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Vitamin D "101"

Posted By Holly Lucille, ND, RN, Monday, May 21, 2012
Updated: Thursday, January 30, 2014

Besides commanding celebrity status these days, with Vitamin D deficiency being fairly common in the general public.,Vitamin D is a fat-soluble vitamin (other fat soluble vitamins are E, A and K) that actually functions as a pro-hormone (a precursor to hormones). Vitamin D plays many roles in the body, enhancing absorption of calcium and phosphorus in the intestines, promoting healthy bone structure, influencing cellular growth, modulating the immune system and in addition, it appears that vitamin D enhances the secretion and action of insulin. There are a couple of different forms to understand. Vitamin D3 is also known as "cholecalciferol” and you can obtain it from foods such as cheese, beef liver and egg yolks. It can also be made in the skin after exposure to sunlight and is the preferable form when it comes to supplementation. Vitamin D2, also called "ergocalciferol” is actually a synthetic form, not normally present in the body, made from fungus.

Potential consequences of low vitamin D levels include a faster rate of bone loss, an increased risk of falls among the elderly, decreased resistance to infection, and a potential increased risk of developing cancer and certain autoimmune diseases. Studies have shown that individuals suffering from diabetes, cancer, hypertension, lower back pain, the seasonal flu, and a myriad of other illnesses typically have depressed levels of Vitamin D in there blood.

And yes, you can get too much. Nausea, vomiting, loss of appetite, headache, dry mouth, abdominal or bone pain, and dizziness are the classic symptoms of vitamin D toxicity. As the condition progresses, signs of impaired kidney function, such as excessive urination, may arise. Itching, calcification of organs and blood vessels, osteoporosis, and seizures are still other signs that develop at the later stages.
A 25-hydroxy Vitamin D test, also referred to as a 25(OH)D is the test usually performed to measure Vitamin D in the blood and optimal levels are between 50-80ng/mL. At this time I recommend that levels be monitored periodically however there is some debate over the accuracy of this particular test.

Recommended dosage for supplementation vary, the Vitamin D Council recommends the following amounts of supplemental vitamin D3 per day in the absence of proper sun exposure.
Healthy children under the age of 1 years – 1,000 IU.
Healthy children over the age of 1 years – 1,000 IU per every 25 lbs of body weight.
Healthy adults and adolescents – at least 5,000 IU.
Pregnant and lactating mothers – at least 6,000 IU.
Additionally, children and adults with chronic health conditions such as autism, MS, cancer, heart disease, or obesity may need as much as double these amounts.
The US Government’s Tolerable Upper Intake Level (UL) for vitamin D is set at 4,000 IU per day.

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Vitamin D Insufficiency

Posted By Administration, Friday, February 4, 2011
Updated: Friday, April 18, 2014

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Tom D. Thacher, MD and Bart L. Clarke, MD

The past decade has seen renewed interest in the sunshine vitamin, vitamin D, because new data suggest that its benefits extend beyond healthy bones. Accompanying this renewed interest has been a proliferation of published studies related to the effects of vitamin D in many varying clinical conditions. This article discusses the definition of vitamin D insufficiency, identifies the sources of variation in vitamin D status, reviews the evidence for the clinical benefits of vitamin D, and recognizes indications for vitamin D testing.

Representative studies were selected to highlight some of the limitations of current knowledge related to vitamin D insufficiency and the clinical benefits of vitamin D. We selected studies with the strongest level of evidence for clinical decision making related to vitamin D and health outcomes from our personal libraries of the vitamin D literature and from a search of the PubMed database using the term vitamin D in combination with the following terms related to the potential nonskeletal benefits of vitamin D: mortality, cardiovascular, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, psychiatric, and pain. The level of evidence was assessed with the following hierarchy: meta-analyses of randomized controlled trials (RCTs), RCTs, nonrandomized intervention studies, meta-analyses of observational studies (cohort and case-control studies), and observational studies.

The road to the discovery of vitamin D began with recognition of the childhood bone disease of rickets. The first formal medical treatise on rickets was published by Francis Glisson in 1650, when it was identified as a new disease that was more frequent in the rich than in the poor. During the industrial revolution of the 1800s, the prevalence of rickets increased dramatically, ranging from 40% to 60% among children in crowded and polluted urban areas. In 1822, Sniadecki was the first to recognize and report the association of rickets with a lack of sunlight exposure. By the mid-1800s, cod liver oil had been established as an effective treatment for rickets. The work of Mellanby and McCollum led to the discovery of vitamin D as the agent in cod liver oil that had antirachitic properties. This discovery eventually led to the fortification of milk and other foods with vitamin D in the 1930s, and as a result rickets all but disappeared in North America and Europe.

