A better understanding of vitamin K's role in health and disease requires the assessment of vitamin K nutritional status in population and clinical studies. This is primarily accomplished using ...dietary questionnaires and/or biomarkers. Because food composition databases in the US are most complete for phylloquinone (vitamin K1, the primary form in Western diets), emphasis has been on phylloquinone intakes and associations with chronic diseases. There is growing interest in menaquinone (vitamin K2) intakes for which the food composition databases need to be expanded. Phylloquinone is commonly measured in circulation, has robust quality control schemes and changes in response to phylloquinone intake. Conversely, menaquinones are generally not detected in circulation unless large quantities are consumed. The undercarboxylated fractions of three vitamin K-dependent proteins are measurable in circulation, change in response to vitamin K supplementation and are modestly correlated. Since different vitamin K dependent proteins are implicated in different diseases the appropriate vitamin K-dependent protein biomarker depends on the outcome under study. In contrast to other nutrients, there is no single biomarker that is considered a gold-standard measure of vitamin K status. Most studies have limited volume of specimens. Strategic decisions, guided by the research question, need to be made when deciding on choice of biomarkers.
Obesity is associated with increased mortality, and weight loss trials show rapid improvement in many mortality risk factors. Yet, observational studies typically associate weight loss with higher ...mortality risk. The purpose of this meta-analysis of randomized controlled trials (RCTs) of weight loss was to clarify the effects of intentional weight loss on mortality.
2,484 abstracts were identified and reviewed in PUBMED, yielding 15 RCTs reporting (1) randomization to weight loss or non-weight loss arms, (2) duration of ≥18 months, and (3) deaths by intervention arm. Weight loss interventions were all lifestyle-based. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12), a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials.
Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30-46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95% CI: 0.73-1.00). There was no evidence for heterogeneity of effect (Cochran's Q = 5.59 (11 d.f.; p = 0.90); I2 = 0). Results were similar in trials with a mean age at randomization ≥55 years (RR = 0.84; 95% CI 0.71-0.99) and a follow-up time of ≥4 years (RR = 0.85; 95% CI 0.72-1.00).
In obese adults, intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality.
Mortality associated with vitamin K deficiency is the consequence of a rare, yet well-documented bleeding disorder among infants ≤8 wk of age 1 . Vitamin K deficiency bleeding (VKDB) in early ...infancy is secondary to insufficient vitamin K stores at birth, low vitamin K intake, and/or absorption. The resultant vitamin K deficiency reduces its ability to function as an enzyme cofactor in the carboxylation of certain vitamin K-dependent proteins involved in blood clotting. Fortunately, VKDB is mostly preventable through vitamin K prophylaxis and/or parenteral vitamin K, depending on the cause and timing of onset of VKDB 1 .
The effect of vitamin D supplementation on muscle function in older adults has been tested in randomized trials with mixed results, which may be due to differences in the study participant ...characteristics, including baseline vitamin D status. The results of 2 meta-analyses of randomized trials suggested a beneficial effect of vitamin D supplementation on muscle function in older adults with low baseline serum 25-hydroxyvitamin D 25(OH)D.
We aimed to test the effect of 12 mo of vitamin D supplementation on lower-extremity power and function in older community-dwelling adults screened for low serum 25(OH)D.
This was a single-center, double-blind, randomized, placebo-controlled trial that included 100 community-dwelling men and women ≥60 y old who had serum 25(OH)D ≤20 ng/mL at screening and a mean ± SD serum 25(OH)D of 20.2 ± 6.7 ng/mL at baseline. Participants were randomly assigned to 800 IU vitamin D3/d (intervention) or placebo. Those in the intervention group whose serum 25(OH)D was <28 ng/mL after 4 mo were given an additional 800 IU vitamin D3/d, whereas all other participants received placebo as an additional pill.
After 12 mo, the mean ± SD serum 25(OH)D was 32.5 ± 5.1 ng/mL in the intervention group and 19.8 ± 7.3 ng/mL in the control group (treatment × time P < 0.001). The change in leg press power, function, and strength did not differ between the 2 groups over 12 mo (all treatment × time P ≥ 0.60), nor did the change in lean mass (treatment × time P ≥ 0.89).
Increasing serum 25(OH)D to >32 ng/mL (on average) over 12 mo did not affect lower-extremity power, strength, or lean mass in older community-dwelling adults. This trial was registered at clinicaltrials.gov as NCT02293187.
