- Weekly And Biweekly Vitamin D2 Prevents Vitamin D Deficiency
- Bulletproof Your Sleep with Vitamin D
- Vitamin D and Sleep
- Why You’re Low in Vitamin D
- How Much Vitamin D Should You Take?
- When to Take Vitamin D
- Start hacking your performance and life with vitamin D
- Join over 1 million fans
- Low on Vitamin D, sleep suffers
- University of Maryland July 2010
- Possible Interactions:
- These drugs may raise the amount of vitamin D in the blood:
- Vitamin D levels may be decreased by the following medications.
- NLM July 2010
- Supplementation with High Doses of Vitamin D to Subjects without Vitamin D Deficiency May Have Negative Effects: Pooled Data from Four Intervention Trials in Tromsø
- 1. Introduction
- 2. Materials and Methods
- 3. Results
- 4. Discussion
- 5. Conclusion
- Related posts:
Weekly And Biweekly Vitamin D2 Prevents Vitamin D Deficiency
The BUSM study appears online in the journal Archives of Internal Medicine.
Vitamin D is essential for strong bones because it helps the body absorb calcium and phosphorus from the food we eat. Vitamin D deficiency can lead to rickets in children and the painful bone disease osteomalacia in adults. Vitamin D deficiency can also cause osteoporosis and has been linked to increased risk of cancer, heart disease, diabetes, autoimmune diseases and infectious diseases including influenza, according to senior author Michael F. Holick, PhD, MD, director of the Bone Healthcare Clinic and the Vitamin D, Skin and Bone Research Laboratory at Boston University School of Medicine.
Of the 86 patients researchers studied, 41 patients who were vitamin D deficient received eight weeks of 50,000 IU of vitamin D2 weekly prior to starting maintenance therapy. For those patients, the mean pre-treatment 25-hydroxyvitamin D status (25(OH)D) level was 19 ng/ml, which increased to 37 ng/ml after eight weeks of weekly therapy. These patients were then treated with 50,000 IU of vitamin D2 every other week and had a mean final 25(OH)D level of 47 ng/ml.
For the 45 patients who received only maintenance therapy of 50,000 IU of vitamin D2 every two weeks, the mean pre-treatment 25(OH)D level was 27 ng/ml and the mean final level was 47 ng/ml.
“Vitamin D2 is effective in raising 25(OH)D levels when given in physiologic and pharmacologic doses and is a simple method to treat and prevent vitamin D deficiency,” said Holick, who is also director of the General Clinical Research Unit and professor of medicine, physiology and biophysics at BUSM. “While treating and preventing vitamin D deficiency, these large doses of vitamin D2 do not lead to vitamin D toxicity.”
According to Holick, this is the first study demonstrating the efficacy of a prescription therapy to prevent vitamin D deficiency longterm in routine clinical practice.
Quest Diagnostics, the nation’s leading provider of diagnostics testing, information and services, analyzed the specimens used in the study.
Bulletproof Your Sleep with Vitamin D
You might know that a large percentage of the U.S. population is low in vitamin D. What you may not know is that low vitamin D levels can lead to insomnia and other sleep disorders. Supplementing with vitamin D is key to getting your levels up, but there are nuances to how much vitamin D you should take and when to take vitamin D.
Vitamin D and Sleep
More than half of the world population is deficient in vitamin D. And low levels of vitamin D are directly related to the amount and quality of sleep you’re getting. In one uncontrolled study, participants who brought up their vitamin D levels saw significant improvement in sleep and neurologic symptoms
In another study, researchers looked at the vitamin D levels and sleep quality of 3,048 men 68 years and older. They measured totally sleep time, wake times and frequency, and “sleep efficiency” which measures the time spent in bed versus the time spent sleeping.
The study found that low levels of Vitamin D were related to poor quality sleep and sleeping less than 5 hours a night. Low levels were also associated with lower sleep efficiency scores.
Sufficient vitamin D can also help reduce pain and control inflammation, among other benefits.
Related: Upgrade Your Energy, Optimize Your Supplements
Why You’re Low in Vitamin D
Most of us are low in vitamin D because of the way we live – we cover our bodies, “protecting” every inch of our skin from the sun and stay inside most of the time. But instead of protecting your sun from skin cancer, you’re really just slowing or stopping your skin’s synthesis of vitamin D from the Sun!