VITAMIN D METABOLISM

The terminology related to the biochemistry of vitamin D can be confusing. Vitamin D has 2 forms and several metabolites. The 2 forms are vitamin D2 and vitamin D3, also calledergocalciferol and cholecalciferol, respectively. Vitamin D3 is produced in the skin in response to ultraviolet B radiation from sunlight or can be obtained from the diet (ie, animal sources such as deep sea fatty fish, egg yolks, or liver) or from supplements. Few foods naturally have substantial vitamin D content, and dietary vitamin D is obtained primarily through fortified foods or supplements. Vitamin D2, which is found in some plants in the diet and is produced commercially by irradiation of yeast, is used for fortification and supplementation. Both vitamin D2 and vitamin D3 can be used for supplementation.

FIGURE

FIGURE.

Vitamin D metabolism. Ca = calcium; 1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; PTH = parathyroid hormone.

 

 

 

Both forms of vitamin D undergo identical metabolism (Figure). Some evidence indicates that vitamin D2 may be metabolized more rapidly than vitamin D3, but with regular daily intake they can be considered bioequivalent. Both forms of vitamin D are converted to 25-hydroxyvitamin [25(OH)D] in the liver, and the serum level of 25(OH) D is measured to determine the adequacy of vitamin D status. In the kidney, 25(OH)D is hydroxylated to 1,25-dihydroxyvitamin D [1,25(OH)2D], which is the only biologically active form of vitamin D. Acting principally on the duodenum, 1,25(OH)2D increases calcium absorption. It also acts on bone cells, both osteoblasts and osteoclasts, to mobilize calcium.

The characteristics of 1,25(OH)2D are those of a hormone, and consequently vitamin D is a prohormone rather than a true vitamin. The structure of 1,25(OH)2D is similar to that of other steroid hormones. As long as sunlight exposure is adequate, 1,25(OH)2D can be produced by the body without the requirement for ingestion in the diet. Like other hormones, 1,25(OH)2D circulates at picogram concentrations that are 1000 times less than those of the precursor 25(OH)D. Based on the need for increased calcium absorption, the synthesis of 1,25(OH)2D is tightly regulated and stimulated primarily by serum parathyroid hormone (PTH), as well as low serum calcium or phosphorus levels, and inhibited by circulating FGF23 produced by osteocytes. Although produced in the kidney, 1,25(OH)2D acts at a distance in the intestinal cell to increase calcium absorption or in the bone to stimulate differentiation and activation of osteoblasts and osteoclasts.

 

 


 

ASSESSING VITAMIN D STATUS

Determination of vitamin D status is not based on measurement of serum 1,25(OH)2D concentrations. Vitamin D status is assessed by measuring the prohormone 25(OH) D, which is an indicator of supply rather than function. The most stable and plentiful metabolite of vitamin D in human serum, 25(OH)D has a half-life of about 3 weeks, making it the most suitable indicator of vitamin D status. In the past, vitamin D deficiency was identified by the presence of bone disease, either rickets or osteomalacia. Bone disease caused by vitamin D deficiency is associated with serum 25(OH)D values below 10 ng/mL (to convert to nmol/L, multiply by 2.496). More recently, the term vitamin D insufficiency has been used to describe suboptimal levels of serum 25(OH)D that may be associated with other disease outcomes. Precisely defining vitamin D deficiency or insufficiency on the basis of 25(OH)D values is still a matter of much debate. A useful but rather simplistic classification of vitamin D status is shown in the Table. A cutoff value of 30 ng/mL is sometimes used for optimal vitamin status. On the basis of measured concentrations of 25(OH)D, many patients are given a diagnosis of vitamin D deficiency or insufficiency when most have no evidence of disease.

TABLE

 

 

TABLE.

