Matthew Nudy

Calcium/vitamin D supplementation, serum 25-hydroxyvitamin D concentrations, and cholesterol profiles in the Women's Health Initiative calcium/vitamin D randomized trial.

ObjectiveThe objective of this study was to evaluate whether increased serum 25-hydroxyvitamin D3 (25OHD3) concentrations, in response to calcium/vitamin D (CaD) supplementation, are associated with improved lipids in postmenopausal women. MethodsThe parent trial was a double-blind, randomized, placebo-controlled, parallel-group trial designed to test the effects of CaD supplementation (1,000 mg of elemental calcium + 400 IU of vitamin D3 daily) versus placebo in postmenopausal women. Women from the general community, including multiple sites in the United States, were enrolled between 1993 and 1998. This cohort included 300 white, 200 African-American, and 100 Hispanic participants who were randomly selected from the Women’s Health Initiative CaD trial. Serum 25OHD3 and lipid (fasting plasma triglycerides [TG], high-density lipoprotein cholesterol [HDL-C], and calculated low-density lipoprotein cholesterol [LDL-C]) levels were assessed before and after CaD randomization. ResultsThere was a 38% increase in mean serum 25OHD3 concentrations after 2 years (95% CI, 1.29-1.47, P < 0.001) for women randomized to CaD (24.3 ng/mL postrandomization mean) compared with placebo (18.2 ng/mL). Women randomized to CaD had a 4.46–mg/dL mean decrease in LDL-C (P = 0.03). Higher concentrations of 25OHD3 were associated with higher HDL-C levels (P = 0.003), along with lower LDL-C and TG levels (P = 0.02 and P < 0.001, respectively). ConclusionsSupplemental CaD significantly increases 25OHD3 concentrations and decreases LDL-C. Women with higher 25OHD3 concentrations have more favorable lipid profiles, including increased HDL-C, lower LDL-C, and lower TG. These results support the hypothesis that higher concentrations of 25OHD3, in response to CaD supplementation, are associated with improved LDL-C.

Identification of a mechanism for increased cardiovascular risk among individuals with low vitamin D concentrations.

Objective:The aim of this study was to investigate the plasma concentrations of vitamin D and its association with plasma lipid profiles. Methods:Plasma vitamin D3 and lipid concentrations were measured in 119 female cynomolgus monkeys (premenopausal, n = 49; ovariectomized, n = 70) consuming approximately 1,000 IU per day of vitamin D3. In a subset of the ovariectomized monkeys (n = 23), vitamin D3 was remeasured after 6 months. The concentrations of vitamin D3 were analyzed as a continuous variable and were divided at the median into high (≥48 ng/mL) versus low (<48 ng/mL) groupings. Results:Among the 119 monkeys, the range of vitamin D3 concentrations was 24.0 to 95.2 ng/mL (mean ± SD, 48.5 ± 12.7 ng/mL). Plasma vitamin D3 concentration was positively associated with high-density lipoprotein cholesterol (HDL-C; P = 0.003). Monkeys in the high vitamin D3 group had a significantly greater plasma HDL-C concentration (57.9 mg/dL) than did those in the low vitamin D3 group (47.1 mg/dL; P = 0.001). Although the difference was not significant (P = 0.120), the monkeys in the high vitamin D3 group had a decreased total plasma cholesterol-to-HDL-C ratio compared with those in the low vitamin D3 group (5.4 and 6.2, respectively), potentially putting them at lower risk of atherosclerosis development. Conclusions:Given that the monkeys all consumed a diet replete in vitamin D3, it seems that individual differences in vitamin D absorption or metabolism may have determined whether the monkeys had high or low concentrations of vitamin D3. Lower vitamin D3 was associated with a more atherogenic lipid profile, a major risk factor for progressing to coronary artery atherosclerosis in monkeys and human beings.

The quantification of vitamin D receptors in coronary arteries and their association with atherosclerosis

OBJECTIVE The activated vitamin D receptor (VDR) may have an important role in vascular health. The objective of this study was to determine whether there is an association between the expression of VDRs in coronary arteries and the extent of diet-induced atherosclerosis. METHODS Utilizing a cohort of 39 postmenopausal female cynomolgus monkeys with varying stages of atherosclerosis, histologic sections of the left anterior descending artery (LAD) were analyzed for plaque cross-sectional area, plaque thickness, and VDR quantity using immunohistochemical H-score analysis. The quantities of VDRs were analyzed as a continuous variable and were divided at the median intimal H-score into high vs. low groupings. RESULTS In the LAD, a significant negative correlation was observed between the quantity of VDR and plaque size (both cross-sectional area [p<0.001] and plaque thickness [p<0.001]). Monkeys in the low VDR group had a significantly greater cross-sectional plaque area (1.2mm(2)) and greater plaque thickness (0.3mm) than those in the high VDR group (0.4mm(2), p=0.005; 0.1mm, p=0.003, respectively). CONCLUSIONS Lower concentrations of VDRs in a main coronary artery were associated with greater atherosclerotic plaque size in postmenopausal female monkeys. Given that coronary artery atherosclerosis is a major cause of coronary heart disease in postmenopausal women, further research to ascertain the relationship between VDRs and atherosclerosis is warranted.