Supplementing with vitamin D3 is essential for most people to get their levels high enough, but that doesn’t mean you can stay out of the sun entirely. Your skin interacts with natural sunlight to produce vitamin D in your body.
The best way to ensure you have adequate levels of this important hormone (yes, vitamin D is actually a hormone), you should expose your skin to natural sunlight for about 15 minutes per day, eat vitamin D-rich foods, and supplement with a high-quality vitamin D3.
See, simply taking a ton of vitamin D is not the complete answer in the long run for preventing vitamin D deficiency. Too much or too little can have side effects, including reducing the quality of your sleep. The amount of International Units (IU) you take and time of day are important aspects when you’re upgrading the amount and quality of your sleep.
How Much Vitamin D Should You Take?
According to the Vitamin D Council, you should get 1,000 IUs per 25 lbs of body weight every day.The US Government’s upper intake level (UL) for vitamin D is set at 4,000 IU per day. Other experts disagree, the current consensus states it should be 10,000 IU. This is the amount your skin would naturally produce from maximum exposure from the sun. An even better way to figure out what your optimal vitamin D levels are, is through testing your body’s responses.
But as we already covered, supplementation only isn’t the full answer.
The best way to determine the exact amount of vitamin D you should take is to get a blood test. Your dose will depend on your existing vitamin D level and may change according to your age, weight, gut health, skin color, and average sun exposure. Aka, more vitamin D is not always better.
In fact, too much vitamin D can cause headaches and inflammation; and chronic over supplementation can be toxic.
As more research is being done on D, we are just beginning to find out the importance of the dosage of vitamin D. Additionally with the amount you take, the time you take vitamin D is a crucial factor in upgrading your sleep.
When to Take Vitamin D
Vitamin D is inversely related to melatonin, your sleep hormone, so it makes sense that taking it at night could disrupt your sleep. I’ve noticed this effect personally.
An n=1 experiment done by gwern.net also concludes that taking vitamin D in the morning is best. Using a ZEO, his morning dose of D increased REM, deep sleep, and number of hours slept. He looked at taking the same dosage at night, and his sleep quality plummeted.
My biohacking experiments have similar results. When I’ve taken D in the morning I had my usual great sleep. When I’ve taken D at night, I had a restless night.
In our busy worlds, healthy sleep is gold. If we do not receive the right amounts of vitamin D, sleep suffers. If you live a stressful life, sleep is even more important.
There are other reasons to figure out how much and when to take vitamin D. In a study with chronic pain patients, vitamin D helped reduce pain, improve quality of life, and increase sleep. Having adequate levels of D may protect against cancer, control inflammation, heart disease, poor mood, and may help regulate the immune system. Most people are vitamin D deficient and do not know how it can help improve their lives.
Start hacking your performance and life with vitamin D
If you are unsure of where to start, there are a few options.
Ask your doctor for updated vitamin D tests every six months or so. You might go to your doctor and find out where your vitamin D levels are right now. Better yet, use WellnessFX or other self-testing labs for testing and advice.
If your level is below 30 ng/ml then you are vitamin D deficient. Increasing intake and knowing when to take vitamin D will help sleep and other health parameters, including bone health and decreased depression.
What are some of the ways that you hack your sleep? Do you have a vitamin D story? Share it in the comments!
READ NEXT: Upgrade Your Energy, Optimize Your Supplements
Join over 1 million fans
Sign-up for the Bulletproof mailing list and receive the latest news and updates!
Low on Vitamin D, sleep suffers
We’re nearing the end of what’s been a long winter for people in many parts of the United States. In the middle and northern regions of the U.S., where winter brings not only cold but limited sun, people aren’t only deprived of warmth, they also may be deficient in an important nutrient: Vitamin D.
The body actually produces its own Vitamin D, in response to exposure to sunlight. For this reason, Vitamin D isn’t actually considered a vitamin at all, but rather is classified as a hormone. Besides sun exposure, people also receive Vitamin D through foods—fatty fish and fish oils, egg yolks, as well as fortified foods like dairy and juice—and also from supplements.
Unfortunately, many people don’t maintain sufficient levels of Vitamin D—and this can lead to health complications. It’s estimated that 50% or more of adults and children may be deficient in Vitamin D, which is now widely recognized as a public health problem.