Classification of Vitamin D Status by 25(OH)D Concentrationa,b

 

 

As discussed in detail in recent reviews, investigators have considered various functional measures to assess the adequacy of vitamin D status. One functional definition of optimal vitamin D status is the 25(OH)D level that maximally suppresses PTH secretion, because the major stimulus for PTH secretion is a low level of serum ionized calcium. In adults, multiple cross-sectional examinations of the relationship between serum PTH and 25(OH)D levels demonstrate a plateau in suppression of PTH when the 25(OH)D level reaches approximately 30 ng/mL. This is the rationale for selecting 30 ng/mL as the cutoff value for defining optimal vitamin D status. However, this definition represents an average value at a population level but does not account for the wide variation in the 25(OH) D level that represents adequacy at an individual level. Many patients have very low 25(OH)D values without evidence of increased production of PTH, and conversely, 25(OH)D levels greater than 30 ng/mL do not guarantee PTH suppression. Another limitation of this definition is that, in children, an elevated PTH level does not indicate inadequate vitamin D status and has been associated with increased calcium absorption. In puberty, the PTH concentration increases, which may stimulate increased periosteal bone formation and increased bone accrual. In fact, preliminary evidence suggests that, with adequate calcium intake, a high-normal PTH level and low-normal 25(OH)D level may result in greater bone size and mass during puberty.

Another method used in some research studies for defining optimal vitamin D status is the 25(OH)D level at which there is no incremental increase in 1,25(OH)2D levels after administration of vitamin D, because the level of 1,25(OH)2D is adequate to meet demand. Similar to the findings related to PTH in adults, an incremental increase in the level of 1,25(OH)2D was observed after administration of vitamin D in children when values of 25(OH)D were less than 25 to 30 ng/mL. In situations of very low calcium intakes, some evidence suggests that the demand for 1,25(OH)2D may be greater. Thus, vitamin D requirements may vary based on customary calcium intake.

Another functional measure of vitamin D status is the 25(OH)D level that results in maximal intestinal calcium absorption. By combining the results of 3 studies in adults, Heaney concluded that optimal calcium absorption occurred at 25(OH)D levels of 32 ng/mL or greater. In contrast, another study found no association between 25(OH)D levels and calcium absorption in healthy women. Fractional calcium absorption was high (>50%) in Nigerian children with presumed dietary calcium deficiency rickets and low dietary calcium intakes despite low normal serum 25(OH)D concentrations. After vitamin D administration and a marked increase in 25(OH) D and 1,25(OH)2D concentrations, fractional calcium absorption did not increase any further. In these studies in children, fractional calcium absorption was not related to serum 1,25(OH)2D levels either before or after vitamin D administration. In a study of adults attending an osteoporosis clinic, concentrations of 1,25(OH)2D and intestinal calcium absorption did not appear to decline until 25(OH) D concentrations fell to 4 ng/mL or less, a level that is generally considered to be indicative of severe vitamin D deficiency.

More recently, the criterion for optimal vitamin D status has moved away from being defined as the 25(OH) D concentration needed to achieve skeletal health to that which demonstrates optimal benefits on nonskeletal health outcomes. The evidence related to these outcomes will be considered later in this review.

SOURCES OF VARIATION IN VITAMIN D STATUS

Factors known to influence 25(OH)D levels include race, vitamin D intake, sun exposure, adiposity, age, and physical activity. Even when all the factors known to influence 25(OH)D concentrations are taken into account, most of the individual variation of 25(OH)D values is difficult to explain. Consequently, it is difficult to assess the risk of clinical or biochemical consequences of vitamin D insufficiency in a patient on the basis of concentrations of 25(OH) D alone. The duration of vitamin D insufficiency, the responsiveness of the vitamin D receptor, dietary calcium intake, and individual calcium requirements likely modify the clinical consequences of vitamin D deficiency or insufficiency based on levels of 25(OH)D.

A single exposure to summer sun in a bathing suit for 20 minutes produces the equivalent of 15,000 to 20,000 IU of vitamin D3. In a study of Hawaiian surfers with sun exposure of at least 15 hours per week for the preceding 3 months, 25(OH)D levels ranged from 11 up to 71 ng/mL, demonstrating wide individual variation. Outdoor sun exposure and time spent outdoors are better predictors of serum 25(OH)D values than dietary vitamin D intake.

The 25(OH)D level achieved with the same oral dose of vitamin D varies widely by individual. The level of 25(OH)D that results in clinical consequences probably varies with calcium intake, race, age, body fat, and individual genetic factors, all of which may influence calcium homeostasis. Genetic variation represented by polymorphisms of certain genes in the vitamin D metabolic pathway explains some of the interindividual variability of 25(OH)D concentrations, particularly polymorphisms of the enzyme 7-dehydrocholesterol reductase in the skin, cytochrome P450 25-hydroxylase in the liver, and vitamin D–binding protein in the circulation. The functional effect of a particular level of 25(OH)D depends on the uptake of 25(OH)D by target cells and the efficiency of 1α-hydroxylation to produce 1,25(OH)2D.