Coronary artery vitamin D receptor expression and plasma concentrations of 25-hydroxyvitamin D: their association with atherosclerosis.

Objective The aim of this study was to analyze coronary artery vitamin D receptor (VDR) expression, the plasma concentrations of 25-hydroxyvitamin D3 (25OHD3), and their relationship with coronary artery atherosclerosis. Methods Premenopausal cynomolgus monkeys were fed atherogenic diets containing the equivalent of 1,000 IU/day of vitamin D3. Protein was derived from casein-lactalbumin (C/L, n = 10), soy protein isolate (soy, n = 10), or a combination (n = 19). After 32 months of consuming the diets, each monkey underwent surgical menopause. After 32 postmenopausal months, coronary atherosclerosis was measured in the left circumflex (LCX) artery and left anterior descending (LAD) artery. VDR expression was determined for the LAD, and 25OHD3 concentrations were assessed. Results Both the cross-sectional area of atherosclerotic plaques (in square millimeters) and plaque thickness (in millimeters) in the LCX as well as the LAD arteries were analyzed in these monkeys. Those with higher plasma vitamin D3 concentrations and higher VDR were compared with those with higher plasma 25OHD3 concentrations and lower VDR. Significantly smaller plaque sizes were noted with higher plasma 25OHD3 concentrations and higher VDR. For the LCX artery, there was also a significantly lower plaque size (both plaque thickness and cross-sectional area) in those with higher quantities of VDR and lower 25OHD3 concentrations versus those with lower quantities of VDR and higher plasma concentrations of 25OHD3 (P = 0.009 and P = 0.040, respectively). Conclusions Cynomolgus monkeys with higher quantities of VDR have significantly less atherosclerosis than do those with lower quantities of VDR and higher plasma 25OHD3 concentrations. If these findings translate to human beings, it might explain why some individuals with higher plasma concentrations of 25OHD3 have more coronary artery atherosclerosis.

A prospective analysis of the association between cardiovascular disease and depression in middle-aged women.

Objective:Experimental and clinical data demonstrate a close association between depression and coronary heart disease (CHD). Because no simple depression instrument for use by general practitioners has been shown to predict CHD, the objective of this study was to evaluate whether such a questionnaire could predict CHD. Methods:The prevalence of CHD and CHD risk factors was assessed in women with depression, measured by a validated three-question depression screening instrument. Among 1,919 participants in the breast arterial calcification and CHD 5-year prospective study, 1,454 women (75.8%) completed a baseline depression inventory. Results:Among the 1,454 women, 72.2% were postmenopausal, and the mean (SD) age at the conclusion of a 5-year prospective study was 61.3 (12.1) years. Among the women with no CHD risk factors at baseline and with one or less positive depression responses compared with those with two or more, 1.6% versus 3.8%, respectively, had at least one CHD risk factor (P = 0.004) by the 5th year of the study. In addition, 2.3% versus 6.0%, respectively, developed CHD (P = 0.005) by the 5th year of the study. Among all women with no positive depression responses compared with those with any positive depression responses, 2.1% versus 5.6%, respectively, had developed CHD by the 5th year of the study (P = 0.002). Finally, more positive depression responses were associated with a greater prevalence of CHD. Conclusions:In this prospective study, depression-detected by a validated three-item questionnaire-was able to predict those women more likely to develop CHD.

Vitamin D deficiency and cardiovascular disease in postmenopausal women: contributions from human and nonhuman primate studies.

ObjectiveCardiovascular disease (CVD) is the leading cause of death among American postmenopausal women and all adult Americans. The medical community and the lay community have recently become intrigued with vitamin D and its potential role in reducing the risk of CVD. Research findings from multiple retrospective studies, few prospective studies, and recent nonhuman primate studies have been inconsistent and conflicting. The objective of this study is to review what is known about the topic, what questions remain unanswered, and where the research community should be focusing. MethodsA literature search was conducted through PubMed and Google Scholar up to August 1, 2014. One hundred six articles, including 18 double-blind, placebo-controlled, randomized clinical trials, relevant to the study topic were identified. All studies were stratified based on study design and primary outcome. The effects of vitamin D on CVD were reviewed and summarized. ResultsAlthough there is an abundance of observational studies suggesting an association with CVD protection, the most well-controlled randomized human trial data available show no benefit of vitamin D on CVD. However, highly controlled nonhuman primate studies indicate a beneficial relationship. ConclusionsWell-designed research, with CVD as primary outcome, is needed to help bridge the gap in our knowledge on this topic. In the meantime, caution should be applied to avoid overdiagnosis and overtreatment of vitamin D deficiency.