Vascular calcification occurs when calcium accumulates in the intima (associated with atherosclerosis) and/or media layers of the vessel wall. Coronary artery calcification (CAC) reflects the calcium ...burden within the intima and media of the coronary arteries. In population-based studies, CAC independently predicts cardiovascular disease (CVD) and mortality. A preventive role for vitamin K in vascular calcification has been proposed based on its role in activating matrix Gla protein (MGP), a calcification inhibitor that is expressed in vascular tissue. Although animal and in vitro data support this role of vitamin K, overall data from human studies are inconsistent. The majority of population-based studies have relied on vitamin K intake to measure status. Phylloquinone is the primary dietary form of vitamin K and available supplementation trials, albeit limited, suggest phylloquinone supplementation is relevant to CAC. Yet observational studies have found higher dietary menaquinone, but not phylloquinone, to be associated with less calcification. Vascular calcification is highly prevalent in certain patient populations, especially in those with chronic kidney disease (CKD), and it is plausible vitamin K may contribute to reducing vascular calcification in patients at higher risk. Subclinical vitamin K deficiency has been reported in CKD patients, but studies linking vitamin K status to calcification outcomes in CKD are needed to clarify whether or not improving vitamin K status is associated with improved vascular health in CKD. This review summarizes the available evidence of vitamin K and vascular calcification in population-based studies and clinic-based studies, with a specific focus on CKD patients.
Abstract
Context
Elevated urine net acid excretion (NAE), indicative of subclinical metabolic acidosis, has been associated with higher bone turnover. Urine citrate, which is a common clinical ...measure, changes in response to acid-base status but its association with bone turnover is uncertain.
Objective
We evaluated the association between change in urine citrate and change in bone turnover and calcium excretion.
Design, Intervention, and Participants
A total of 233 healthy men and women ≥60 years old were randomly assigned to 1.0 mmol/kg/d potassium bicarbonate (KHCO3), 1.5 mmol/kg/d KHCO3, or placebo for 84 days.
Outcome Measures
Urine citrate, NAE, N-telopeptide of collagen type-I (NTX), calcium excretion, and serum amino-terminal propeptide of type 1 procollagen (P1NP) were measured before and after intervention.
Results
Urine citrate increased dose dependently after KHCO3 supplementation (P trend < 0.001). The urine citrate change was significantly inversely associated with P1NP change (P = 0.021) but not with change in NTX (P = 0.051) or calcium excretion (P = 0.652). The NAE change was positively associated with change in NTX and calcium excretion (P ≤ 0.003) but not with change in P1NP (P = 0.051). When the urine citrate change and NAE change were included in the same model, the urine citrate change was not associated with change in NTX, calcium excretion, or serum P1NP (P ≥ 0.086), whereas change in NAE remained associated with change in NTX and calcium excretion (P ≤ 0.003).
Conclusion
Urine citrate may not be a suitable alternative to NAE when assessing acid-base status in relation to bone turnover in older adults.
In older adults, urine citrate excretion increased in response to alkali supplementation, but the change in urine citrate was not a robust indicator of change in bone resorption or calcium excretion.
Menaquinone-4 (MK4), a vitamin K metabolite, is converted from phylloquinone through a process that requires intermediates of endogenous cholesterol production. Recent evidence suggests that MK4 is ...involved in kidney function.
The purpose of this study was to determine the effect of atorvastatin treatment on MK4 formation in young and old male mice.
C57BL/6 male mice (4-mo-old and 20-mo-old) were randomly assigned to either a diet containing 300 mg atorvastatin/kg with 3 mg phylloquinone/kg or a control diet containing 3 mg phylloquinone/kg for 8 wk. During week 8, all mice received deuterium-labeled phylloquinone in the diet. Labeled and unlabeled phylloquinone and MK4 in liver, kidney, brain, and intestine were measured by atmospheric pressure chemical ionization LC/MS. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene expression was quantified by reverse transcriptase-PCR. Tissue MK4 and phylloquinone concentrations were compared between atorvastatin treatment groups with use of general linear models.
There was no age-treatment interaction on MK4 tissue concentrations. In atorvastatin-treated mice, total MK4 and percentage of deuterium-labeled MK4 in kidney were both approximately 45% lower compared to values in mice not given atorvastatin (all P < 0.05). MK4 concentrations did not differ between groups in any other tissue measured.
In male mice, atorvastatin reduced endogenous MK4 formation in the kidney, but not other organs. These observations are consistent with our hypothesis that cholesterol metabolism is involved in the generation of MK4. Further research is needed to understand potential regulatory mechanisms and the unique functions of MK4 in the kidney.
