226% more oxidative stress with Statins.

Thursday, March 15, 2012

March 14, 2012, 12:01 AM

Do Statins Make It Tough to Exercise?

By GRETCHEN REYNOLDS, Columnist

Epperson/Getty ImagesCan a statin ruin your workout?

For years, physicians and scientists have been aware that statins, the most widely prescribed drugs in the world, can cause muscle aches and fatigue in some patients. What many people don’t know is that these side effects are especially pronounced in people who exercise.

To learn more about the effect statins have on exercising muscles, scientists in Strasbourg, France, recently gave the cholesterol-lowering drug Lipitor to a group of rats for two weeks, while a separate control group was not medicated. Some of the rats from both groups ran on little treadmills until they were exhausted.

It was immediately obvious that the medicated animals couldn’t run as far. They became exhausted much earlier than the rats that had not been given statins.

Editor's note:
Oxidative Stress is the single biggest scavenger of Nitric Oxide in the bloodstream. This is one of the reasons ProArgi-9+ has anti-oxidents, Resveratrol and pomegranate in the formula.  If statins increase oxidation by 226% imagine how much Nitric Oxide is being lost.  No wonder the test subjects were exhausted after exercise.

The differences were even more striking at a cellular level. When the scientists studied muscle tissues, they found that oxidative stress, a measure of possible cell damage, was increased by 60 percent in sedentary animals receiving statins, compared with the unmedicated control group.

The effect was magnified in the runners, whose cells showed 226 percent more oxidative stress than exercising animals that had not been given statins.

Over all, the study data showed that working out while taking statins “exacerbated metabolic perturbations” in muscles, the study’s authors conclude. The drug made running harder and more damaging for the rats.The medicated running rats also had less glycogen or stored carbohydrates in their muscles than the unmedicated runners. And their mitochondria, tiny mechanisms within cells that generate power, showed signs of dysfunction; mitochondrial respiratory rates were about 25 percent lower than in the unmedicated runners.

Statins’ safety has come under considerable scrutiny in recent weeks. Last month, the Food and Drug Administration added safety alerts to prescribing information for statins, warning of risks for memory loss and diabetes, as well as muscle pain. (Read more about those concerns here.)

More than 20 million Americans are taking statins, and by most estimates, at least 10 percent of them will experience some degree of muscle achiness or fatigue. That proportion rises to at least 25 percent among people taking statins who regularly exercise, and may be 75 percent or higher among competitive athletes.

Why and how exercise interacts with statins to cause muscle problems remains unknown, in part because it’s more difficult to study molecular responses in people than in animals. (People generally dislike muscle biopsies.) But an eye-opening 2005 study of healthy young people taking statins showed that the gene expression profiles in their leg muscles after exercising were very different from those of volunteers not using statins. In particular, genes associated with muscle building and repair were “down-regulated,” or expressed less robustly, in the group using statins.

“It seems possible that statins increase muscle damage” during and after exercise “and also interfere somewhat with the body’s ability to repair that damage,” says Dr. Paul Thompson, the chief of cardiology at Hartford Hospital in Connecticut and senior author of the study.

The finding creates a worrisome conundrum for patients and their doctors. Statin users typically are at high risk for cardiovascular problems, making them the very people who could most benefit from regular exercise. But it may be that as a result of muscle problems, some people taking statins exercise less or not at all. “Lower energy is linked to less interest in activity,” says Dr. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego, who is studying exercise habits in statin users, “and fatigue with exertion is linked to less actual activity.”

And less activity has its own consequences. Move less and you increase your risk of premature death and other undesirable outcomes, even if your cholesterol is under control.

So what does the emerging science about statins and muscles mean for someone who is taking or considering the drugs? “Statins save lives,” Dr. Thompson says. “Most people cannot control their cholesterol with diet and exercise alone.” He advises athletes to stop taking the drugs several days before a competition or strenuous workout, to avoid exacerbating muscle damage. But if you have intractably high cholesterol or a history of heart disease or stroke, he says, “you should be on statins.”

