Vitamin D(3) and vitamin K(1) supplementation of Dutch postmenopausal women with normal and low bone mineral densities: effects on serum 25-hydroxyvitamin D and carboxylated osteocalcin

OBJECTIVE: Improvement of vitamin D and K status of about 60 -y-old postmenopausal Dutch women. DESIGN: In a randomized study postmenopausal women with normal (T-score >-1; n=96) and low (T-score< or =-1; n=45) bone mineral density (BMD) of the lumbar spine, were supplemented with 350-400 IU vitamin D(3), 80 microg vitamins K(1) vitamins K(1)+D(3), or placebo for 1 y. Serum 25-hydroxyvitamin D [25(OH)D] and percentage carboxylated osteocalcin (%carbOC) were measured at baseline and after 3, 6 and 12 months. RESULTS: Baseline %carbOC of the entire study population was positively correlated with BMD of the lumbar spine and femoral neck. Correspondingly, women with low BMD had lower %carbOC at baseline than women with normal BMD but this difference disappeared after 1 y of supplementation with vitamin K(1) ((mean+/-s.d.) 68+/-11% (95% CI, 64. 5-71.2%) vs 72+/-6% (95% CI, 70.1-72.9%), respectively). One year of supplementation with vitamin D(3) showed maximum increases in 25(OH)D of 33+/-29% (95% CI, 24.8-41.8%) and 68+/-58% (95% CI, 50.1-84.6%) in women with normal and low BMD, respectively. During winter, however, a 29% decline in maximum 25(OH)D levels was not prevented in women with low BMD. CONCLUSION: Daily supplementation of Dutch postmenopausal women with >400 IU vitamin D(3) is indicated to prevent a winter decline in 25(OH)D and to control serum parathyroid hormone levels. Daily supplementation with 80 microg vitamin K(1) seems to be necessary to reach premenopausal %carbOC levels. A stimulatory effect of calcium and/or vitamin D on %carbOC cannot be excluded. European Journal of Clinical Nutrition (2000) 54, 626-631.     

Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial

BACKGROUND: Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking. OBJECTIVE: The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types. DESIGN: This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were randomly assigned to receive 1400-1500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo. RESULTS: When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk. CONCLUSIONS: Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00352170.     

Vitamin D supplementation and bone mineral density in early postmenopausal women

BACKGROUND: Increased vitamin D intake may preserve or increase bone mineral density (BMD) in older persons. OBJECTIVE: A 2-y double-blind study was undertaken to determine whether weekly administration of 10 000 units of vitamin D(2) maintained or increased BMD in younger postmenopausal women more efficiently than did calcium supplements alone. DESIGN: One hundred eighty-seven women who were >or= 1 y postmenopausal were randomly assigned to take either 1000 mg Ca/d after the evening meal or 1000 mg Ca/d plus 10 000 U vitamin D(2)/wk in a double-blind, placebo-controlled format. The BMD of the proximal forearm, lumbar spine, femoral neck, Ward's triangle, and femoral trochanter was measured at 6-mo intervals by osteodensitometry. RESULTS: During the 2-y period, there was no significant difference in the change in BMD at any site between the subjects taking calcium supplements and those taking calcium plus vitamin D(2). Both groups significantly (P < 0.005) gained BMD in Ward's triangle and the femoral trochanter but significantly (P < 0.005) lost bone in the proximal radius. There was no significant change in the lumbar spine or femoral neck BMD. CONCLUSION: In younger postmenopausal women ( age: 56 y) whose average baseline serum 25-hydroxyvitamin D concentration was well within the normal range, the addition of 10 000 U vitamin D(2)/wk to calcium supplementation at 1000 mg/d did not confer benefits on BMD beyond those achieved with calcium supplementation alone.     