MEASUREMENT OF 25(OH)D LEVELS

Some controversy exists regarding the best method for measuring 25(OH)D levels. Radioimmunoassay has been the most common method reported in the literature and was the method used in some of the large-scale population studies of vitamin D, such as the National Health and Nutrition Examination Survey (NHANES) and the Women's Health Initiative (WHI).

The accuracy of measurement varies widely between individual laboratories and between different assay methods. In one study, identical serum samples were provided to 6 different laboratories, and the chemiluminescent assay tended to return higher values for 25(OH)D. Competitive protein-binding assays are also known to generally yield higher 25(OH)D values. When serum samples were spiked with an additional 20 ng/mL of 25(OH)D, the increment in 25(OH)D level was less than 20 ng/mL in all the laboratories, except the one using high-performance liquid chromatography. Antibodies used in some radioimmunoassays do not detect both 25(OH)D2 and 25(OH)D3. The use of a standard cutoff value for adequate vitamin D status is problematic if applied to all laboratories and all methods. A single serum sample could be assessed as showing adequate vitamin D status in one laboratory and an insufficient level in another, with differences of up to 17 ng/mL.

More recently, large medical laboratories have begun using liquid chromatography–tandem mass spectrometry, which identifies the 25-hydroxylated forms of both vitamin D2and D3. The total 25(OH)D, which is the sum of 25(OH)D2 and 25(OH)D3, is used to evaluate vitamin D status. Since 2003, there has been more than a 15-fold increase in the volume of 25(OH)D measurements at Mayo Clinic in Rochester, MN (Singh R., personal communication), reflecting the increasing attention clinicians are giving to vitamin D status.

CLINICAL MANIFESTATIONS OF VITAMIN D DEFICIENCY

Nutritional Rickets

The classical manifestation of vitamin D deficiency is nutritional rickets, which results from inadequate mineralization of growing bone. Consequently, rickets is a disease of children. Far from being eradicated, nutritional rickets continues to occur throughout the world, with reports from at least 60 countries in the past 20 years. In a review of published cases of rickets in the United States, most occurred in children younger than 30 months. The vast majority of cases in the United States occurred in African American infants who were fed with breast milk rather than formula. Florid rickets manifests with leg deformities; enlargement of the growth plates of the wrists, ankles, and costochondral junctions; and rib cage deformities. Subtle symptoms that should raise the clinical suspicion of rickets in children include bone pain in the legs, delayed age of standing or walking, frequent falling, and delayed growth. Hypocalcemic seizures in the first year of life may be the initial manifestation of rickets.

Radiography of the long bones at the knees and the wrists is necessary to confirm the diagnosis of rickets. Radiography demonstrates impaired mineralization of the growth plates, evident by widening of the growth plate and fraying of the margin of the metaphyses. Biochemical features most consistently include hypophosphatemia and an elevated alkaline phosphatase level. As a result of vitamin D deficiency, serum concentrations of 25(OH)D are very low in patients with rickets, usually less than 5 ng/mL. However, concentrations of 25(OH)D may not be markedly reduced if rickets results from calcium deficiency or if the child has recently received vitamin D or sun exposure. In some tropical countries, where sun exposure is plentiful, calcium deficiency is more important than vitamin D deficiency as a cause of rickets. However, even in the United States, only 22% of children with nutritional rickets had deficient levels of 25(OH)D, indicating that calcium deficiency as a cause of rickets needs to be considered domestically as well.

Osteomalacia

Osteomalacia refers to the failure of organic osteoid formed by osteoblasts to become mineralized with calcium and phosphorus. Although histological osteomalacia is characteristic of rickets, the term osteomalacia is generally used to describe the bone disease caused by vitamin D deficiency in adults, who no longer have growing bones. The clinical manifestations of these 2 conditions are different.

