulating calcitriol. In the multivariable analysis of the large single cohort, nine parameters remained significant, explaining 30.0 % (32.4 % after exclusion of 22 potential outliers) of the variation in circulating calcitriol (r=0.548). Log-transformed 25-hydroxyvitamin D [25(OH)D] and log-transformed glomerular filtration rate were the strongest predictors, explaining 17.6 % and 6.6 %, respectively, of the variation in calcitriol. In the analysis of the combined other cohorts, including heart transplant candidates, the multivariable model explained a total of 42.6 % (46.1 % after exclusion of 21 potential outliers) of the variation in calcitriol (r=0.653) with log-transformed fibroblast growth factor-23 and log-transformed 25(OH)D explaining 29.0 % and 6.2 %, respectively. Circulating 25(OH)D was positively and FGF-23 inversely associated with circulating calcitriol. Although significant, PTH was only a weak predictor of calcitriol in both analyses (<2.5 %). In patients with CVD, FGF-23 and 25(OH)D are important independent determinants of circulating calcitriol. The relative importance of these two parameters may vary according to CVD severity. Future studies should focus on the clinical importance of regulating circulating calcitriol by different parameters.

Effects of Vitamin D3 on asymmetric- and symmetric dimethylarginine in arterial hypertension.

BACKGROUND AND AIMS: Accumulating evidence has proposed a correlation between vitamin D (25(OH)D) insufficiency and cardiovascular (CV) disease. Vitamin D associated effects on endothelial function have been suggested to be a possible culprit. The present study investigated the association of vitamin D3 treatment on markers of endothelial dysfunction in patients with arterial hypertension. METHODS AND RESULTS: The Styrian Vitamin D Hypertension Trial is a double-blind, placebo-controlled, single-centre study conducted at the Medical University of Graz, Austria. A total of 200 study participants with arterial hypertension and 25(OH)D levels below 30ng/mL were enrolled. The study participants were randomized to receive 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for a duration of eight weeks. The present study uses an analysis of covariance (ANCOVA) to investigate the effect of vitamin D3 treatment on symmetric (SDMA) and asymmetric dimethylarginine (ADMA). A total of 187 participants (mean [SD] age 60.0 [11.3] years; 47% women; 25(OH)D 21.2 [5.6]ng/mL; mean systolic blood pressure of 131.4 [8.9] mmHg on a median of 2 antihypertensive drugs) completed the trial. Mean treatment effect was -0.004 (95%CI [-0.03 to 0.04]; P=0.819) on ADMA and 0.001 (95%CI [-0.05 to 0.05]; P=0.850) on SDMA. In the subgroup analysis patients with a 25(OH)D concentration <20ng/mL had a significant increase in their log l-arginine/ADMA ratio (mean treatment effect 18.4 95%CI [1.84-34.9]µmol/L/µmol/L; P=0.030). ClinicalTrials.gov Identifier: NCT02136771 EudraCT number: 2009-018125-70 CONCLUSIONS: Vitamin D3 supplementation in hypertensive patients with low 25-hydroxyvitamin D has no significant effect on ADMA and SDMA.

Effect of vitamin D3 on bone turnover markers in critical illness: post hoc analysis from the VITdAL-ICU study.

In this post hoc analysis of the VITdAL-ICU study, an RCT in critically ill adults with 25-hydroxyvitamin D levels ≤20 ng/ml, vitamin D3 did not have a significant effect on ß-Crosslaps and osteocalcin. INTRODUCTION: Observational studies have shown accelerated bone loss in ICU survivors. A reversible contributor is vitamin D deficiency. In a post hoc analysis of the VITdAL-ICU study, we evaluated the effect of high-dose vitamin D3 on the bone turnover markers (BTM) ß-Crosslaps (CTX) and osteocalcin (OC). METHODS: The VITdAL-ICU study was a randomized, double-blind, placebo-controlled trial in critically ill adults with 25-hydroxyvitamin D levels ≤20 ng/ml who received placebo or high-dose vitamin D3 (a loading dose of 540,000 IU and starting 1 month after the loading dose five monthly maintenance doses of 90,000 IU). In this analysis on 289 survivors (209 telephone, 80 personal follow-up visits), BTM were analyzed on days 0, 3, 7, 28, and 180; self-reported falls and fractures were assessed. Bone mineral density (BMD) was measured after 6 months. RESULTS: At baseline, CTX was elevated; OC was low in both groups-after 6 months, both had returned to normal. There were no differences between groups concerning BTM, BMD, falls, or fractures. In linear mixed effects models, CTX and OC showed a significant change over time (p < 0.001, respectively), but there was no difference between the vitamin D and placebo group (p = 0.688 and p = 0.972, respectively). CONCLUSIONS: Vitamin D supplementation did not have a significant effect on BTM. Further studies should assess the effectiveness of vitamin D on musculoskeletal outcomes in ICU survivors.