Effects of caffeine, vitamin D, and other nutrients on quantitative phalangeal bone ultrasound in postmenopausal women

OBJECTIVE: We investigated the controversial effects of coffee and other nutrients on bone mass.METHODS: In a study of 93 healthy postmenopausal women (mean +/- standard deviation: 57.3 +/- 7.1 y old and 8.9 +/- 7.5 y since menopause) selected on the basis of not having changed their eating habits since premenopause, not smoking, not exercising, not receiving hormone-replacement therapy, and having a weight in the range of 70% to 130% of their ideal weights, amplitude-dependent speed of sound (Ad-SOS) was determined by quantitative bone ultrasound, and a prospective 7-d diet survey evaluated the intake of caffeine and nutrients involved in calcium metabolism. Women were stratified according to their caffeine, calcium, and vitamin D intakes and ratios of calcium to phosphorus and to protein. Ad-SOS differed only with vitamin D intake and was greater in the group taking at leasst 400 IU/d (P < 0.0001).RESULTS: In simple and multiple regression analyses, the only significant variable that affected Ad-SOS and nutrient intake was vitamin D (P < 0.0001). Phalangeal bone Ad-SOS was influenced only by the intake of vitamin D, not of caffeine or other nutrients.CONCLUSIONS: This lack of effect of caffeine and protein may be related to good nutritional intake or the low levels of caffeine consumed.     

Dietary calcium and vitamin D intake in an adult Middle Eastern population: food sources and relation to lifestyle and PTH

Little is known about calcium and vitamin D intakes in Middle Eastern countries, where the prevalence of hypovitaminosis D is high. This study identifies major sources of calcium and vitamin D in the Lebanese diet, examines lifestyle factors that may influence intake of these nutrients and investigates the relationship between nutritional or lifestyle factors and parathyroid hormone (PTH). Three hundred sixteen young healthy volunteers aged 30 to 50 (men, non-veiled and veiled women) were recruited from different rural and urban Lebanese community centers. Food frequency questionnaire was used to evaluate the consumption of vitamin D and calcium-rich foods. We also measured serum PTH levels. Mean daily calcium and vitamin D intake were respectively 683.8 +/- 281.2 mg and 100.6 +/- 71.0 IU. Daily vitamin D sources were divided as follows: 30.4 +/- 46.4 IU from milk and dairy products, 28.2 +/- 26.3 IU from meat and poultry, 25.8 +/- 25 IU from fish, 8.5 +/- 8.6 IU from eggs, and 7.8 +/- 14.3 IU from sweets (respectively 30.2%, 28%, 25.6%, 8.4% and 7.7% of the total vitamin D intake). Mean daily calcium from animal and vegetable sources were respectively 376.3 +/- 233.6 mg and 307.9 +/- 118.5 mg. Animal/total calcium intake ratio was 52% and was only statistically significantly higher in urban people compared to rural ones. Multivariate analysis showed that male sex and urban residence were independent predictors of both vitamin D and calcium intakes (p < 0.01 and p < 0.01 respectively). In addition, veiling was an independent predictor of low vitamin D intake (p < 0.05) and a high body mass index (BMI) was an independent predictor of low calcium intake (p < 0.05). Finally, PTH was inversely correlated with vitamin D intake and the animal/total calcium intake ratio (r = -0.18 and r = -0.22, p < 0.01), while no significant results were achieved for the vegetable calcium. In a multivariate model, urban living, female gender, low vitamin D and calcium intakes, low animal/total calcium intake ratio, and high BMI, are independent predictors of hyperparathyroidism. The deficient nutritional status of vitamin D and calcium in Lebanon justify the implementation of dietary public health measures. People at most risk for secondary hyperparathyroidism should be advised to increase their dietary calcium (mostly animal calcium) and vitamin D, to take supplements, or to increase their sun exposure.     

Vitamin D supplementation and depression in the women's health initiative calcium and vitamin D trial

While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D(3) combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995-2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D(3) along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.     

Optimal vitamin D status and serum parathyroid hormone concentrations in African American women