OBJECTIVE:--Vitamin K has a potentially beneficial role in insulin resistance, but evidence is limited in humans. We tested the hypothesis that vitamin K supplementation for 36 months will improve ...insulin resistance in older men and women. RESEARCH DESIGN AND METHODS--This was an ancillary study of a 36-month, randomized, double-blind, controlled trial designed to assess the impact of supplementation with 500 μg/day phylloquinone on bone loss. Study participants were older nondiabetic men and women (n = 355; aged 60-80 years; 60% women). The primary outcome of this study was insulin resistance as measured by homeostasis model assessment (HOMA-IR) at 36 months. Fasting plasma insulin and glucose were examined as the secondary outcomes. RESULTS:--The effect of 36-month vitamin K supplementation on HOMA-IR differed by sex (sex x treatment interaction P = 0.02). HOMA-IR was statistically significantly lower at the 36-month visit among men in the supplement group versus the men in the control group (P = 0.01) after adjustment for baseline HOMA-IR, BMI, and body weight change. There were no statistically significant differences in outcome measures between intervention groups in women. CONCLUSIONS:--Vitamin K supplementation for 36 months at doses attainable in the diet may reduce progression of insulin resistance in older men.
Background: Older patients with heart failure with preserved ejection fraction have severe exercise intolerance. Vitamin D may play a role in cardiovascular and skeletal muscle function, and may ...therefore be implicated in exercise intolerance in heart failure with preserved ejection fraction. However, there are few data on vitamin D status and its relationship to exercise capacity in heart failure with preserved ejection fraction patients.
Methods: Plasma 25-hydroxyvitamin D (25OHD) and exercise capacity (peak oxygen consumption, VO2, 6-minute walk distance) were measured in 112 older heart failure with preserved ejection fraction patients (mean ± SD age = 70 ± 8 years) and 37 healthy age-matched controls. General linear models were used to compare 25(OH)D between heart failure with preserved ejection fraction patients and healthy controls, and to determine the cross-sectional association between 25(OH)D and exercise capacity. The association between 25(OH)D and left ventricular function was evaluated secondarily in heart failure with preserved ejection fraction patients.
Results: 25(OH)D concentrations were significantly lower in heart failure with preserved ejection fraction vs healthy controls (11.4 ± 0.6 ng/mL vs 19.1 ± 2.1 ng/mL; P = .001, adjusted for age, race, sex, body mass index, season). More than 90% of heart failure with preserved ejection fraction patients had 25(OH)D insufficiency (<20 ng/mL) and 30% had frank 25(OH)D deficiency (<10 ng/mL). In heart failure with preserved ejection fraction patients, but not healthy controls, 25(OH)D was significantly correlated with peak VO2 (r = 0.26; P = 0.007) and 6-minute walk distance (r = 0.34; P < .001).
Conclusions: More than 90% of heart failure with preserved ejection fraction patients had 25(OH)D insufficiency, and 30% were frankly deficient. Lower 25(OH)D was associated with lower peak VO2 and 6-minute walk distance in heart failure with preserved ejection fraction, suggesting that 25(OH)D insufficiency could contribute to exercise intolerance in this patient population. These findings provide the data and rationale for a future randomized trial designed to test the potential for vitamin D supplementation to improve exercise intolerance in heart failure with preserved ejection fraction.
Context: Vitamin K has been implicated in bone health, primarily in observational studies. However, little is known about the role of phylloquinone supplementation on prevention of bone loss in men ...and women.
Objective: The objective of this study was to determine the effect of 3-yr phylloquinone supplementation on change in bone mineral density (BMD) of the femoral neck bone in older men and women who were calcium and vitamin D replete.
Design, Participants, and Intervention: In this 3-yr, double-blind, controlled trial, 452 men and women (60–80 yr) were randomized equally to receive a multivitamin that contained either 500 μg/d or no phylloquinone plus a daily calcium (600 mg elemental calcium) and vitamin D (400 IU) supplement.
Main Outcome Measures: Measurements of the femoral neck, spine (L2–L4), and total-body BMD, bone turnover, and vitamins K and D status were measured every 6–12 months. Intent-to-treat analysis was used to compare change in measures in 401 participants who completed the trial.
Results: There were no differences in changes in BMD measurements at any of the anatomical sites measured between the two groups. The group that received the phylloquinone supplement had significantly higher phylloquinone and significantly lower percent undercarboxylated osteocalcin concentrations compared with the group that did not receive phylloquinone. No other biochemical measures differed between the two groups.
Conclusions: Phylloquinone supplementation in a dose attainable in the diet does not confer any additional benefit for bone health at the spine or hip when taken with recommended amounts of calcium and vitamin D.
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