25(OH)D3 and Cardiovascular Risk Factors in Female Nonhuman Primates

OBJECTIVE To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D(3) (25(OH)D(3)) have pathophysiologic significance, we evaluated a cohort of female monkeys, seeking to identify associations with clinically relevant cardiovascular risk factors, including age, abdominal obesity (waist circumference), and high-density lipoprotein cholesterol (HDL-C). METHODS One hundred fifty-five female vervet monkeys (Chlorocebus aethiops sabaeus) aged 3-25 years consumed a typical western diet for 7-8 weeks that provided a womans equivalent of approximately 1000 IU/day of vitamin D(3). Measurements of vitamin D(3) and HDL-C concentrations, as well as waist circumference, were obtained. RESULTS Among young monkeys (aged 3-5 years), compared to older monkeys (aged 16-25 years), the mean plasma 25(OH)D(3) concentrations were 82.3±3.2 ng/mL and 58.6±2.9 ng/mL (p<0.0001), respectively. Plasma 25(OH)D(3) concentrations had a range of 19.6-142.0 ng/mL (mean±standard error [SE] 66.4±1.7 ng/mL). 25(OH)D(3) concentrations were inversely associated with age (p<0.0001) and waist circumference (p=0.016) and were positively correlated with HDL-C (p=0.01). However, when statistically controlling for age, none of these relationships remained significant. CONCLUSIONS Higher plasma concentrations of 25(OH)D(3) were associated with more favorable cardiovascular risk factors, with inverse associations observed between 25(OH)D(3) and abdominal obesity, HDL-C, and age. These associations were no longer significant when controlling for age.

Vitamin D and conjugated equine estrogen: the association with coronary artery atherosclerosis in cynomolgus monkeys.

Objective:To analyze vitamin D3 plasma concentrations among monkeys randomized to oral conjugated equine estrogen (CEE) versus control and the association with coronary artery atherosclerosis (CAA). Methods:Surgically postmenopausal monkeys (N = 50) were fed an atherogenic diet containing a womans equivalent of 1000 IU/day of vitamin D3. The monkeys were randomized at baseline to receive CEE (equivalent of 0.45 mg/d, n = 25) or placebo (n = 25). 25-hydroxyvitamin D3 (25OHD3) was measured at baseline and 20 months later. At 20 months, CAA evidence of coronary artery remodeling, and American Heart Association (AHA) severity scores were assessed. Results:The percent change in 25OHD3 concentrations from baseline to 20 months postrandomization was inversely correlated with plaque area of the right coronary artery (P = 0.048), left circumflex artery (P = 0.039), left anterior descending artery (P = 0.017), and AHA severity score (AHA LADmax) (P = 0.016). Those with increased 25OHD3 concentrations who were taking CEE also had significantly lower AHA scores compared with those who were not taking CEE and did not have an increase in 25OHD3 (P = 0.01). Conclusions:Monkeys with increases in 25OHD3 concentrations had significantly less severe CAA. Those with increases in 25OHD3 with CEE were associated with significantly decreased AHA lesion scores, decreased plaque, and greater coronary artery remodeling. If these findings are present in women, achieving higher 25OHD3 concentrations (or being a vitamin D supplementation “responder”) may be associated with cardioprotection, and further studies to evaluate a synergistic effect with CEE and vitamin D on cardiovascular health are needed.

Effects of vitamin D and calcium supplementation on hypercalcemia and hypercalciuria.