BACKGROUND: Optimal vitamin D status for the prevention of osteoporosis has been inferred from examinations of the serum 25-hydroxyvitamin D [25(OH)D] concentration below which there is an increase in serum parathyroid hormone (PTH). OBJECTIVE: The objectives of the study were to ascertain whether a threshold for serum 25(OH)D exists below which serum PTH increases and whether persons with 25(OH)D above this threshold have lower rates of bone loss than do persons with 25(OH)D below the threshold. DESIGN: The relation of serum 25(OH)D to serum PTH was analyzed in 208 African American women studied longitudinally for 3 y. These healthy women in midlife were randomly assigned to receive placebo or 800 IU vitamin D3/d; after 2 y, the vitamin D3 supplementation was increased to 2000 IU/d. Both groups received calcium supplements to ensure an adequate calcium intake. A systematic literature review found a wide range of threshold values in part due to varied calcium intake. RESULTS: A Loess plot suggested a breakpoint between 40 and 50 nmol/L for serum 25(OH)D. A line-line model was fitted to the data, and it showed a spline knot at 44 nmol/L. A heuristic approach verified that PTH does not decline as rapidly when the serum concentration of 25(OH)D is >40 nmol/L as when it is <40 nmol/L. We found no significant difference in rates of bone loss between persons with 25(OH)D concentrations above and below 40 nmol/L. CONCLUSION: Although a threshold for 25(OH)D can be identified, we suggest that it should not be used to recommend optimal vitamin D status.     

Dose response to vitamin D supplementation among postmenopausal African American women

BACKGROUND: Reports on the dose response to vitamin D are conflicting, and most data were derived from white men and women. OBJECTIVE: The objective was to determine the response of serum 25-hydroxyvitamin D [25(OH)D] to oral vitamin D(3) supplementation in an African American population. DESIGN: Healthy black postmenopausal women (n = 208) participated in a vitamin D(3) supplementation trial for a period of 3 y. Analyses were done in the vitamin D supplementation arm (n = 104) to quantify the response in serum 25-hydroxyvitamin D concentrations at a steady state vitamin D input. The participants received 20 microg/d (800 IU) oral vitamin D(3) for the initial 2 y and 50 microg/d (2000 IU) for the third year. RESULTS: Supplementation with 20 microg/d (800 IU/d) vitamin D(3) raised the mean serum 25(OH)D concentration from a baseline of 46.9 +/- 20.6 nmol/L to 71.4 +/- 21.5 nmol/L at 3 mo. The mean (+/-SD) concentration of serum 25(OH)D was 87.3 +/- 27.0 nmol/L 3 mo after supplementation increased to 50 microg/d (2000 IU/d). All participants achieved a serum 25(OH)D concentration >35 nmol/L, 95% achieved a concentration >50 nmol/L, but only 60% achieved a concentration >75 nmol/L. All patients had concentrations <153 nmol/L. On the basis of our findings, an algorithm for prescribing vitamin D so that patients reach optimal serum concentrations was developed. The algorithm suggests a dose of 70 microg (2800 IU/d) for those with a concentration >45 nmol/L and a dose of 100 microg (4000 IU/d) for those with a concentration <45 nmol/L. CONCLUSIONS: Supplementation with 50 microg/d (2000 IU/d) oral vitamin D(3) is sufficient to raise serum 25-hydroxyvitamin D concentrations to >50 nmol/L in almost all postmenopausal African American women. However, higher doses were needed to achieve concentrations >75 nmol/L in many women in this population.     

A food frequency questionnaire for the assessment of calcium, vitamin D and vitamin K: a pilot validation study

The study objective was to validate a food frequency questionnaire (FFQ) to assess calcium, vitamin D and vitamin K intakes in overweight and obese postmenopausal community-dwelling women. The FFQ was validated against intakes derived from a 5-day diet record (5DDR) that also included assessment of supplement intake. Strong correlations between methods were observed for all nutrients (r = 0.63, 0.89, 0.54 for calcium, vitamin D and vitamin K, respectively) and cross-classification analyses demonstrated no major misclassification of participants into intake quartiles. Bland-Altman analysis showed that the FFQ overestimated intakes for calcium, by 576 mg/day (95% CI, -668 to 1,821 mg/day), for vitamin D by 75 IU/day (95% CI, -359 to 510 IU/day), and for vitamin K by 167 mcg/day (95% CI, -233 to 568 mcg/day). This pilot study showed promising validation evidence for the use of this FFQ, which focuses on calcium, vitamin D and vitamin K intakes in postmenopausal women, as a screening tool in clinical and research settings.     

The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial

In the Women's Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.     