For people with lower heart disease risks, though, the benefits are equivocal. A 2010 study by Dr. Golomb and colleagues found that a majority of statin users reporting muscle problems “were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy.” The patients were not at high risk of dying from heart disease, but were suffering from sore muscles and potentially a more sedentary life.

“Any indication of harm shifts the pendulum” toward risk, Dr. Golomb says, and should be considered before anyone decides whether to continue with statins.

The good news is that “muscle aches almost always disappear as soon as someone stops using statins,” Dr. Thompson says, and your vascular system may have benefited in the meantime.

“Statins are anti-aging for arteries,” he says. “If you take them, you’ll have younger arteries. Unfortunately,” he adds, “they are not anti-aging for muscles.”

Aspirin and Plavix treatment impair nitric oxide biosynthesis by platelets.

Aspirin and clopidogrel (Plavix) treatment impair nitric oxide biosynthesis by platelets.
O'Kane PD, Reebye V, Ji Y, Stratton P, Jackson G, Ferro A.
Source


Department of Clinical Pharmacology, Cardiovascular Division, 3.07 Franklin-Wilkins Building, King's College London, 150 Stamford Street, London SE1 9NH, UK.
J Mol Cell Cardiol. 2008 Aug;45(2):223-9. Epub 2008 Jul 7.
http://www.ncbi.nlm.nih.gov/pubmed/18606420 

Abstract


Aspirin and clopidogrel (Plavix) are used therapeutically for their anti-platelet effects. We examined the effects of aspirin and clopidogrel on basal and beta-adrenoceptor (beta-AR)-mediated platelet nitric oxide (NO) synthesis in healthy subjects and patients with coronary heart disease (CHD). Healthy subjects (n=19) were randomized in a double-blind cross-over manner to receive aspirin or clopidogrel, each at 75 mg daily, for 14 days. Patients (n=17) of similar age with CHD, taking aspirin, were randomized double-blind to either continue on aspirin 75 mg daily or to receive clopidogrel 75 mg daily for 14 days. NO synthase (NOS) activity was measured from l-[(3)H]arginine to l-[(3)H]citrulline conversion, and cGMP was determined by radioimmunoassay, in platelets basally and following incubation with isoproterenol or albuterol (each at 10(-5) mol/L).


In healthy subjects, aspirin did not affect basal NOS activity or cGMP in platelets, but suppressed the normal increase in both by isoproterenol and albuterol. Clopidogrel suppressed platelet NOS activity and cGMP both basally and in response to beta-AR agonists. In platelets from CHD patients, clopidogrel suppressed basal and beta-AR-stimulated NOS activity and cGMP as compared with aspirin. Platelet NOS activity and cGMP were lower in CHD subjects pre-randomization compared with healthy subjects both pre-randomization and post-aspirin. 


We conclude that chronic aspirin treatment suppresses beta-AR-stimulated but not basal platelet NO synthesis, as previously described, whereas chronic clopidogrel (Plavix) treatment suppresses both, with resultant functional consequences. Moreover, CHD may itself be associated with decreased platelet NO biosynthesis.




PMID:
18606420
[PubMed - indexed for MEDLINE]

Men who love soda at higher risk for heart attack, say Harvard scientists; Sugary drink habit could kill

Drinking two sugary beverages a day increases cardiac risk by 42%

Experts have some not-so-sweet news for men who drink sodas and sugary drinks.

Downing just one sugary beverage a day can up your heart attack risk by 20%, according to research published by Harvard scientists in the journal Circulation.

The more soda or noncarbonated fruity drinks, the higher your risk.

Two servings ups your heart risk by 42%. Drink a soda with all three meals? Your risk increases by 69%.

The team of Harvard researchers found a strong correlation between sugary drinks and heart attack risk that held up even after factoring in smoking, physical activity, alcohol, family history and BMI, reports MSNBC.com.