Bone pain is a characteristic feature of osteomalacia, and it can be confused with arthritis or fibromyalgia. Bone pain due to osteomalacia primarily affects the bones between the joints, whereas arthritis usually causes predominantly joint pain, and fibromyalgia causes more diffuse muscle and soft tissue pain; however, it can be difficult to distinguish between these disorders. Proximal muscle weakness and gait instability are often present. Because the growth plates have closed in adults, the radiographic features differ from those typical of rickets. Radiography may reveal pseudofractures of the pelvis, femurs, metatarsals, or lateral margins of the scapulae. The biochemical features of osteomalacia are similar to those of rickets, with increased serum alkaline phosphatase and PTH values, and low calcium, phosphorus, and 25(OH)D values in most cases. A review of all the archived cases of bone biopsy–proven osteomalacia seen by the Bone Histomorphometry Laboratory at Mayo Clinic concluded that radiographic examination as well as serum calcium, phosphorus, and alkaline phosphatase assays are adequate screening tests in patients who have a clinical presentation suggestive of osteomalacia, but that 25(OH)D values may be normal.

In a cross-sectional study of iliac bone biopsy specimens obtained at autopsy, an excess accumulation of osteoid, which corresponds with histological osteomalacia, was found only in patients with 25(OH)D values less than 25 ng/mL. However, even patients with very low values of 25(OH)D did not consistently have evidence of osteomalacia.

POTENTIAL BENEFITS OF VITAMIN D

Apart from the deficiency diseases of rickets and osteomalacia, recent evidence suggests other skeletal and nonskeletal benefits of vitamin D. In evaluating the evidence, it is important to recognize the limitations inherent in the study design and methodology. Important issues that apply to vitamin D research include the following:

  1. Was the study design observational, which can only demonstrate associations and is subject to confounding, or was it an RCT that generally balances unmeasured confounding variables?

  2. How was the intake of vitamin D measured? Was the serum 25(OH)D value considered a proxy measure of vitamin D intake?

  3. What outcome was measured to assess the benefit of vitamin D? Was it the achieved 25(OH)D level or a specific clinical outcome that matters to the patient? Was assessment of the outcome the primary aim of the study?

  4. Is 25(OH)D the most appropriate biomarker of vitamin D status in all situations?

 

In the following section, representative studies of the available evidence related to the skeletal and nonskeletal effects of vitamin D are reviewed.

Skeletal Benefits

Bone Density. In addition to the treatment and prevention of vitamin D–deficiency rickets in children, vitamin D has been associated with other beneficial skeletal effects. A retrospective cohort study of pubertal girls demonstrated increased bone mineral density (BMD) of the femoral neck, but not of the spine or radius, among those who received supplemental vitamin D in infancy. Evidence of a positive association between BMD and serum 25(OH)D concentrations in adolescents is fair, but the evidence for a positive association in infants is inconsistent. Serum 25(OH)D concentration was related to hip BMD in community-dwelling women and men aged at least 20 years who participated in the US NHANES III survey. Higher calcium intake was significantly associated with higher BMD only for women with 25(OH)D values less than 20 ng/mL. One of the limitations of a cross-sectional study like the NHANES survey is that it can demonstrate only associations, not cause-and-effect relationships. Another confounding factor may be associated with low vitamin D intake and low bone density. For example, healthier people who exercise more outside in the sun may have greater bone density because of their exercise and higher 25(OH)D levels because of sun exposure. The WHI calcium and vitamin D supplementation trial showed that hip bone density was 1.06% higher in women receiving calcium and vitamin D supplementation vs placebo at 9 years, but that their lumbar spine and total body bone density did not differ significantly from those receiving placebo during this interval.

Fractures and Falls. On the basis of RCTs, the strongest evidence for the benefit of vitamin D relates to the prevention of fractures and falls. In a meta-analysis of 12 RCTs, a reduced nonvertebral fracture risk was demonstrated only for doses of vitamin D greater than 400 IU/d (relative risk [RR], 0.80; 95% confidence level [CI], 0.72-0.89). Similarly, a meta-analysis of 8 RCTs demonstrated that vitamin D reduced the risk of falls (RR, 0.78; 95% CI, 0.64-0.94), but only if the dose was 700 IU/d or greater and the 25(OH)D concentration was at least 25 ng/mL. The benefit of vitamin D could have been limited to those with unrecognized osteomalacia, which is associated with proximal muscle weakness and gait instability. These high-quality studies provide clear evidence that a minimum dose of 800 IU/d of vitamin D will reduce the risk of falls and fractures in older adults. However, a recent RCT of a 500,000 IU annual dose of vitamin D in women of advanced age increased the median 25(OH)D concentration from 20 ng/mL to 48 ng/mL one month later but resulted in an increased risk of falls and fractures in the group receiving this regimen.