The bioavailability of vitamin D from fortified cheeses and supplements is equivalent in adults

There is a need to increase the options for vitamin D fortification. We have developed a method to fortify hard cheese with vitamin D. Our aim was to characterize the bioavailability of vitamin D from fortified cheeses. Eighty adults were randomized to weekly servings of fortified cheddar cheese (DC) (34 g; n = 20); fortified low-fat cheese (DLF) (41 g; n = 10); liquid vitamin D supplement (1 mL), taken with food (DS+) (n = 20) or without food (DS-) (n = 10); placebo cheddar cheese (n = 10); or placebo supplement (n = 10). The treatments contained 28,000 IU cholecalciferol (vitamin D3), equivalent to 4000 IU (100 microg/d). The primary outcome was the comparison of vitamin D bioavailability, as measured by the serum 25-hydroxyvitamin D [25(OH)D] response, between fortified cheeses and supplement. In the placebo groups, initial 25(OH)D, 55.0 +/- 25.3 nmol/L, declined over the 8-wk winter protocol, to 50.7 +/- 24.2 nmol/L (P = 0.046). In the vitamin D-treated groups, the mean increases in 25(OH)D over 8 wk were: 65.3 +/- 24.1 (DC), 69.4 +/- 21.7 (DLF), 59.3 +/- 23.3 (DS+), and 59.3 +/- 19.6 nmol/L (DS-); these changes differed from the placebo groups (P < 0.0001) but not from one another (P = 0.62). Compared with baseline, serum parathyroid hormone decreased with both fortification (P = 0.003) and supplementation (P = 0.012). These data demonstrate that vitamin D is equally bioavailable from fortified hard cheeses and supplements, making cheese suitable for vitamin D fortification.     

Supplementation with calcium + vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein concentrations

BACKGROUND: Adequate calcium intake can have a favorable effect on some metabolic variables. OBJECTIVE: The objective of the study was to determine the effects of daily calcium intake and of supplementation with calcium and vitamin D (calcium+D) during a weight-loss intervention on blood pressures, plasma lipid and lipoprotein concentrations, and glucose and insulin concentrations in low calcium consumers. DESIGN: Healthy, overweight or obese women (n = 63) with a daily calcium intake of < 800 mg/d were randomly assigned in a double-blind manner to 1 of 2 groups: the group consuming 2 tablets/d of a calcium + vitamin D supplement (600 mg elemental calcium and 200 IU vitamin D/tablet) or the group consuming placebo; both groups observed a 700 kcal/d energy restriction. These 63 women then completed a 15-wk weight-loss intervention. RESULTS: Initial daily calcium intake was significantly correlated with plasma HDL cholesterol (r = 0.41, P < 0.001) and with 2-h postload glycemia (r = -0.29, P < 0.05) during an oral-glucose-tolerance test, independent of fat mass and waist circumference. After the 15-wk intervention, significantly greater decreases in total:LDL and LDL:HDL (P < 0.01 for both) and of LDL cholesterol (P < 0.05) were observed in the calcium+D group than in the placebo group. The differences in total:HDL and LDL:HDL were independent of changes in fat mass and in waist circumference. A tendency for more beneficial changes in HDL cholesterol, triacylglycerol, and total cholesterol was also observed in the calcium+D group (P = 0.08). CONCLUSION: Consumption of calcium+D during a weight-loss intervention enhanced the beneficial effect of body weight loss on the lipid and lipoprotein profile in overweight or obese women with usual low daily calcium intake.     

Calcium, vitamin D supplementation, and physical function in the Women's Health Initiative

OBJECTIVES: The Women's Health Initiative (WHI) randomized trial of calcium/vitamin D supplementation found reduced bone loss with active treatment compared to placebo. Now we examine whether the treatment affected self-reported physical functioning and objective measures of physical functioning. DESIGN: A randomized, double-blind, placebo-controlled trial of 1,000 mg calcium carbonate plus 400 IU vitamin D(3) per day or matching placebo pills. SUBJECTS/SETTING: The study included 33,067 women (50 to 79 years old) at 40 US study centers. MAIN OUTCOME MEASURES: Physical functioning was assessed by questionnaire at enrollment in WHI, 1 year prior to calcium/vitamin D trial randomization and at study close-out (average follow-up 7.1 years). Objective physical performance and self-reported exercise measures were collected at WHI baseline (1 year prior to calcium/vitamin D enrollment) and 2 years and 4 years after calcium/vitamin D trial enrollment in a subsample (n=3,137). STATISTICAL ANALYSES PERFORMED: Calcium/vitamin D effects were tested in unadjusted and interaction linear models for each of the physical function measures. Covariates were baseline total calcium intake, fracture risk score, treatment arm in the hormone therapy and dietary modification trials (ie, active drug or placebo, low-fat diet intervention or usual diet, respectively) and age. RESULTS: Neither intention to treat nor high adherence analyses produced substantial effects of calcium/vitamin D compared to placebo on physical functioning or performance. The interaction analyses also did not result in differences because of calcium/vitamin D. CONCLUSIONS: As the first long-term randomized trial to examine the effectiveness of calcium and vitamin D in protecting against decline of physical functioning in older women, the results did not support benefit.     

