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November 2002

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Maintenance of trabecular structure and bone volume by vitamin K(2) in mature rats with long-term tail suspension.

Bone volume loss is one of the major health problems during long-term spaceflight. We examined the effects of vitamin K(2) on bone abnormalities in tail-suspended mature male Sprague-Dawley rats (13 weeks old). In this model, increased bone resorption and sustained suppression of bone formation resulted in progressive bone loss in four weeks, which simulates bone changes in humans during spaceflight. A significant decrease in bone mineral density (BMD), as well as a decreased mineral apposition rate (MAR), increased the number of osteoclasts per bone perimeter (N.Oc/B.Pm), and increased osteoclast surface per bone surface (Oc.S/BS) in the suspended group was effectively prevented by vitamin K(2), given orally (menatetrenone, 22 mg/kg body weight). Microfocus computed tomography (CT) and node-strut analyses revealed that the volume and structure of trabecular bone were maintained near normal by the vitamin K(2) treatment. A recent report has suggested the abnormal metabolism or action of vitamin K in a microgravity environment, and our data therefore suggest that vitamin K(2) may be useful for the prevention of bone loss and for the maintenance of normal trabecular structure during spaceflight.

J Bone Miner Metab 2002;20(4):216-22

Vitamin K intake and hip fractures in women: a prospective study.

BACKGROUND: Vitamin K mediates the gamma-carboxylation of glutamyl residues on several bone proteins, notably osteocalcin. High serum concentrations of undercarboxylated osteocalcin and low serum concentrations of vitamin K are associated with lower bone mineral density and increased risk of hip fracture. However, data are limited on the effects of dietary vitamin K. OBJECTIVE: We investigated the hypothesis that high intakes of vitamin K are associated with a lower risk of hip fracture in women. DESIGN: We conducted a prospective analysis within the Nurses’ Health Study cohort. Diet was assessed in 72,327 women aged 38 to 63 y with a food-frequency questionnaire in 1984 (baseline). During the subsequent 10 y of follow-up, 270 hip fractures resulting from low or moderate trauma were reported. RESULTS: Women in quintiles 2 to 5 of vitamin K intake had a significantly lower age-adjusted relative risk (RR: 0.70; 95% CI: 0.53, 0.93) of hip fracture than women in the lowest quintile (< 109 microg/d). Risk did not decrease between quintiles two and five and risk estimates were not altered when other risk factors for osteoporosis, including calcium and vitamin D intakes, were added to the models. Risk of hip fracture was also inversely associated with lettuce consumption (RR: 0.55; 95% CI: 0.40, 0.78) for one or more servings per day compared with one or fewer servings per week), the food that contributed the most to dietary vitamin K intakes. CONCLUSIONS: Low intakes of vitamin K may increase the risk of hip fracture in women. The data support the suggestion for a reassessment of the vitamin K requirements that are based on bone health and blood coagulation.

Am J Clin Nutr 1999 Jan;69(1):74-9

Warfarin exposure and calcification of the arterial system in the rat.

There is evidence from knock-out mice that the extrahepatic vitamin K-dependent protein, matrix gla protein, is necessary to prevent arterial calcification. The aim of this study was to determine if a warfarin treatment regimen in rats, designed to cause extra-hepatic vitamin K deficiency, would also cause arterial calcification. Sprague-Dawley rats were treated from birth for five to 12 weeks with daily doses of warfarin and concurrent vitamin K1. This treatment causes an extrahepatic vitamin K deficiency without affecting the vitamin K-dependent blood clotting factors. At the end of treatment the rats were killed and the vascular system was examined for evidence of calcification. All treated animals showed extensive arterial calcification. The cerebral arteries and the veins and capillaries did not appear to be affected. It is likely that humans on long-term warfarin treatment have extrahepatic vitamin K deficiency and hence they are potentially at increased risk of developing arterial calcification.

Int J Exp Pathol 2000 Feb;81(1):51-6

High blood pressure and bone-mineral loss in elderly white women: a prospective study. Study of Osteoporotic Fractures Research Group.