Nonskeletal Benefits

Interest in the nonskeletal effects of vitamin D has been increasing since the discovery of vitamin D receptors and the 1α-hydroxylase enzyme in multiple tissues, including cells of the pancreas, immune system, macrophages, vascular endothelium, stomach, epidermis, colon, and placenta. In these tissues, 25(OH)D can be converted to 1,25(OH)2D locally, without altering serum 1,25(OH)2D concentrations. Through these paracrine effects, 1,25(OH)2D influences the expression of genes in local tissues. However, the evidence for the nonskeletal benefits of vitamin D is not as strong as the evidence for the skeletal effects.

Lower Mortality Rate. In a prospective observational study of adults older than 65 years participating in NHANES III, the risk of death was 45% lower in those with 25(OH)D values greater than 40 ng/mL compared with those with values less than 10 ng/mL (hazard ratio [HR], 0.55; 95% CI, 0.34-0.88). However, this may simply reflect the fact that people with underlying illness or immobility (who are more likely to die) tend to have lower 25(OH)D levels, in part as a result of having spent less time outdoors or of having less adequate nutrition. Because vitamin D is sequestered in adipose tissue, obesity is also associated with lower 25(OH)D levels. However, observational studies cannot prove whether low 25(OH)D status is the cause of greater mortality or just a marker of other underlying risk factors.

In contrast, a meta-analysis of 18 RCTs of vitamin D supplementation in postmenopausal women of advanced age, with dosages ranging from 300 to 2000 IU/d, reported a 7% lower risk of death in those receiving a vitamin D supplement (RR, 0.93; 95% CI, 0.87-0.99). This highlights the difference often found between RCTs and observational studies. The effect sizes found in observational studies are often attenuated or absent in RCTs. The situation with vitamin D is analogous to that of hormone replacement therapy (HRT) in postmenopausal women. The beneficial effects of HRT were demonstrated for multiple health outcomes in observational studies, but the WHI RCT in older postmenopausal women failed to confirm the beneficial effects of HRT on dementia and cardiovascular disease. In the observational trials, healthier women were more likely to use estrogen replacement and had fewer adverse health outcomes, indicating a “healthy user” bias. Only an RCT definitively demonstrated that the risks of first-time use of HRT outweighed the benefits in women older than 60 years.

Despite the slight reduction in mortality associated with vitamin D supplementation, the primary aim of the RCTs included in the meta-analysis was not to assess mortality. Not all trials of vitamin D reported mortality outcomes, so those trials could not be included in the meta-analysis. Trials that showed a mortality effect would be more likely to report this outcome, leading to a high likelihood of reporting bias that could render the slight mortality reduction statistically insignificant.

Lower Cardiovascular Mortality. The reduced mortality in the aforementioned observational study mirrored in large part the reduced cardiovascular mortality in those with 25(OH)D values greater than 40 ng/mL compared with those with values less than 10 ng/mL (HR, 0.42; 95% CI, 0.21-0.85). In another observational cohort study, patients who had angiography and 25(OH)D measurements were followed up for 8 years. Those from the highest 25(OH)D quartile (median, 28 ng/mL) had a lower mortality (HR, 0.45; 95% CI, 0.32-0.64) than those from the lowest quartile (median, 8 ng/mL). Although these observational studies do not demonstrate that low 25(OH)D values accelerate cardiovascular mortality, low 25(OH)D concentrations were associated with serum markers of inflammation that are indicators of cardiac risk.

Recently, concern has been expressed that vitamin D could potentially accelerate vascular disease. In a study of African Americans with type 2 diabetes mellitus, 25(OH)D levels correlated with increased calcified plaque in the aorta and carotids, but not in the coronary arteries. Vascular disease associated with chronic kidney disease, especially that associated with very low bone turnover, may also be accelerated with supplementation with standard doses of vitamin D. Furthermore, concern has been raised recently that other disorders characterized by vascular inflammation, such as diabetes mellitus, rheumatoid arthritis, or systemic lupus erythematosus, may not benefit from standard recommended doses of vitamin D supplementation.

Vitamin D may affect other cardiovascular and metabolic disease risks. In an observational study of adolescents in NHANES III, those with the lowest 25(OH)D values (<15 ng/mL) had more than a 2-fold greater odds of having an elevated blood pressure compared with the group of adolescents with higher 25(OH)D levels (>26 ng/mL) (odds ratio [OR], 2.4; 95% CI, 1.3-4.2).