E merging data from observational and experimental studies support a link between vitamin D and beneficial effects on extraskeletal tissues. Results of these studies have shown an association between plasma vitamin D concentrations and prevention of certain cancers, autoimmune diseases (such as multiple sclerosis), type I and type II diabetes, and cardiovascular disease. However, there is a lack of well-designed randomized controlled trials to support the belief that vitamin D supplementation results in nonskeletal benefits. A recent Institute of Medicine (IOM) report on dietary reference intakes for calcium and vitamin D concluded that available evidence supports the roles of vitamin D and calcium in skeletal health but that evidence supporting the roles of vitamin D and calcium in extraskeletal health has been inconsistent. Despite this, there is extensive use of vitamin D supplementation among individuals for reasons other than osteoporosis. In fact, from 2001 to 2009, a sixfold increase in the sales of over-the-counter vitamin D was observed in the United States. In addition, there is widespread use of vitamin D and calcium supplementation for the prevention and treatment of osteoporosis in postmenopausal women. The recommended daily allowance (RDA)Vdietary and supplementalVfor vitamin D, based on the recent IOM report, is 600 IU/day for individuals aged 1 to 70 years and 800 IU for individuals aged 71 years or older. Vitamin D can be obtained from sun exposure and through the diet. However, very few foods naturally contain vitamin D, although many foods are fortified with vitamin D, including orange juice, breads, cereals, and milk. Those at risk for vitamin D deficiency include individuals with obesity, kidney or liver disease, and disorders affecting fat absorption; those older than 65 years; and those with darker skin pigmentation. The tolerable upper level for vitamin D intake is 4,000 IU/day, as established by the IOM, although the daily dose at which vitamin D toxicity occurs is not known. The RDA for calcium intake is 1,200 mg/day for women older than 50 years and 1,000 mg/day for women aged 19 to 50 years. The tolerable upper level for calcium intake is 2,000 mg/day. Interestingly, higher dietary calcium intake may reduce the incidence of nephrolithiasis, whereas oral supplementation can increase the incidence. Although data are not conclusive and information has been conflicting, oral supplementation with calcium has been thought to increase the incidence of cardiovascular disease and/or stroke. It is believed that calcium derived from supplementation may raise plasma concentrations of calcium more rapidly than dietary calcium, thus leading to small increases in adverse effects. For this reason, women should strive to attain as much of their daily calcium goals through a diet rich in calcium. Appropriate foods high in calcium include milk, yogurt, oily fish, broccoli, and collard greens. Women should consider calcium supplements to bring them to their daily intake goals only when their dietary intake of calcium is below the RDA. The adverse effects and safety profiles of calcium and vitamin D supplementation are less clear despite their widespread use. Because of this, further data and research on the safety of these supplements are warranted. In the Women’s Health Initiative, a large prospective randomized trial, the effects of calcium (1,000 mg/d) and vitamin D (400 IU/d) supplementation were investigated. A 17% increase in the risk of kidney stone formation was seen among women in the treatment group after 7 years. However, the average total calcium intake of those in the treatment group was high (92,000 mg/d). In this issue of Menopause, Gallagher et al found that 8.8% of women developed hypercalcemia and 32% of women developed hypercalciuria during a 1-year period when study participants were taking calcium supplements and daily vitamin D at varying doses. This 1-year randomized, double-blind, placebo-controlled study included 163 vitamin DYdeficient (25-hydroxyvitamin D G20 ng/mL) postmenopausal women aged 57 to 90 years who were randomized to receive daily doses of vitamin D at 400, 800, 1,600, 2,400, 3,200, 4,000, or 4,800 IU/day. After review and quantification of dietary calcium intake from a 7-day food diary, calcium supplements were provided to maintain a total calcium intake of 1,200 to 1,400 mg/day in all participants. Blood and urine samples were collected every 3 months for 1 year. Besides showing that hypercalcemia and hypercalciuria were common among women taking vitamin D and calcium supplements, the results showed no relationship between vitamin D dose or plasma 25-hydroxyvitamin D concentration and episodes of hypercalcemia and hypercalciuria. In fact, even women receiving placebo vitamin D had episodes of hypercalcemia and hypercalciuria. This suggests that even standard intake of calcium (mean supplementation of 600 mg/d and mean total calcium intake of 1,280 mg/d) may be too much for some women. Urine calcium concentrations did not change with varying vitamin D doses. In addition, serum calcium concentrations did not vary with differing vitamin D doses. Daily supplementation with vitamin D 4,800 IU/day did not result in significantly more hypercalciuria and hypercalcemia when compared with lower daily doses of vitamin D. They concluded

Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative: A Randomized Controlled Trial.

OBJECTIVE To analyze the treatment effect of calcium+vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors. METHODS We conducted a prospective, randomized, double-blind, placebo-controlled trial among Womens Health Initiative (WHI) participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C). RESULTS Between September 1993 and October 1998, a total of 68,132 women aged 50-79 years were recruited and randomized to the WHI-Dietary Modification (n=48,835) and WHI-Hormone Therapy trials (n=27,347). Subsequently, 36,282 women from WHI-Hormone Therapy (16,089) and WHI-Dietary Modification (n=25,210) trials were randomized in the WHI-Calcium+Vitamin D trial to 1,000 mg elemental calcium carbonate plus 400 international units vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the hormone therapy and calcium+vitamin D trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared with placebo, was -1.6, (95% confidence interval [CI] -5.5 to 2.2) mg/dL for calcium+vitamin D alone, -9.0 (95% CI -13.0 to -5.1) mg/dL for hormone therapy alone, and -13.8 (95% CI -17.8 to -9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium+vitamin D+hormone therapy on LDL-C (P value for interaction=.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (P value for interaction=.03). CONCLUSION Reductions in LDL-C were greater among women randomized to both calcium+vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium+vitamin D+hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611.