Calcium,vitamin D,milk consumption,and hip fractures: a prospective study among postmenopausal women

BACKGROUND: Short trials of calcium supplementation show that it reduces loss of bone density in postmenopausal women; longer observational studies do not generally find a lower risk of hip fracture with higher-calcium diets. Fewer studies have focused on vitamin D in preventing postmenopausal osteoporosis or fractures. OBJECTIVE: We assessed relations between postmenopausal hip fracture risk and calcium, vitamin D, and milk consumption. DESIGN: In an 18-y prospective analysis in 72 337 postmenopausal women, dietary intake and nutritional supplement use were assessed at baseline in 1980 and updated several times during follow-up. We identified 603 incident hip fractures resulting from low or moderate trauma. Relative risks (RRs) from proportional hazards models were controlled for other dietary and nondietary factors. RESULTS: Women consuming > or = 12.5 microg vitamin D/d from food plus supplements had a 37% lower risk of hip fracture (RR = 0.63; 95% CI: 0.42, 0.94) than did women consuming < 3.5 microg/d. Total calcium intake was not associated with hip fracture risk (RR = 0.96; 95% CI: 0.68, 1.34 for > or = 1200 compared with < 600 mg/d). Milk consumption was also not associated with a lower risk of hip fracture (P for trend = 0.21). CONCLUSIONS: An adequate vitamin D intake is associated with a lower risk of osteoporotic hip fractures in postmenopausal women. Neither milk nor a high-calcium diet appears to reduce risk. Because women commonly consume less than the recommended intake of vitamin D, supplement use or dark fish consumption may be prudent.     

Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level

BACKGROUND: The Food and Nutrition Board of the National Academy of Sciences states that 95 microg vitamin D/d is the lowest observed adverse effect level (LOAEL). OBJECTIVE: Our objective was to assess the efficacy and safety of prolonged vitamin D3 intakes of 25 and 100 microg (1000 and 4000 IU)/d. Efficacy was based on the lowest serum 25-hydroxyvitamin D [25(OH)D] concentration achieved by subjects taking vitamin D3; potential toxicity was monitored by measuring serum calcium concentrations and by calculating urinary calcium-creatinine ratios. DESIGN: Healthy men and women (n = 61) aged 41 +/- 9 y (mean +/- SD) were randomly assigned to receive either 25 or 100 microg vitamin D3/d for 2-5 mo, starting between January and February. Serum 25(OH)D was measured by radioimmunoassay. RESULTS: Baseline serum 25(OH)D was 40.7 +/- 15.4 nmol/L (mean +/- SD). From 3 mo on, serum 25(OH)D plateaued at 68.7 +/- 16.9 nmol/L in the 25-microg/d group and at 96.4 +/- 14.6 nmol/L in the 100-microg/d group. Summertime serum 25(OH)D concentrations in 25 comparable subjects not taking vitamin D3 were 46.7 +/- 17.8 nmol/L. The minimum and maximum plateau serum 25(OH)D concentrations in subjects taking 25 and 100 microg vitamin D3/d were 40 and 100 nmol/L and 69 and 125 nmol/L, respectively. Serum calcium and urinary calcium excretion did not change significantly at either dosage during the study. CONCLUSIONS: The 100-microg/d dosage of vitamin D3 effectively increased 25(OH)D to high-normal concentrations in practically all adults and serum 25(OH)D remained within the physiologic range; therefore, we consider 100 microg vitamin D3/d to be a safe intake.     