Volunteers who kicked their soda and sweet-drink habits experienced lower blood pressure.

While this study didn’t take diet soda into account, recent studies have linked artificially sweetened drinks to increased stroke and heart attack risk.

While this research focused on men, researchers say, sweet drinks aren’t good for women either.

It’s a problem that can easily be solved if people just stopped sipping the high calorie beverages and paid more attention to what they’re imbibing, according to lead study author, Lawrence de Koning, a research fellow in the department of nutrition at the Harvard School of Public Health.

“The first thing to do is to reduce the intake of sodas and then eventually eliminate them,” he said.

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• Original Research Article

Sweetened Beverage Consumption, Incident Coronary Heart Disease and Biomarkers of Risk in Men

1. Lawrence de Koning1; 
2. Vasanti S. Malik2; 
3. Mark D. Kellogg3;
4. Eric B. Rimm4; 
5. Walter C. Willett4; 
6. Frank B. Hu4*

+Author Affiliations

1. ¹ Harvard School of Public Health & Children's Hospital Boston, Boston MA;
2. ² Harvard School of Public Health, Boston, MA;
3. ³ Children's Hospital Boston, Boston MA;
4. ⁴ Harvard School of Public Health & Medical School & Brigham and Women's Hospital, Boston, MA

1. ↵* Corresponding author; email: fhu@hsph.harvard.edu

Abstract

Background—Sugar-sweetened beverage consumption is associated with weight gain and risk of type 2 diabetes. Few studies have tested for a relationship with coronary heart disease (CHD), or intermediate biomarkers. The role of artificially sweetened beverages is also unclear.

Methods and Results—We performed an analysis of the Health Professionals Follow-up study, a prospective cohort study including 42 883 men. Associations of cumulatively averaged sugar-sweetened (e.g. sodas) and artificially sweetened (e.g. diet sodas) beverage intake with incident fatal and non-fatal CHD (myocardial infarction) were examined using proportional hazard models. There were 3683 CHD cases over 22 years of follow-up. Participants in the top quartile of sugar-sweetened beverage intake had a 20% higher relative risk of CHD than those in the bottom quartile (RR=1.20, 95% CI: 1.09, 1.33, p for trend < 0.01) after adjusting for age, smoking, physical activity, alcohol, multivitamins, family history, diet quality, energy intake, BMI, pre-enrollment weight change and dieting. Artificially sweetened beverage consumption was not significantly associated with CHD (multivariate RR=1.02, 95% CI: 0.93, 1.12, p for trend = 0.28). Adjustment for self-reported high cholesterol, high triglycerides, high blood pressure and diagnosed type 2 diabetes slightly attenuated these associations. Intake of sugar-sweetened but not artificially sweetened beverages was significantly associated with increased triglycerides, CRP, IL6, TNFr1, TNFr2, decreased HDL, Lp(a), and leptin (p values < 0.02).

Conclusions—Consumption of sugar-sweetened beverages was associated with increased risk of CHD and some adverse changes in lipids, inflammatory factors, and leptin. Artificially sweetened beverage intake was not associated with CHD risk or biomarkers.

Vitamin D Update from ConsumerLab.com

What It Is:Vitamin D is a fat-soluble vitamin. There are two major forms of vitamin D  D₂ (ergocalciferol) and D₃ (cholecalciferol). Both vitamin D₂ and D₃ and appear to be absorbed with equal efficiency and, at moderate doses, are equally able to raise levels of 25-hydroxyvitamin D the hormonally active form of vitamin D and a clinical measure of vitamin D status.  However, at very high doses, D₃, may be more efficient at raising 25-hydroxyvitamin D levels.

Vitamin D₂ (ergocalciferol) is made by the conversion of a sterol found in plants and yeast. Vitamin D₂ is used in some dietary supplements.
Vitamin D₃ is produced naturally in human skin exposed to ultraviolet B light and occurs in some animal products, such as cod liver oil, and, in smaller amounts, in other fatty fish such as herrings, mackerel, sardines, and tuna. Vitamin D₃ is the most common form used in dietary supplements and is the form generally used to fortify foods such as milk (which naturally contains a small amount of vitamin D₃). Vitamin D₃ is made by the conversion of cholesterol compounds, such as 7-dehydroxycholesterol from lanolin found in sheep's wool.