[Biochemical markers of bone metabolism and their importance]. / Biochemische Marker des Knochenstoffwechsels und ihre Bedeutung.

Laboratory analyses of biochemical markers for bone and mineral metabolism can play a key role in the assessment of patients with osteoporosis. They may help to assess bone turnover in the diagnostic work-up and aid decision-making as well as selection of pharmaceutical therapy options. Recent publications on therapy response have shown that biochemical markers of bone turnover are valuable tools for the evaluation of therapy success in individual osteoporosis patients and the assessment of bone mineral density gain during therapy.

Lower bone turnover markers in metabolic syndrome and diabetes: the population-based Study of Health in Pomerania.

BACKGROUND AND AIMS: Accumulating evidence demonstrates an important interaction between bone and energy metabolism. We aimed to study the associations of three bone turnover markers (BTM: osteocalcin, beta-crosslaps, procollagen type 1 N-terminal propeptide) as well as of 25-hydroxyvitamin D and parathyroid hormone with metabolic syndrome (MetS) or type 2 diabetes mellitus (T2DM) in a large population-based cohort. METHODS AND RESULTS: This cross-sectional study comprised 2671 adult men and women participating in the first follow-up of the population-based Study of Health in Pomerania (SHIP-1). Multivariable logistic regression analyses were performed to assess sex-specific associations between the BTMs, 25-hydroxyvitamin D or parathyroid hormone and metabolic disease. All models were adjusted for age, body mass index, smoking status, physical activity, estimated glomerular filtration rate and month of blood sampling. The models for women were further adjusted for menopausal status. Higher BTM or 25-hydroxyvitamin D concentrations were associated with significantly lower odds for metabolic disease, while there was no association between parathyroid hormone and MetS or T2DM. CONCLUSION: Our results contribute to the accumulating evidence of a cross-sectional association between high BTM or 25-hydroxyvitamin D concentrations and a lower prevalence of MetS or T2DM. Further research is necessary to evaluate the mechanisms underlying these results.

Testicular synthesis and vitamin D action.

CONTEXT: The vitamin D system has pleiotropic effects not only in bone metabolism. Its role in testicular steroidogenesis is new and deserves intensive research. OBJECTIVE: We hypothesize that vitamin D, especially 1,25 dihydroxyvitamin D3 [1,25(OH)2D3 (calcitriol)] induces male steroidogenesis and intend to identify its impact on genes and pathways in testicular androgen regulation. METHODS: Human adult primary testicular cells were isolated, treated with 1,25(OH)2D3, and their gene expression levels profiled by microarray analysis. Highly regulated genes were confirmed by real-time quantitative PCR. In addition, the effects of 1,25(OH)2D3 in combination with LH and IGF-I on the gene expression level of androgens were assessed. T levels in the culture media were determined by a high-resolution ELISA. The expression of vitamin D receptor was confirmed at baseline and after 1,25(OH)2D3 stimulation using immunocytochemistry. RESULTS: Microarrays depicted 63 genes significantly regulated by 1,25(OH)2D3, including genes related to male androgen and vitamin D metabolism, mainly triggered by the vitamin D receptor/retinoid X receptor activation. 1,25(OH)2D3 led to significant changes in the expression profiles of reproductive genes and significantly increased T synthesis in human testicular cell cultures. CONCLUSIONS: Data from our human primary testicular cell culture model suggest that vitamin D plays a major role in male steroidogenesis in vitro.

Association of bone turnover markers with mortality in women referred to coronary angiography: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