Vitamin D is critical to the body’s mental and physical function. It assists the body in absorbing calcium and phosphorus, and contributes to bone health. Healthy levels of Vitamin D may help with weight loss and weight management. Research suggests that low levels of Vitamin D are associated with higher risks for several serious diseases, including cancer, diabetes, cardiovascular disease, and multiple sclerosis. Insufficiency of Vitamin D is also linked to greater risk for depression and other mood disorders. In healthy people, maintaining higher levels of Vitamin D may offer protection against these same conditions.
Vitamin D may also be important for maintaining healthy sleep. Recent research indicates that Vitamin D may influence both sleep quality and sleep quantity. Researchers analyzed the sleep patterns and Vitamin D levels among a group of older adult men, and found that Vitamin D deficiency was associated with less sleep overall and also with more disrupted sleep. The study included 3,048 men ages 68 and older. Researchers measured Vitamin D serum levels using a blood test. They measured sleep using wrist actigraphy, recording measurements of total sleep time, wake time after sleep onset, and sleep efficiency—a measurement that results from comparing time spent in bed to the time actually spent sleeping.
Among participants, 16% had low levels of Vitamin D. To identify the possible influence of Vitamin D over sleep, researchers controlled for several other factors, including age, season of the year, other health conditions, body-mass index, and both physical and cognitive function. They found that low levels of Vitamin D were linked to several problems with sleep:
- Low Vitamin D increased the likelihood that participants experienced insufficient sleep, sleeping less than 5 hours a night
- Low levels of Vitamin D were linked to lower sleep efficiency scores, and a greater chance of scoring below 70%. A healthy sleep efficiency score is generally considered to be 85% or higher.
A lower sleep efficiency score is an indicator of difficulties with sleep quality, as well as perhaps with sleep quantity. A low sleep efficiency score may mean it takes a long time to fall asleep or may indicate waking very early. A low sleep efficiency can also mean sleep is fragmented and restless, with many awakenings throughout the night.
This study is noteworthy because it appears to be the first study to objectively show that Vitamin D deficiency has negative effects on sleep. Other research has demonstrated links between low levels of Vitamin D and sleep problems. But these studies have measured sleep subjectively, using survey data and reports from participants who assess their own sleep, in terms of both quality and quantity. This study measured sleep using objective tools—specifically wrist sensors—before analyzing that data in relation to levels of Vitamin D.
Overall, there’s not been enough research devoted to this relationship—likely a complicated one—between Vitamin D and sleep. The results of this study ought to encourage more attention and focus on this relationship and its potential influence over long-term health.
What’s the best way to increase your Vitamin D? There’s no better source than the sun. Direct sun exposure to skin triggers the synthesis of Vitamin D. But sun exposure can’t always be relied upon for a steady, consistent source of Vitamin D. There are a number of factors that can influence how effectively sun exposure can trigger Vitamin D production in the body, including air pollution, time of day, season of the year, and level of cloud cover. Sunscreen and clothing can also impede the effects of sun exposure for Vitamin D. People with higher levels of skin pigmentation absorb less of the UVB rays necessary to begin the synthesis of Vitamin D, and may be more likely to have low levels as a result. Older adults are also at greater risk for low Vitamin D levels.
Protecting your skin from excessive sun exposure is important—I am not suggesting you abandon wearing sunscreen. But some limited time in the sun without sunscreen to allow for Vitamin D production may be useful for health, and for sleep. The recommendations for sun exposure to boost Vitamin D generally fall in the range of 5-10 minutes of exposure, from a few times a week to daily.
Adding Vitamin D rich and fortified foods to your diet can also help increase levels. Fatty fish like salmon, tuna, swordfish, and sardines are all excellent sources of Vitamin D. So are eggs. Many dairy products, including milk and yogurt, are fortified with Vitamin D, as are citrus juices and many cereals. Supplements are another important option to help you maintain healthy Vitamin D levels, especially for people who are at high risk for deficiency, because of age, ethnicity, health conditions, or where they live.
The best way to know if your Vitamin D levels are low is to have your physician perform a blood test. If like so many people, your levels are low, you and your doctor can put together a plan that may include diet, controlled sun exposure, and supplements, to bring levels up and make sure they stay that way. Maintaining sufficient levels of Vitamin D is good for overall health wellness, and likely also to be good for your sleep.