See ConsumerTips for more information about the two forms of vitamin D and dosing.
(See separate reviews of Calcium and Vitamin K, which are also used in bone health).
What It Does:

Bone

Vitamin D regulates the amount of calcium and phosphorus in the body, partly by controlling their levels of absorption. Vitamin D treats and prevents rickets in children and osteomalacia (bone softening) in adults. Given to breast-fed infants, vitamin D may help increase bone density.

Taken with calcium, vitamin D can help decrease post-menopausal bone loss and prevent osteoporosis (loss of bone density), as well as improve tooth retention in the elderly. In girls ages 9 to 13, regular supplementation with calcium and vitamin D has been shown to significantly increase bone density and bone strength (measured in arms and legs) compared to placebo (Greene, Osteoporosis Int 2011).Other effects:

A study found that older women (69 years and older) whose vitamin D levels were not between 20 and 29.9 ng/mL had a greater risk of being frail.¹⁸ Frail individuals were those experiencing at least three of the following criteria: weight loss, weakness, exhaustion, slowness, and low physical activity.  The risk of frailty was increased by 47% among those with vitamin D levels below 15 ng/mL, 24% among those with levels below 20 ng/mL, and 32% among those with levels above 29.9 ng/mL.  An average of 4.5 years after these measurements were made, those originally not frail but whose blood levels had been below 20 ng/mL were 21% more likely to have become frail or died. These findings correspond with the 2010 report from the Institute of Medicine (IOM) indicating that 20 ng/mL is a sufficient level for vitamin D and that levels above 30 ng/mL may be associated with certain risks.¹⁷

Research has found that men with low levels of vitamin D in the blood (15 ng/mL and lower) were at increased risk for heart attack compared to those with levels at 30 ng/mL and higher, even after adjusting for other risk factors and physical activity. This may contribute to the higher rate of cardiovascular mortality among black Americans compared to white Americans, as blacks tend to have lower vitamin D levels.¹ More recently, an analysis of two large studies showed that men who consumed 600 IU or more per day of vitamin D from foods and supplements were 16% less likely to have cardiovascular disease and stroke over a period of approximately 20 years compared to men consuming less than 100 IU per day. The same association was not seen among women; the reason for this is unclear but one possible explanation given is that women may need higher intake of vitamin D because they tend to have a higher percentage of body fat than men and vitamin D is fat soluble. In addition, vitamin D intake during the study period, which ended in 2006, may have been too low to produce meaningful differences.²¹ A large trial giving 2,000 IU per day as a supplement is underway and may yield additional insights (principal investigator is J.E. Manson).

Possibly shedding light on vitamin D’s cardiovascular effects is a study of of overweight and obese premenopausal women which found that daily supplementation for 12 weeks with 1,000 IU vitamin D3 increased HDL (“good”) cholesterol by 7%. However, total cholesterol increased 1.7% and there was also a 4% increase in LDL (“bad”) cholesterol – although it contained less ApoB, suggesting less plaque-forming ability. Interestingly, body fat decreased by 9.6% (about 6 lbs), although total body weight was unchanged.³¹

Raising low levels of vitamin D may also reduce inflammation in the body. In a study of blood from thousands of adult Americans, levels of C-reactive protein (CRP), a marker of inflammation, decreased as vitamin D levels increased to just below 21 ng/mL²⁸ However, there was no further benefit when vitamin D levels reached and exceeded 21 ng/mL. In fact, after adjusting for cardiovascular risk factors, it was found that CRP levels slowly but progressively increasedat that point, suggesting a slight inflammatory action of vitamin D at these higher levels. The results seem to reinforce the importance of maintaining a plasma vitamin D level of at least 20 ng/mL and suggest some potential downside of higher levels of vitamin D.