Safety of vitamin D3 in adults with multiple sclerosis

BACKGROUND: Vitamin D3 may have therapeutic potential in several diseases, including multiple sclerosis. High doses of vitamin D(3) may be required for therapeutic efficacy, and yet tolerability--in the present context, defined as the serum concentration of 25-hydroxyvitamin D [25(OH)D] that does not cause hypercalcemia--remains poorly characterized. OBJECTIVE: The objective of the study was to characterize the calcemic response to specific serum 25(OH)D concentrations. DESIGN: In a 28-wk protocol, 12 patients in an active phase of multiple sclerosis were given 1200 mg elemental Ca/d along with progressively increasing doses of vitamin D3: from 700 to 7000 microg/wk (from 28 000 to 280 000 IU/wk). RESULTS: Mean (+/- SD) serum concentrations of 25(OH)D initially were 78 +/- 35 nmol/L and rose to 386 +/- 157 nmol/L (P < 0.001). Serum calcium concentrations and the urinary ratio of calcium to creatinine neither increased in mean values nor exceeded reference values for any participant (2.1-2.6 mmol/L and <1.0, respectively). Liver enzymes, serum creatinine, electrolytes, serum protein, and parathyroid hormone did not change according to Bonferroni repeated-measures statistics, although parathyroid hormone did decline significantly according to the paired t test. Disease progression and activity were not affected, but the number of gadolinium-enhancing lesions per patient (assessed with a nuclear magnetic brain scan) decreased from the initial mean of 1.75 to the end-of-study mean of 0.83 (P = 0.03). CONCLUSIONS: Patients' serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data support the feasibility of pharmacologic doses of vitamin D3 for clinical research, and they provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin.     

Vitamin C augments lymphocyte glutathione in subjects with ascorbate deficiency

BACKGROUND: Ascorbate and glutathione play central roles in the defense against free radicals and oxidants that are implicated in chronic diseases. OBJECTIVE: The objective was to determine the ability of vitamin C supplements to modulate the concentration of glutathione in human lymphocytes. DESIGN: The effect of vitamin C supplements was determined in a sequential study with time points before supplementation, after 13 wk of vitamin C supplements (500 or 1000 mg/d), and after 13 wk of matching placebo. The supplementation group was selected on the basis of low plasma ascorbate (<33 mmol/L) and consisted of 48 healthy men and women, smokers and nonsmokers, aged 25-64 y. Ascorbate and glutathione were measured in purified lymphocytes. RESULTS: At baseline, the mean (+/-SD) concentration of plasma ascorbate was 19.5 +/- 7.2 micro mol/L, 22.5 micro mol/L below the median of normal distribution. The ascorbate concentration in plasma was linearly associated with that in lymphocytes (r = 0.53, P < 0.001). On supplementation with vitamin C, lymphocyte ascorbate increased by 51% (from 16.7 +/- 4.9 to 25.3 +/- 6.9 nmol/mg protein; P < 0.001) and was accompanied by an increase of lymphocyte glutathione by 18% (from 22.5 +/- 4.5 to 26.6 +/- 6.5 nmol/mg protein; P < 0.001). After placebo, the ascorbate and glutathione concentrations fell to near baseline concentrations (17.1 +/- 5.4 and 23.5 +/- 6.4 nmol/mg protein, respectively). No significant interaction was observed for sex and smoking status. Finally, the changes in lymphocyte ascorbate after supplementation were strongly associated with changes in lymphocyte glutathione (r = 0.71, P < 0.001). The association suggests that every 1-mol change in ascorbate is accompanied by a change of approximately 0.5 mol in glutathione. CONCLUSION: Vitamin C supplements increase glutathione in human lymphocytes.     

Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes.