Michael J. Breus, PhD
The Sleep Doctor™
University of Maryland July 2010
Side effects may include:
- Excessive thirst
- Metal taste in mouth
- Poor appetite
- Weight loss
- Bone pain
- Sore eyes
- Itchy skin
- A frequent need to urinate
- Muscle problems
You cannot get too much vitamin D from sunlight, and it would be very hard to get too much from food.
Generally, too much vitamin D is a result of taking supplements in too high a dose.
People with the following conditions should be careful when considering taking vitamin D supplements:
- High blood calcium or phosphorus levels
- Heart problems
- Kidney disease
If you are currently being treated with any of the following medications, you should not use vitamin D supplements without first talking to your health care provider.
- Atorvastatin (Lipitor) – Taking vitamin D may reduce the amount of Lipitor absorbed by the body, making it less effective. If you take Lipitor or any statin (drugs used to lower cholesterol), ask your doctor before taking vitamin D.
- Calcium channel blockers – Vitamin D may interfere with these medications, used to treat high blood pressure and heart conditions. If you take any of these medications, do not take vitamin D without first asking your doctor. Calcium channel blockers include:
- Nifedipine (Procardia)
- Verapamil (Calan)
- Nicardipine (Cardene)
- Diltiasem (Cardizem, Dilacor)
- Amlodipine (Norvasc)
- Corticosteroids (prednisone) – Taking corticosteroids long-term can cause bone loss leading to osteoporosis. Supplements of calcium and vitamin D can help maintain bone strength. If you take corticosteroids for 6 months or more, ask your doctor about taking a calcium and vitamin D supplement.
- Digoxin (Lanoxin) – a medication used to treat irregular heart rhythms. Vitamin D improves absorption of calcium, and calcium, in turn, can increase the likelihood of a toxic reaction from this medication.
These drugs may raise the amount of vitamin D in the blood:
- Estrogen – Hormone replacement therapy with estrogen appears to raise vitamin D levels in the blood, which may have a positive effect on calcium and bone strength. In addition, taking vitamin D supplements along with estrogen replacement therapy (ERT) increases bone mass more than ERT alone. However, this benefit may be lost with the addition of progesterone.
- Isoniazid (INH) — a medication used to treat tuberculosis.
- Thiazide — This kind of diuretic (water pills) can increase vitamin D activity and can lead to high calcium levels in the blood.
Vitamin D levels may be decreased by the following medications.
If you take any of these medications, ask your doctor if you need more vitamin D:
Antacids – Taking certain antacids for long periods of time may alter the levels, metabolism, and availability of vitamin D.
Anti-seizure medications – these medications include:
- Phenytoin (Dilantin)
- Primidone (Mysoline)
- Valproic acid (Depakote)
Bile acid sequestrants – used to lower cholesterol. These medications include
- Cholestyramine (Questran, Prevalite)
- Cholestipol (Colestid)
- Rifampin – used to treat tuberculosis
- Mineral oil – Mineral oil also interferes with absorption of vitamin D.
- Orlistat (Alli) – a medication used for weight loss that prevents the absorption of fat.
- Because of its effect on fat, orlistat may also prevent the absorption of fat-soluble vitamins such as vitamin D. Physicians who prescribe orlistat also add a multivitamin with fat soluble vitamins.
NLM July 2010
Side Effects and Warnings
- Vitamin D is generally well tolerated in recommended “Adequate Intake (AI)” doses. One study found a greater likelihood of daytime sleepiness for patients given vitamin D analogues.
- Vitamin D toxicity can result from regular excess intake of this vitamin, and may lead to hypercalcemia and excess bone loss. Individuals at particular risk include those with hyperparathyroidism, kidney disease, sarcoidosis, tuberculosis, or histoplasmosis. Chronic hypercalcemia may lead to serious or even life-threatening complications, and should be managed by a physician. Early symptoms of hypercalcemia may include nausea, vomiting, and anorexia (appetite/weight loss), followed by polyuria (excess urination), polydipsia (excess thirst), weakness, fatigue, somnolence, headache, dry mouth, metallic taste, vertigo, tinnitus (ear ringing), and ataxia (unsteadiness). Kidney function may become impaired, and metastatic calcifications (calcium deposition in organs throughout the body) may occur, particularly affecting the kidneys. Treatment involves stopping the intake of vitamin D or calcium, and lowering the calcium levels under strict medical supervision, with frequent monitoring of calcium levels. Acidification of urine and corticosteroids may be necessary.
Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.
Interactions with Drugs
- Hypermagnesemia (high blood magnesium levels) may develop when magnesium-containing antacids are used concurrently with vitamin D, particularly in patients with chronic renal failure.
- Decreased vitamin D effects may occur with the use of certain anti-seizure drugs, as they may induce hepatic microsomal enzymes and accelerate the conversion of vitamin D to inactive metabolites.
- Based on mechanism of action, use of vitamin D and calcium together may alter inflammatory response.
- Intestinal absorption of vitamin D may be impaired with the use of these agents. Patients on cholestyramine or colestipol should be advised to allow as much time as possible between the ingestion of these drugs and vitamin D.
- Use of corticosteroids can cause osteoporosis and calcium depletion with long-term administration. This calcium depletion creates a greater need for both supplemental calcium and vitamin D (which is necessary for calcium absorption).
- Vitamin D should be used with caution in patients taking digoxin, because hypercalcemia (which may result with excess vitamin D use) may precipitate abnormal heart rhythms.
- Intestinal absorption of vitamin D may be impaired with the use of mineral oil.
- Orlistat (an obesity drug) can reduce vitamin D levels. Patients should consider taking a multivitamin with fat-soluble vitamins at least two hours before or after orlistat or at bedtime.
- Rifampin increases vitamin D metabolism and reduces vitamin D blood levels. The need for vitamin D supplementation with rifampin has not been thoroughly studied, although additional supplementation may be necessary.
- Stimulant laxatives can reduce dietary vitamin D absorption. Stimulant laxatives should be limited to short-term use if possible.
- Concurrent administration of thiazide diuretics and vitamin D to hypoparathyroid patients may cause hypercalcemia, which may be transient or may require discontinuation of vitamin D. Examples of thiazide diuretics include chlorothiazide (Diuril®), chlorthalidone (Hygroton®, Thalitone®), hydrochlorothiazide (HCTZ®, Esidrix®, HydroDIURIL®, Ortec®, Microzide®), indapamide (Lozol®), and metolazone (Zaroxolyn®).
Interactions with Herbs and Dietary Supplements
- Based on mechanism of action, the use of vitamin D and calcium together may alter inflammatory response.
- Vitamin D should be used with caution in patients taking herbs with similar properties on the heart as digoxin, because hypercalcemia (which may result with excess vitamin D use) may precipitate abnormal heart rhythms.
- Vitamin D is necessary for calcium absorption. Vitamin D is often included in calcium supplement products.
See also VitaminDWiki
- Interactions with Vitamin D category listing has
101 items along with related searches
- Review of vitamin D interaction with drugs – Jan 2014
- Drug–Vitamin D Interactions, A Systematic Review – Jan 2013
- Is more medication needed with high level of vitamin D – March 2012
See also on the web
- Average Drug Label Lists Over Whopping 70 Side Effects Mercola June 2011
- “In fact, the more commonly prescribed drugs averaged around 100 side effects each . . . “
Side Effects and Warning for vitamin D
76235 visitors, last modified 14 Jan, 2016, URL: Copy URL
Printer Friendly PDF this page! Follow this page for updates
- Links to this page 1
- Carmel used to color some vitamin D gel caps may cause problems in some people
Supplementation with High Doses of Vitamin D to Subjects without Vitamin D Deficiency May Have Negative Effects: Pooled Data from Four Intervention Trials in Tromsø
Data were pooled from four randomized clinical trials with vitamin D performed in Tromsø with weight reduction, insulin sensitivity, bone density, and depression scores as endpoints. Serum lipids, glycated hemoglobin ( ), and high sensitivity C-Reactive Protein, (HS-CRP) were measured at baseline and after 6–12 months of supplementation with vitamin D 20 000 IU–40 000 IU per week versus placebo. A total of 928 subjects who completed the interventions were included. At baseline the mean serum 25-hydroxyvitamin D (25(OH)D) level in those given vitamin D was 55.9 (20.9) nmol/L and the mean increase was 82.4 (40.1) nmol/L. Compared with the placebo group there was in the vitamin D group at the end of the studies a slight, but significant, increase in of 0.04%, an increase in HS-CRP of 0.07 mg/L in those with serum 25(OH)D < 50 nmol/L, and in those with low baseline HDL-C and serum 25(OH)D < 50 nmol/L a slight decrease serum HDL-C of 0.08 mmol/L ( ). No serious side-effects were seen. In conclusion, in subjects without vitamin D deficiency, there is no improvement in serum lipids, , or HS-CRP with high dose vitamin D supplementation. If anything, the effect is negative.