 

A small study of women with primary dysmenorrhea (painful menstrual cramping) found that giving those with vitamin D levels less than 45 ng/mL a single high dose (300,000 IU) of vitamin D3 reduced pain by 41% during the next two menstrual periods. None of the women who received vitamin D needed anti-inflammatory medicine to manage menstrual pain during the two months, whereas 40% of those taking placebo used it at least once.²⁹ A concern, however, is that  high dose vitamin D has been shown to increased the risk of falls and fractures – at least in the elderly (as noted above) and the dose given works out to 5,000 IU vitamin D per day, more than the tolerable upper intake level of 4,000 IU per day (see Concerns and Cautions).  

Lower levels are also associated with a higher risk and severity of depression.  A study in Italy, for example, showed that older women with low vitamin D levels (below 20 ng/mL) were twice as likely to develop depressive mood as those with higher levels.  Older men with low levels were 60% more likely to develop depressive mood.⁹ Data from the same study showed that those who were severely vitamin D deficient (below 10 ng/mL) were approximately 60% more likely than those with vitamin D levels above 30 ng/mL to experience substantial cognitive decline, although there was no such association attention level.¹³ In a separate study lasting 3 years, the risk of depression was found to be 21% lower among women (aged 50 to 79) who reported total daily vitamin D intake (from foods and supplements) of at least 800 IU compared to women with intake of less than 100 IU. Excluding women with evidence of depression at the beginning of the study, a 20% lower risk of depression was seen with intake of just 400 IU or more per day. However, further analyses showed no reduction in the risk of depression resulting from vitamin D supplements alone. The reductions were only associated with higher vitamin D intake from foods.²⁴

A study from Finland suggested that high vitamin D status provides protection against Parkinson's disease. People with the highest vitamin D levels (above 20 ng/mL) had a 65% lower risk of developing Parkinson disease than those with the lowest vitamin D levels (below 10 ng/mL).  A limitation of the study was that none of the groups had sufficient vitamin D levels (due to limited sun exposure in Finland).¹⁴ It is possible that greater risk reduction would have been observed in people with sufficient vitamin D levels.

 

Low levels of vitamin D are also associated with a higher risk in women of developing rheumatoid arthritis. There is conflicting evidence about whether vitamin D helps reduce the overall risk of dying from cancer, although studies have consistently shown that higher vitamin D serum levels were associated with decreased risk of death from gastrointestinal cancers.

A review of 13 studies found that vitamin D supplements (800 to 1,000 IU daily) may improve balance and muscle strength, but not gait, among older adults.³⁰ Vitamin D may also improve balance and reduce the risk of falls in older adults, for reasons that aren't clear. However, a recent study in women aged 70 and older who were at-risk for bone fracture showed an increase in falls and fractures among those given an extremely high, single, annual dose (500,000 IU) of vitamin D₃¹⁰  This unexpected finding may have resulted from unusual effects of the extreme dose.¹¹

 

A review of studies found that daily vitamin D intake over 500 IU decreased the risk of type 2 diabetes by 13% compared with intake of less than 200 IU. Similarly, individuals with vitamin D levels over 25 ng/mL had a 43% lower risk of developing type 2 diabetes compared to those with levels under 14 ng/mL. However, vitamin D supplementation was not shown to effect glucose tolerance among people with established type 2 diabetes.²³ There is preliminary evidence that giving vitamin D supplements to infants might decrease the risk of type 1 diabetes later in life.

 

Weak evidence hints that if women avoid vitamin D deficiency it might reduce their risk of multiple sclerosis.

A study in post-menopausal women showed 400 IU of vitamin D₃ and 1,000 mg of calcium daily were less likely to gain small to moderate amounts of weight compared to women taking placebo.