UNLABELLED: We examined the association of fatal events with beta-crosslaps (ß-CTX) and osteocalcin (OC) concentrations in women. We observed an independent association of ß-CTX and OC concentrations with fatal events in women at high to intermediate cardiovascular risk. INTRODUCTION: There is some evidence suggesting an association of ß-CTX and OC with fatal events in men and frail elderly subjects. We aimed to examine the association of fatal events with ß-CTX and OC in women. METHODS: We measured ß-CTX and OC in 986 women aged 65 (58-72) years referred to coronary angiography. RESULTS: Compared to the first ß-CTX quartile, the crude hazard ratios (HRs) for all-cause and cardiovascular mortality in the highest ß-CTX quartile were 2.50 (1.65-3.81) and 3.28 (1.82-5.91), respectively. In multivariate adjusted models, HRs for all-cause and cardiovascular mortality in the highest ß-CTX quartile were 1.72 (1.09-2.70) and 2.31 (1.24-4.32), respectively. The lowest 25-hydroxyvitamin D [25(OH)D] quartile was significantly associated with increased risk of all-cause and cardiovascular mortality in multivariate adjusted models. In those models, the highest ß-CTX quartile was associated with an increased risk of all-cause and cardiovascular mortality. For OC concentrations, we found a reverse J-shaped association with noncardiovascular mortality. Using the first quartile as reference, crude and multivariate adjusted HRs for noncardiovascular mortality in the second and third OC quartile were 0.41 (0.19-0.90) [multivariate: 0.40 (0.18-0.88)] and 0.51 (0.25-1.06) [multivariate: 0.43 (0.20-0.94)], respectively. The lowest 25(OH)D quartile was associated with a trend towards increased risk of noncardiovascular mortality in multivariate analysis. In that analysis, OC quartile 2 and 3 were significantly associated with lower risk of noncardiovascular mortality. CONCLUSIONS: We observed an independent association of high ß-CTX with all-cause and cardiovascular mortality and a reverse J-shaped association of OC with noncardiovascular mortality.

Assessment of glucose metabolism in polycystic ovary syndrome: HbA1c or fasting glucose compared with the oral glucose tolerance test as a screening method.

STUDY QUESTION: Are HbA1c and fasting glucose (FG) useful in predicting the presence of prediabetes and type 2 diabetes (T2DM) in a large cohort of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: HbA1c and FG are not suitable as screening tools for prediabetes in a large cohort of PCOS women but do show a good level of agreement with T2DM. WHAT IS KNOWN ALREADY: Women with PCOS have an increased risk of prediabetes and T2DM. As performing an oral glucose tolerance test (OGTT) is time consuming, HbA1c and FG have been suggested as screening tools for prediabetes and T2DM. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study of 671 women with PCOS conducted from 2006 to 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was carried out at the endocrinological outpatient department of the Medical University of Graz, Austria. We performed 75 g 2-h OGTTs and measured HbA1c in 671 women with PCOS aged 16-45 years with a median BMI of 24.2 (21.3-30.1) kg/m². PCOS was defined according to the Rotterdam criteria. Prediabetes (FG 100-125 mg/dl and/or 2-h glucose 140-199 mg/dl and/or HbA1c 5.7-6.4%) and T2DM (FG ≥ 126 mg/dl and/or 2-h glucose ≥200 mg/dl and/or HbA1c ≥ 6.5%) were diagnosed according to the American Diabetes Association (ADA) criteria. Levels of agreement between different definitions were analyzed using κ-index. MAIN RESULTS AND THE ROLE OF CHANCE: According to the ADA criteria, we found prediabetes and T2DM in 12.8% (n = 76) and 1.5% (n = 9) of PCOS women, respectively. When using elevated HbA1c (5.7-6.4%) for defining prediabetes, 19 (3.2%) of all PCOS women had prediabetes with a κ-index of 0.36. When using elevated FG (100-125 mg/dl) for defining prediabetes, 31 (5.2%) of all the PCOS women were diagnosed with prediabetes with a κ-index of 0.05. Further, elevated HbA1c (≥6.5% defining T2DM) was found in six (0.9%) PCOS women (κ-index 0.80), and elevated FG (≥126 mg/dl diagnosing T2DM) was found in seven PCOS women (1%; κ-index 0.82). LIMITATIONS, REASONS FOR CAUTION: Our results are limited to an Austrian cohort of PCOS women diagnosed by Rotterdam criteria with a median BMI in the normal weight range. WIDER IMPLICATIONS OF THE FINDINGS: Our results are in line with results from previous smaller PCOS cohorts. Our findings do not support the recommendation that FG or HbA1c can be used for the screening of prediabetes in women with PCOS. For such women, OGTT should be performed for screening of prediabetes. Whether this finding is generalizable to other cohorts remains to be determined in further studies.

Osteocalcin is not a strong determinant of serum testosterone and sperm count in men from infertile couples.