In recent years there has been a great interest in the relation between vitamin D and health outcomes . As the vitamin D receptor (VDR) is found in tissues throughout the body it is reasonable to assume that effects of vitamin D are not restricted to its classical effects on calcium metabolism . Thus, the levels of serum 25-hydroxyvitamin D (25(OH)D), which is the metabolite used to evaluate a subject’s vitamin D status , are in cross-sectional studies associated with risk factors for type 2 diabetes (T2DM) and cardiovascular disease and in prospective studies associated with increased risk of these diseases and also cancer and even death . One would therefore expect that it should be easy to demonstrate a positive effect of vitamin D supplementation on health, but so far the evidence from properly performed randomized clinical trials (RCTs) is lacking.
We have previously performed four large RCTs with high dose vitamin D intervention in Tromsø, northern Norway, studying specifically the effects on weight , insulin sensitivity , bone density , and depression scores . In addition to these endpoints we have also included other measures of glucose and lipid metabolism and inflammation markers. We have included more than 900 subjects in these studies, a number high enough to disclose an effect on these secondary endpoints, if present. Furthermore, it also enabled us to examine separately subjects with low serum 25(OH)D levels, subjects with deranged lipid and/or glucose metabolism, and also combinations of these subgroups.
2. Materials and Methods
In the present study we have pooled data from four intervention studies.(i)The vitamin D and obesity study in which 438 subjects 21–70 years old and with BMI 28–47 kg/m2 were included and randomized to 40 000 IU vitamin D per week, 20 000 IU vitamin D per week, or placebo for one year. All subjects were given 500 mg calcium daily . In the present study those given 40 000 and 20 000 IU were combined to one vitamin D group. The study was registered at ClinicalTrials.gov (NCT00243256).(ii)Vitamin D and insulin sensitivity study where 108 subjects 30–75 years old with serum 25(OH)D < 50 nmol/L were included and randomized to vitamin D 20 000 IU twice per week versus placebo for six months . The study was registered at ClinicalTrials.gov (NCT00809744).(iii)The vitamin D and bone density study including 297 postmenopausal women 50–80 years old, with a T-score in total hip or lumbar spine (L2-4) −2.0 and randomized to vitamin D 20 000 IU twice per week versus placebo for one year. In addition all subjects were given daily supplements with 1 g calcium and 800 IU vitamin D . The study was registered at ClinicalTrials.gov (NTC00491920).(iv)The vitamin D and depression study comprising 243 subjects 30–75 years old, with serum 25(OH)D 55 nmol/L measured in the sixth Tromsø study and randomized to vitamin D 20 000 IU twice per week versus placebo for six months . The study was registered at ClinicalTrials.gov (NCT00960232).
Height and weight were measured wearing light clothing and no shoes. BMI was calculated as weight divided by height squared. Blood samples were drawn before and at the end of the intervention period, fasting in the obesity and insulin sensitivity study and non-fasting in the bone density and depression study. Serum calcium, PTH, total cholesterol (TC), triglycerides (TG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), apolipoprotein A1 (Apo A1), apolipoprotein B (Apo B), glycated hemoglobin ( ), high sensitivity C-reactive protein (HS-CRP), and serum 25(OH)D were measured as previously described .
2.3. Statistical Analyses
Distribution of the dependent variables was evaluated with skewness and kurtosis and visual inspection of histograms and found normal except for HS-CRP and delta (value at the end of study minus value at baseline) HS-CRP. Because of negative values log-transformation could not be performed and therefore comparisons between groups regarding HS-CRP were performed with the Mann-Whitney U test. For the other variables comparisons between groups were done with Student’s t-test and also with a general linear model with gender, baseline age, and BMI as covariates. Interactions between treatment groups, gender, and use of lipid lowering medication were also tested in this model. The data are shown as mean (SD) except for HS-CRP which are shown as median (25, 75 percentile). A P value < 0.05 was considered statistically significant.