The NHANES III data in adults indicated that those with 25(OH)D levels of less than 21 ng/mL had an increased risk of hypertension, diabetes, obesity, and high triglyceride levels—all metabolic manifestations associated with increased cardiovascular mortality. Although obesity is associated with lower serum 25(OH)D levels because of the sequestration of vitamin D in adipose tissue, it is likely not the consequence of low 25(OH)D levels. Additionally, the 25(OH)D level may be a marker of other factors associated with obesity, such as physical inactivity and reduced outdoor sun exposure.

Reduced Risk of Diabetes Mellitus. A meta-analysis of 5 observational studies of vitamin D supplementation in childhood reported a nearly 30% reduction in the risk of type 1 diabetes in children who had ever received vitamin D supplements (OR, 0.71; 95% CI, 0.60-0.84). Unfortunately, most studies had no information about vitamin D dosage or adherence. Because these were observational studies, and vitamin D was not randomly assigned to children, it is possible that characteristics of families who provided supplemental vitamin D to their children contributed to the decreased risk of type 1 diabetes in children receiving supplements.

Vitamin D receptors are present in pancreatic β cells, and vitamin D may augment insulin secretion and insulin sensitivity. Adolescents in NHANES III with serum 25(OH)D levels of less than 15 ng/mL were more likely to have elevated blood glucose levels than those with the highest 25(OH)D values (>26 ng/mL) (OR, 2.5; 95% CI, 1.0-6.4). The observational Nurses Health Study found that vitamin D supplementation and calcium supplementation were both associated with a reduction in risk of type 2 diabetes. Current data related to vitamin D and the risk of type 2 diabetes are limited by inadequate adjustment for confounding variables, post hoc analyses, and inability to identify the separate effects of calcium and vitamin D. Because milk is the major source of both vitamin D and calcium in the diet, it is difficult to identify the independent effects of dietary calcium and vitamin D on the basis of intake or 25(OH)D levels. Skim milk intake is also inversely associated with obesity, which could account for an association between the intake of dietary calcium and vitamin D and a reduced risk of type 2 diabetes.

Reduced Risk of Cancer. Vitamin D is known to promote cellular differentiation, inhibit cellular proliferation, and reduce the growth of certain tumors in laboratory animals. A meta-analysis of case-control studies of those with and without colon cancer found that, for each 20 ng/mL increase in serum 25(OH)D levels, the odds of colon cancer were reduced by more than 40% (OR, 0.57; 95% CI, 0.43-0.76). Other studies have shown that dietary calcium intake is also associated with reduced colon cancer risk and adenoma formation. Because milk intake is a major determinant of serum 25(OH)D levels, it is difficult to separate the effect of vitamin D from that of calcium intake.

In the case of colon cancer, one large RCT was performed to evaluate the effect of combined supplementation with calcium and vitamin D on the risk of colon cancer. In the WHI trial, supplementation with calcium and vitamin D had no significant effect on the risk of colorectal cancer during 8 years of follow-up. Several limitations of this study may have contributed to this lack of effect. Colorectal cancer is a long latency disease, and 8 years may not have been sufficient time to observe the effect of calcium and vitamin D. Another criticism is that the relatively low dose of 400 IU of vitamin D may have not been protective or sufficient to increase serum 25(OH)D levels adequately. Concentrations of 25(OH)D were measured at baseline but not during follow-up. Declining adherence over time would have further reduced the effective doses of calcium and vitamin D.

Breast cancer has also been associated with vitamin D insufficiency. A meta-analysis combining 7 observational studies reported a lower risk of breast cancer among women in the highest compared with the lowest quartile of 25(OH) D values (OR, 0.55; 95% CI, 0.38-0.80). As with colon cancer, calcium intake was also associated with a reduced risk of breast cancer. Because obesity is associated with an increased risk of breast cancer and low 25(OH)D levels, it is a confounding factor in the association between breast cancer risk and vitamin D.

As with colon cancer, the WHI RCT of a combined regimen of calcium and vitamin D showed no benefit of supplementation on the risk of breast cancer, again highlighting the different conclusions of observational studies and RCTs. The limitations of the breast cancer study are similar to those of the study focused on colon cancer. This study demonstrated the potential confounding effects of physical activity and obesity. Baseline 25(OH)D levels were greater among women with lower body mass index and more recreational physical activity. When controlling for body mass index and physical activity, serum 25(OH)D concentration was not associated with breast cancer risk.