BACKGROUND: High blood pressure is associated with abnormalities in calcium metabolism. Sustained calcium loss may lead to increased bone-mineral loss in people with high blood pressure. We investigated the prospective association between blood pressure and bone-mineral loss over time in elderly white women. METHODS: We studied 3,676 women who were initially assessed in 1988 to 90 (mean age 73 years [SD 4, range 66-91 years]; mean bodyweight 65.3 kg [11.5]; blood pressure 137/75 mm Hg [17/9]) who were not on thiazide diuretics. Mean follow-up was 3.5 years. Anthropometry, blood pressure and bone-mineral density at the femoral neck were measured at baseline and bone densitometry was repeated after 3.5 years by dual-energy X-ray absorptiometry. FINDINGS: After adjustment for age, initial bone-mineral density, weight and weight change, smoking and regular use of hormone-replacement therapy, the rate of bone loss at the femoral neck increased with blood pressure at baseline. In the quartiles of systolic blood pressure, yearly bone losses increased from 2.26 mg/cm2 (95% CI 1.48-3.04) in the first quartile to 3.79 mg/cm2 in the fourth quartile (3.13-4.45; test for heterogeneity, p=0.03; test for linear trend, p=0.01), equivalent to yearly changes of 0.34% (0.20-0.46) and 0.59% (0.49-0.69; test for heterogeneity, p=0.02; test for linear trend, p=0.005). There was no significant interaction with age. The exclusion of women on antihypertensive drugs did not alter the results. For diastolic blood pressure, there was an association with bone loss in women younger than 75 years. INTERPRETATION: Higher blood pressure in elderly white women is associated with increased bone loss at the femoral neck. This association may reflect greater calcium losses associated with high blood pressure, which may contribute to the risk of hip fractures.

Lancet 1999 Sep 18;354(9183):971-5

Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group.

BACKGROUND: Osteoporotic fractures, including clinically detected vertebral fractures, are associated with increased mortality. However, only one-third of vertebral fractures are diagnosed. It is unknown whether vertebral fractures, whether clinically apparent or not, are associated with greater mortality. OBJECTIVES: To test the hypothesis that women with prevalent vertebral fractures have greater mortality than those without fractures and to describe causes of death associated with vertebral fractures. DESIGN: Prospective cohort study with mean follow-up of 8.3 years. SETTING: Four clinical centers in the United States. PARTICIPANTS: A total of 9,575 women aged 65 years or older and enrolled in the Study of Osteoporotic Fractures. MEASUREMENTS: Vertebral fractures by radiographic morphometry; calcaneal bone mineral density; demographic, medical history and lifestyle variables; blood pressure; and anthropometric measures. In a subset of 606 participants, thoracic curvature was measured during a second clinic visit. MAIN OUTCOME MEASURES: Hazard ratios for mortality and cause-specific mortality. RESULTS: At baseline, 1,915 women (20.0%) were diagnosed as having vertebral fractures. Compared with women who did not have a vertebral fracture, women with one or more fractures had a 1.23-fold greater age-adjusted mortality rate (95% confidence interval, 1.10-1.37). Mortality rose with greater numbers of vertebral fractures, from 19 per 1000 woman-years in women with no fractures to 44 per 1000 woman-years in those with five or more fractures (P for trend, <.001). In particular, vertebral fractures were related to the risk of subsequent cancer (hazard ratio, 1.4 95% confidence interval, 1.1-1.7) and pulmonary death (hazard ratio, 2.1 95% confidence interval, 1.4-3.0). In the subset of women who underwent thoracic curvature measurements, severe kyphosis was also related to pulmonary deaths (hazard ratio, 2.6;95% confidence interval, 1.3-5.1). CONCLUSION: Women with radiographic evidence of vertebral fractures have an increased mortality rate, particularly from pulmonary disease and cancer.

Arch Intern Med 1999 Jun 14;159(11):1215-20

Whey protein

The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress.