Osteocalcin (OC) - released by osteoblasts and known as a marker of bone turnover - has been suggested to influence male fertility in murine models by enhancing testosterone production and sperm count. Results from clinical studies are scarce, however. The aim of this cross-sectional study was to investigate the proposed association of OC, undercarboxylated osteocalcin (ucOC) or carboxylated osteocalcin (cOC) with testosterone and sperm count in a cohort of 159 young male adults from infertile couples. Semen analysis was performed. Testosterone, free testosterone, LH, OC and ucOC were measured in serum samples after an overnight fast. cOC and OC correlated weakly but significantly with testosterone (OC: r = 0.165, p = 0.040, cOC: r = 0.193, p = 0.017), but not after adjusting for age and body mass index (BMI) or waist-hip ratio (WHR). %ucOC (ucOC levels expressed as percentage of total OC) correlated inversely with LH (r = -0.184, p = 0.023) and remained significant after the same adjustment. No significant correlations were observed between OC, cOC, ucOC, %ucOC and sperm count, semen volume and number of vital spermatozoa. In binary logistic regression analyses, none of the parameters of OC were predictors of oligozoospermia after adjusting for age and BMI or WHR. The weak association between %ucOC and LH has marginal clinical importance because of the lack of associations of parameters of OC with testosterone and sperm count. The current data thus cannot support the notion that OC is associated with male fertility in young men from infertile couples.

Association of bone turnover markers with mortality in men referred to coronary angiography.

UNLABELLED: We aimed to examine the association of fatal events with osteocalcin (OC) and beta-crosslaps (ß-CTX) levels in men. We observed a U-shaped association of OC and ß-CTX levels with fatal events in a large cohort of men at high cardiovascular risk. INTRODUCTION: Accumulating evidence suggests an association of low OC levels with metabolic disturbances. Whether OC levels are related to fatal events is, however, less clear. Further, high ß-CTX levels are linked to increased mortality. We aimed to examine the association of fatal events with both OC and ß-CTX in men. METHODS: We measured OC and ß-CTX in 2,271 men referred to coronary angiography (1997-2000). RESULTS: We observed a U-shaped association of OC and ß-CTX with fatal events. Crude hazard ratios (HRs) for all-cause and non-cardiovascular mortality in the highest OC quintile were 1.38 (1.04-1.83) and 1.47 (0.89-2.40), respectively, and 2.11 (1.61-2.75) and 2.06 (1.29-3.29) for men in the lowest compared to the third OC quintile. In multivariate-adjusted models, HRs for all-cause, and non-cardiovascular mortality in the lowest OC quintile were 1.63 (1.23-2.16) and 1.79 (1.10-2.92), respectively, compared to the third OC quintile, whereas the association of high OC with mortality lost its significance. Crude and multivariate-adjusted HRs for cardiovascular mortality in the lowest OC quintile compared to the third OC quintile were 2.08 (1.49-2.90) and 1.74 (1.24-2.46), respectively. Moreover, high as well as low ß-CTX levels were independently associated with all-cause (quintile 1 vs. quintile 3: HR 1.42 (1.05-1.92); quintile 5 vs. quintile 3: HR 1.79 (1.31-2.45)) and cardiovascular mortality (quintile 1 vs. quintile 3: HR 1.55 (1.05-2.28); quintile 5 vs. quintile 3: HR 1.85 (1.23-2.77)). CONCLUSIONS: We observed a U-shaped association of OC and ß-CTX with fatal events in a large cohort of men at high cardiovascular risk.

Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, is one of the most common hormonal disorders among premenopausal women and is associated with infertility, obesity, and insulin resistance. Accumulating evidence suggests a role of the blood coagulation factor gene F13A1 in obesity (GeneBank ID: NM_000129.3). The aim of this study was to investigate the association of intronic allelic variants of the F13A1 gene with PCOS susceptibility and metabolic parameters in lean and obese PCOS women. In a case-control study, we determined an intronic F13A1 single nucleotide polymorphism (SNP) (dbSNP ID: rs7766109) in 585 PCOS and 171 control women and tested for PCOS susceptibility and associations with anthropometric, metabolic and hormonal parameters. Genotype frequencies of the F13A1 SNP rs7766109 were equivalent in PCOS and control women. In PCOS women, F13A1 gene variants were significantly associated with body mass index (BMI) (p=0.013), systolic blood pressure (p=0.042), insulin response (AUCins) (p=0.015), triglycerides (TG) (p=0.001), and high density lipoprotein cholesterol (HDL) (p=0.012). In the subgroup of obese PCOS women free androgen index (FAI), free testosterone and sex hormone binding globulin (SHBG) as well as glucose measurements showed a significantly different pattern across F13A1 gene variants (p=0.043; p=0.039 and p=0.013, respectively). We report for the first time an association of the F13A1 SNP rs7766109 with BMI, androgens, and insulin resistance in PCOS women. Further studies are needed to confirm our findings and to evaluate whether F13A1 is causally involved in the pathogenesis of PCOS related metabolic and hormonal disturbances.