In the obesity, insulin sensitivity, bone density, and depression studies a total number of 333, 94, 273, and 228 subjects, respectively, completed the intervention period and had complete data sets. At baseline there were no significant differences between the vitamin D and placebo groups except for age and BMI (Table 1). The subjects in the combined vitamin D group had significantly lower age than those in the placebo group (53.1 (11.6) versus 55.7 (10.8) years, )) and significantly higher BMI (29.7 (5.5) versus 28.6 (5.6) kg/m2, ). The difference in age was mainly due to a significant difference between the vitamin D and placebo groups in the obesity study (48.1 (11.3) versus 51.4 (10.6) years, ).
Table 1 Baseline characteristics in all subjects, the four separate studies, and according to intervention.
3.1. Effects of Vitamin D Supplementation
In all the studies there was an increase in serum 25(OH)D and a decrease in serum PTH after vitamin D supplementation, as expected (Table 2). There was no significant difference in delta BMI neither between the groups pooled together, nor in the separate study groups, when only evaluating subjects with low serum 25(OH)D levels (< 50 nmol/L) or when stratifying according to baseline BMI (data not shown).
Table 2 Delta values ( , value at the end of study minus value at baseline) in the four separate studies and pooled together.
Among the 928 subjects, 70 were on lipid lowering medication and were therefore excluded when analyzing the effect on serum lipids. Furthermore, for HbA1c there was a significant interaction between treatment groups and use of lipid lowering medication ( ), which was also borderline significant for HS-CRP ( ). In the following, the delta values for the lipids, , and HS-CRP are therefore presented in the 858 subjects not using lipid lowering medication, and with the four groups pooled together unless otherwise stated. When pooling all the studies together, there were for the serum lipids no significant differences between the delta values for the vitamin D and the placebo groups. However, in the osteoporosis group a significant increase in serum HDL-C after vitamin D was seen when compared to placebo, but this difference was not statistically significant after adjusting for age, gender, and BMI. For there was in the combined vitamin D group an increase in of 0.02 (0.26)%, whereas in those given placebo there was a decrease of 0.02 (0.26)% ( between groups). This difference was also statistically significant after adjusting for age, gender, and BMI. For delta HS-CRP there was in the combined group a slight increase in those given vitamin D whereas in the placebo group there was a slight decrease, but the difference was not statistically significant (Table 2).
3.2. Effect of Baseline 25(OH)D
3.3. Effect of Baseline Lipid, HbA1c, and HS-CRP Levels on Effects of Vitamin D Supplementation
Separate analyses were performed for subjects with serum TC, TG, LDL-C, Apo B, and above the respective 75th percentiles and for subjects with serum HDL-C and Apo A1 below the 25th percentiles. For TC, TG, LDL-C, Apo B, HS-CRP, and subgroups no significant differences in delta values between those given vitamin D versus placebo were found.
However, for HDL-C the effects of vitamin D supplementation appeared to depend on the baseline serum HDL-C and Apo A1 levels. Thus, for subjects with baseline HDL-C and Apo A1 below the 25th percentiles supplementation with vitamin D caused a significant ( ) decrease in serum HDL-C (but not in other lipids) as compared to placebo. For baseline HDL-C below the 25th percentile (<1.21 mmol/L) the delta HDL values were for the 144 subjects given vitamin D 0.00 (0.17) mmol/L versus 0.06 (0.16) mmol/L in the 96 subjects given placebo. Correspondingly, for subjects with baseline Apo A1 below the 25th percentile (<1.35 g/L) the delta HDL-C values were −0.01 (0.15) g/L in the 137 subjects given vitamin D and 0.04 (0.16) g/L in the 82 subjects given placebo. These differences were also statistically significant after adjustment for age, gender, and BMI.
3.4. Combined Effects of Baseline Lipid, HbA1c, HS-CRP, and 25(OH)D Levels
Combinations of TC, TG, LDL, Apo B, HS-CRP 50th or 75th percentile subgroups, or Apo A1 50th or 25th subgroups with serum 25(OH)D < 50 nmol/L (or even lower cut-offs) did not reveal significant differences in delta values between those given vitamin D versus placebo.