BACKGROUND: Increased brain serotonin may improve the ability to cope with stress, whereas a decline in serotonin activity is involved in depressive mood. The uptake of the serotonin precursor, tryptophan, into the brain is dependent on nutrients that influence the cerebral availability of tryptophan via a change in the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). Therefore, a diet-induced increase in tryptophan availability may increase brain serotonin synthesis and improve coping and mood, particularly in stress-vulnerable subjects. OBJECTIVE: We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, may increase the plasma Trp-LNAA ratio and reduce depressive mood and cortisol concentrations in stress-vulnerable subjects under acute stress. DESIGN: Twenty-nine highly stress-vulnerable subjects and 29 relatively stress-invulnerable subjects participated in a double-blind, placebo-controlled study. Subjects were exposed to experimental stress after the intake of a diet enriched with either alpha-lactalbumin or sodium-caseinate. Diet-induced changes in the plasma Trp-LNAA ratio and prolactin were measured. Changes in mood, pulse rate, skin conductance, and cortisol concentrations were assessed before and after the stressor. RESULTS: The plasma Trp-LNAA ratio was 48% higher after the alpha-lactalbumin diet than after the casein diet (P = 0.0001). In stress-vulnerable subjects this was accompanied by higher prolactin concentrations (P = 0.001), a decrease in cortisol (P = 0.036), and reduced depressive feelings (P = 0.007) under stress. CONCLUSIONS: Consumption of a dietary protein enriched in tryptophan increased the plasma Trp-LNAA ratio and, in stress-vulnerable subjects, improved coping ability, probably through alterations in brain serotonin.

Am J Clin Nutr 2000 Jun;71(6):1536-44

Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects.

BACKGROUND: Cognitive performance often declines under chronic stress exposure. The negative effect of chronic stress on performance may be mediated by reduced brain serotonin function. The uptake of the serotonin precursor tryptophan into the brain depends on nutrients that influence the availability of tryptophan by changing the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). In addition, a diet-induced increase in tryptophan may increase brain serotonergic activity levels and improve cognitive performance, particularly in high stress-vulnerable subjects. OBJECTIVE: We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, would increase the plasma Trp-LNAA ratio and improve cognitive performance in high stress- vulnerable subjects. DESIGN: Twenty-three high stress-vulnerable subjects and 29 low stress-vulnerable subjects participated in a double-blind, placebo-controlled, crossover study. All subjects conducted a memory-scanning task after the intake of a diet enriched with either alpha-lactalbumin (alpha-lactalbumin diet) or sodium caseinate (control diet). Blood samples were taken to measure the effect of dietary manipulation on the plasma Trp-LNAA ratio. RESULTS: A significantly greater increase in the plasma Trp-LNAA ratio after consumption of the alpha-lactalbumin diet than after the control diet (P = 0.0001) was observed; memory scanning improved significantly only in the high stress-vulnerable subjects (P = 0.019). CONCLUSION: Because an increase in the plasma Trp-LNAA ratio is considered to be an indirect indication of increased brain serotonin function, the results suggest that dietary protein rich in alpha-lactalbumin improves cognitive performance in stress-vulnerable subjects via increased brain tryptophan and serotonin activities.

Am J Clin Nutr 2002 Jun;75(6):1051-6

A pre-exercise alpha-lactalbumin-enriched whey

protein meal preserves lipid oxidation and decreases adiposity in rats.
The composition of the pre-exercise food intake is known to affect substrate utilization during exercise and thus can affect long-term changes in body weight and composition. These parameters were measured in male rats exercised two h daily over five wk, either in the fasting state or 1 h after they ingested a meal enriched with glucose (Glc), whole milk protein (WMP), or alpha-lactalbumin-enriched whey protein (CPalphaL). Compared with fasting, the Glc meal increased glucose oxidation and decreased lipid oxidation during and after exercise. In contrast, the WMP and CPalphaL meals preserved lipid oxidation and increased protein oxidation, the CPalphaL meal increasing protein oxidation more than the WMP meal. At the end of the study, body weight was larger in the WMP-, Glc-, and CPalphaL-fed rats than in the fasted ones. This resulted from an increased fat mass in the WMP and Glc rats and to an increased lean body mass, particularly muscles, in the CPalphaL rats. We conclude that the potential of the CPalphaL meal to preserve lipid oxidation and to rapidly deliver amino acids for use during exercise improved the efficiency of exercise training to decrease adiposity.

Am J Physiol Endocrinol Metab 2002 Sep;283(3):E565-72

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