 

Researchers in Japan studied the effect of vitamin D₃ supplements (1,200 IU per day from December through March) on the incidence of seasonal influenza A in school children. Influenza A infection occurred in 18.6% of children in a placebo group versus 10.8% of children who received the supplement a 42% reduction in risk among those taking the supplement. The reduction was more prominent among children who had not been taking other vitamin D supplements. Influenza infection was not reduced among a subgroup of asthmatic children but those who became infected were significantly less likely to have an asthmatic attack if they received vitamin D than if they had not. Supplementation did not affect the incidence of influenza B (which is less common than influenza A and is not seasonal).¹⁴

A review of medical studies published from 1950 to 2009 that looked at, among other variables, vitamin D intake and asthma, suggested that vitamin D deficiency may be linked to airway inflammation, decreased lung function and poor asthma control. The researchers conducting the review hypothesized that vitamin D supplementation may lead to improved asthma control, although this cannot be established as many of the studies were not specifically designed to test the effects of vitamin D supplementation on patients with asthma.¹⁵
Higher serum vitamin D levels are associated with a reduced risk of allergy in children and adolescents. A review of data from a nationwide study of over 6,000 individuals showed that allergic sensitization was more common in those with serum vitamin D of less than 15 ng/mL compared to those with 30 ng/mL or greater for 11 out of 17 allergens.  Results were adjusted for potentially confounding factors like time spent on indoor activities. The strongest associations were for allergy to oak (5 times the risk), peanut (2.4 times the risk), and ragweed (1.8 times the risk). There was also increased risk of allergy to dog, cockroach, mite, shrimp, ryegrass, Bermuda grass, birch and thistle. In adults, there was no consistent association between allergy and vitamin D levels.¹⁹

Laboratory studies suggest that vitamin D may inhibit pancreatic cancer cell growth and a review of five large epidemiologic studies concluded that higher levels of serum vitamin D were associated with a lower risk of developing pancreatic cancer.²⁷ Compared to people whose serum vitamin D levels were less than 20 ng/mL, the risk of developing pancreatic cancer over the following 12 to 18 years was 25% lower among those with levels of 20 mg to 29 ng/mL, and 29% lower among those with levels above 30 ng/mL.

REFERENCES:

¹ Fiscella, et al, Vitamin D, Race, and Cardiovascular Mortality: Findings From a National US Sample, Annals of Family Medicine, 2010; 8:11-18.

² Armas, et al, Vitamin D₂ is Much Less Effective than Vitamin D₃ in Humans, The Journal of Clinical Endocrinology & Metabolism, 2004; 89(1):5387-5391.

³ Trang, et al, Evidence that vitamin D₃ increases serum 25-hydroxyvitamin-D more efficiently than does vitamin D₂, American Journal of Clinical Nutrition, 1998; 68:854-8.

 

⁴ Kumar, et al, Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES 2001-2004, Pediatrics, 2009; 124(3):362-370.

 

⁵ Holick, et al, Vitamin D2 is as Effective as Vitamin D3 in Maintaining Circulating Concentrations of 25-Hydroxyvitamin D, J Clin Endocrinol Metab, March 2008, 93(3):677-681.

 

⁶ Hollis, B. W., Circulating 25-Hydroxyvitamin D Levels Indicative of Vitamin D Sufficiency: Implications for Establishing a New Effective Dietary Intake Recommendation for Vitamin D, J.

Nutri. 135:317-322, February 2005.

⁷ Biancuzzo, et al, Fortification of orange juice with vitamin D2 or vitamin D3 is as effective as an oral supplement in maintaining vitamin D status in adults, Am J Clin Nutr, April 28, 2010 (Epub ahead of print].

 

⁸ Vitamin D Consumer Fact Sheet, Office of Dietary Supplements, National Institutes of Health, Updated: 3/5/2010. 

 

⁹ Milaneschi, et al, Serum 25-Hydroxyvitamin D and Depressive Symptoms in Older Women and Men, J. Clin Endocrinol Metab, May, 5 2010 [Epub ahead of print].