BACKGROUND: The role of caffeine as a risk factor for bone loss is controversial. OBJECTIVE: Our goals were 1) to compare in both a cross-sectional study and a 3-y longitudinal study the bone mineral density (BMD) of postmenopausal women consuming high or low amounts of caffeine and 2) to study the interaction between caffeine intake, vitamin D receptor (VDR) polymorphism, and BMD in the longitudinal study. DESIGN: The results are derived from cross-sectional measurements of BMD in 489 elderly women (aged 65-77 y) and from longitudinal measurements made in 96 of these women who were treated with a placebo for 3 y. Changes in BMD were adjusted for confounding factors and were compared between groups with either low (< or =300 mg/d) or high (>300 mg/d) caffeine intakes and between the VDR genotype subgroups of the low- and high-caffeine groups. RESULTS: Women with high caffeine intakes had significantly higher rates of bone loss at the spine than did those with low intakes (-1.90 +/- 0.97% compared with 1.19 +/- 1.08%; P = 0.038). When the data were analyzed according to VDR genotype and caffeine intake, women with the tt genotype had significantly (P = 0.054) higher rates of bone loss at the spine (-8.14 +/- 2.62%) than did women with the TT genotype (-0.34 +/- 1.42%) when their caffeine intake was >300 mg/d. CONCLUSIONS: Intakes of caffeine in amounts >300 mg/d ( approximately 514 g, or 18 oz, brewed coffee) accelerate bone loss at the spine in elderly postmenopausal women. Furthermore, women with the tt genetic variant of VDR appear to be at a greater risk for this deleterious effect of caffeine on bone.     

Effect of withdrawal of calcium and vitamin D supplements on bone mass in elderly men and women

BACKGROUND: Supplementation with calcium and vitamin D reduces bone loss and prevents fractures in elderly people, but it is not known whether any lasting benefit remains if the supplements are discontinued. OBJECTIVE: The objective was to determine whether gains in bone mineral density (BMD) induced by calcium and vitamin D supplementation persist after supplement withdrawal. DESIGN: Two-hundred ninety-five healthy, elderly men and women (aged >/=68 y) who had completed a 3-y randomized, placebo-controlled trial of calcium and vitamin D supplementation were followed for an additional 2 y during which no study supplements were given. BMD was measured by dual-energy X-ray absorptiometry, and biochemical variables related to calcium metabolism and bone turnover were measured. RESULTS: In the 128 men, supplement-induced increases in spinal and femoral neck BMD were lost within 2 y of supplement discontinuation, but small benefits in total-body BMD remained. In the 167 women, there were no lasting benefits in total-body BMD or at any bone site. Consistent with the observations on BMD, the bone turnover rates in both men and women (as measured by serum osteocalcin concentrations) returned to their original higher concentrations within the same 2-y period. CONCLUSION: Discontinued calcium and vitamin D supplementation has limited cumulative effect on bone mass in men and women aged >/=68 y.     

Calcium Plus Vitamin D Supplementation and Joint Symptoms in Postmenopausal Women in the Women's Health Initiative Randomized Trial

BackgroundLow vitamin D intake and levels have been associated with increased joint symptoms in some observational studies but the findings are mixed and evidence from randomized trials sparse.ObjectiveTo evaluate the influence of supplemental calcium and vitamin D on joint symptoms in the Women’s Health Initiative randomized, placebo-controlled, clinical trial.DesignIn post hoc analyses, the results of the Women’s Health Initiative randomized clinical trial in which 36,282 postmenopausal women were randomized to receive calcium carbonate (1,000 mg as elemental calcium) with vitamin D-3 (400 IU) daily or placebo were examined in the 6% subgroup of 1,911 participants, oversampled for minorities, who had serial joint symptom assessment. Qualitative information on joint pain and joint swelling was collected by questionnaire before entry and 2 years after randomization. Logistic regression models were used to compare the occurrence and severity of joint symptoms across randomization groups.ResultsAt baseline, total calcium and vitamin D intakes from diet and supplements were similar in the two randomization groups. In addition, both joint pain (reported by 73%) and joint swelling (reported by 34%) were commonly reported and comparable in the supplement and placebo groups. Two years after randomization, no statistically significant differences between supplement and placebo groups were seen for joint pain frequency (74.6% compared with 75.1% [P=0.79] for supplement and placebo groups, respectively) or joint swelling frequency (34.6% compared with 32.4% [P=0.29], respectively) or in severity scores for either outcome. Subgroup analyses suggested study participants also using nonprotocol calcium supplements at study entry may have less joint pain with supplement group randomization (interaction P=0.02).ConclusionsJoint symptoms are relatively common in postmenopausal women. However, daily supplementation with 1,000 mg calcium carbonate and 400 IU vitamin D-3 in a randomized, placebo-controlled clinical trial setting did not reduce the self-reported frequency or severity of joint symptoms.