In the present study we have found high dose vitamin D supplementation to cause a slight but significant increase in and HS-CRP, and a decrease in serum HDL-C. Similarly, we have previously published the observation of a slight increase in systolic blood pressure by vitamin D supplementation in the obesity study .
The reason for starting the obesity, insulin sensitivity, bone density, and depression studies was the hypothesis that high doses of vitamin D (20 000–40 000 IU per week) would have beneficial effects even in a fairly vitamin D sufficient population as the one in Tromsø, northern Norway. However, in the original four publications we did not see any clear benefits on the main endpoints body weight, insulin sensitivity as evaluated by a hyperglycemic clamp, bone density, or symptoms of depression. This could be related to power if the true effect of vitamin D supplementation is small, to inclusion of subjects with adequate vitamin D status where an effect of vitamin D supplementation would be hard to disclose, and to studying subjects with basically normal lipid and glucose metabolism and without severe symptoms of depression. We therefore pooled all the four studies together which at least to some extent enabled us to overcome the previous shortcomings. However, even with this approach we were not able to find any beneficial effect of high dose vitamin D supplementation. On the contrary, possible negative effects regarding lipid and glucose metabolism as well as on the inflammation marker HS-CRP were seen. These effects were small, with an absolute increase of 0.04% for mean , a decrease in mean HDL-C of 0.05 mmol/L, and an increase in median HS-CRP of 0.05 mg/L in the vitamin D group versus the placebo group. It was also noteworthy that looking separately at subjects with lower serum 25(OH)D levels at baseline did not make high dose vitamin D supplementation appear more favorable as compared to subjects with higher baseline vitamin D levels. These effects individually, if true, can hardly be considered to be of clinical significance, at least not in the short run. However, if added together and if persisting over years, there might at a population level be negative effects.
Our negative results are in line with recent reviews, meta-analyses, and large studies regarding serum lipids and vitamin D supplementation , and we have previously concluded in an editorial that it is questionable if more such studies are needed . With a few exceptions most intervention studies have not been able to show an effect on glucose metabolism , and similarly, most studies on vitamin D effects on inflammatory markers have also been negative .
The present study does have many shortcomings. First of all, we have pooled data from different studies together, with length of intervention ranging from six months to one year, with doses of vitamin D ranging from 20 000 IU per week up to 45 600 IU per week; the subjects included were highly selected based on BMI, BMD, and serum 25(OH)D levels; in two of the studies the placebo group and the vitamin D group were given calcium; and in one of the studies the high dose of vitamin D (45 600 IU per week) was compared with a standard dose of 5600 IU per week. Accordingly, we cannot firmly state that high doses of vitamin D are harmful, but it is fair to conclude that it is highly unlikely that high doses of vitamin D will have a significant positive effect on serum lipids or measures of glucose metabolism. On the other hand, one may also interpret our data the other way around that giving these high doses of vitamin D appears to be safe.
Our study also has some strengths. We pooled data from studies from a single centre, and to our knowledge there are no RCTs that have included as many subjects as we have. Also, we gave high doses of vitamin D with the expected effect on the serum 25(OH)D levels.
It must also be emphasized that we have only measured risk markers, and what is of real importance is the effect of vitamin D on hard endpoints like development of T2DM, cardiovascular disease, and ultimately mortality. So far this has not been evaluated in studies designed for that purpose, and meta-analyses of intervention studies (primarily with fractures or BMD as main endpoints) have been inconclusive . There are several large RCTs ongoing in Europe, New Zealand, and the USA that will answer these questions in populations with a reasonable good vitamin D status. However, it should be recalled that vitamin D deficiency is a worldwide problem , and RCTs are particularly important in populations at higher risk than those at present being studied .
We have not found a beneficial effect of high dose vitamin D supplementation on lipid and glucose metabolism in a population that is not vitamin D deficient. If anything, the effect appears to be negative.
The present studies were supported by grants from the Northern Norway Regional Health Authority, The University of Tromsø, The Norwegian Women Public Health Association in Tromsø, and the Norwegian Council of Cardiovascular Disease. The superb assistance by the nurses at the Clinical Research Unit at the University Hospital of North Norway is gratefully acknowledged. The authors declare that there is no conflict of interests that could be perceived as prejudicing the impartiality of the research reported.