¹⁰ Sanders, et al, Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women, JAMA. 2010;303(18):1815-1822.

 

¹¹ Dawson-Hughes, et al, High-Dose Vitamin D Supplementation: Too Much of a Good Thing? JAMA. 2010;303(18):1861-1862.

 

¹² Terushkin, et al, Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes, J. Am Acad Dermatol 2010; 62(10), 929.e1-929.e9.

 

¹³ Llewellyn, et al, Vitamin D and Risk of Cognitive Decline in Elderly Persons, Arch Intern Med, July 12, 2010; 170(13):1135-1141.

 

¹⁴ Knekt, et al, Serum Vitamin D and the Risk of Parkinson Disease, Arch Neurol, July 2010; 67(7): 808-811.

 

¹⁵ Urashima, et al, Randomized Trial of Vitamin D Supplementation to Prevent Seasonal Influenza A in Schoolchildren, Am J Clin Nutr 2010; 91(5):1255-60.

 

¹⁶ Sandu, et al, The Role of Vitamin D in Asthma, Ann Allergy Asthma Immunol 2010; 105(3):191-199.

 

¹⁷ Dietary Reference Intakes for Calcium and Vitamin D (2010), Food and Nutrition Board, National Acadamies Press.

 

¹⁸ Ensrud, et al, Circulating 25-Hydroxyvitamin D Levels and Frailty Status in Older Women, J. Clin Endocrinol Metab, 2010 95: 5266-5273.

 

¹⁹ Sharief, at al, Vitamin D levels and food and environmental allergies in the United States: Results from the National Health and Nutrition Examination Survey 2005 - 2006, J. Allergy Clin Immunol, 2011 Published online February 17, 2011.

 

²⁰ Green, et al, Calcium and vitamin-D supplementation on bone structural properties in peripubertal female identical twins: a randomised controlled trial,Osteoporosis Int 2011; 22(2):489-981.

 

²¹ Sun et al, Vitamin D intake and risk of cardiovascular disease in US men and women, Am J Clin Nutr. 2011 June 8 [Epub ahead of print].

 

²²  Wallace, et al, Urinary tract stone occurrence in the Women's Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements, Am J Clin Nutr 2011; 94: 5-6.

²³ Mitri, et al, Vitamin D and type 2 diabetes: a systematic review, Eur J Clin Nutr, 2011, 1-11.

 

²⁴ Bertone-Johnson, et al, Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women, Am J Clin Nutr 2011 August 24 [Epub ahead of print]. 

 

²⁵ Mulligan, Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitaminD, J Bone and Min Res 2010; 25(4): 928-930.  

 

²⁶ Belenchia, et al, Safety and efficacy of using high-dose (4,000 IU) vitamin D supplementation to improve the vitamin D status of obese adolescents, The FASEB Journal. 2011; 25:343.4., The FASEB Journal. 2011; 25:343.4

 

²⁷ Wolpin, et al, Plasma 25-Hydroxyvitamin D and Risk of Pancreatic Cancer, Cancer Epidemiol Biomarkers Prev. 2011 Dec.7 [Epub ahead of print]

 

²⁸ Amer, et al, Relation between serum 25-vitamin D and C-reactive protein in asymptomatic adults (from the continuous national health and nutrition examination survey 2001 to 2006), Am J Cardiol 2012 Jan.15 [Epub ahead of print], Am J Cardiol 2012 Jan.15[Epub ahead of print]

 

²⁹ Lasco A, et al (2012). Improvement of Primary Dysmenorrhea Caused by a Single Oral Dose of Vitamin D: Results of a Randomized, Double-blind, Placebo-Controlled Study. Arch Intern Med. 172(4):366-7.

 

³⁰ Muir SW, et al (2011). Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis, J Am Geriatr Soc. 59(12):2291-300.

 

³¹ Salehpour A, et al (2012). Vitamin D3 and the risk of CVD in overweight and obese women: a randomised controlled trial. Br J Nutr. Feb 9 2012 [Epub ahead of print]