In a meta-analysis of 11 observational studies, prostate cancer was not associated with serum 25(OH)D levels. The evidence regarding an association between pancreatic cancer and 25(OH)D levels is conflicting. A multinational cohort study found no protective association between greater 25(OH)D values and gastric, esophageal, endometrial, ovarian, kidney, non-Hodgkin lymphoma, and pancreatic cancers. Drake et al recently showed that event-free survival and overall survival were reduced in vitamin D–insufficient patients newly diagnosed as having diffuse large B-cell lymphoma and T-cell lymphoma during 34.8 months of follow-up.

To date, studies have not shown impressive effects of vitamin D treatment on malignancies.

Reduced Risk of Multiple Sclerosis. The incidence of multiple sclerosis increases with increasing latitude, corresponding with reduced ultraviolet B sun exposure and lower serum levels of 25(OH)D. A case-control study demonstrated that the odds of having multiple sclerosis were lower in the group with the highest 25(OH)D levels. However, the association was found only in white patients [OR, 0.59; 95% CI, 0.36-0.97 for a 20 ng/mL increase in 25(OH)D], not in African American patients. It is difficult to exclude the possibility that other confounding exposures associated with increasing latitude and greater indoor activity during winter months contribute to the risk of multiple sclerosis. Little evidence supports a therapeutic role for vitamin D in the treatment of multiple sclerosis.

Reduced Risk of Allergy and Asthma. Several lines of evidence demonstrate the effects of vitamin D on proinflammatory cytokines, regulatory T cells, and immune responses, with conflicting interpretation of the effects of vitamin D on allergic diseases. In a cross-sectional study of Costa Rican children, low 25(OH)D levels were associated with elevated IgE and eosinophil counts, as well as with increased asthma-related hospitalizations and use of anti-inflammatory medication. However, an association does not prove causation, and alternative explanations can account for this association. For example, children with more severe asthma may spend more time indoors and have less sun exposure.

Low maternal vitamin D intake in pregnancy has been associated with an increased likelihood of childhood wheezing at ages 3 and 5 years. In contrast, maternal 25(OH)D levels of greater than 30 ng/mL in pregnancy have been associated with childhood eczema at age 9 months and asthma at age 9 years. Vitamin D supplementation in infancy has been associated with increased atopy and allergic rhinitis in adulthood. Increasing 25(OH)D levels were associated with increasing risk of allergic rhinitis among adults in NHANES III. The conflicting data indicate the need for RCTs to demonstrate the effect of vitamin D on the prevention and control of allergic diseases.

Reduced Risk of Infection. Vitamin D is required for the expression of cathelicidin by macrophages, which is involved in bacterial killing. A meta-analysis of 7 observational studies noted a reduced risk of active tuberculosis in those with the highest vs the lowest values of 25(OH)D (OR, 0.68; 95% CI, 0.43-0.93). However, an RCT in a West African population with baseline mean 25(OH)D values of 31 ng/mL showed no effect of 100,000 IU of supplemental vitamin D given at the beginning and at 3 and 8 months of tuberculosis treatment on the rate of sputum conversion or resolution of markers of clinical severity. However, this dose of vitamin D may have been insufficient because the increase in 25(OH)D concentration during treatment did not differ between the supplement and placebo groups.

In observational data from NHANES III, persons with 25(OH)D values lower than 10 ng/mL were more likely to have had a recent upper respiratory tract infection than those with higher 25(OH)D values in all 4 seasons of the year. This association was even stronger in those with asthma or chronic obstructive pulmonary disease. Whether this association is explained by the fact that people who remain indoors are more likely to catch colds remains unclear.

A case-control study reported that mean 25(OH)D values were lower in children with bronchiolitis or pneumonia admitted to the pediatric intensive care unit than in healthy control children or in children with pneumonia admitted to the general pediatric ward.

Reduced Risk of Mental Illness. A cohort of Finnish children who received supplemental vitamin D in their first year of life had a lower risk of developing schizophrenia. However, the significance of this association is unclear because it was unrelated to adherence to vitamin D supplementation, was only evident in males, and was not found with any other mental illness.

To examine the effect of vitamin D on depression, overweight and obese patients were randomized to receive 20,000 or 40,000 IU of vitamin D or placebo weekly for 1 year. At baseline, those with 25(OH)D concentrations lower than 16 ng/mL had greater Beck Depression Inventory scores, indicating that they were more depressed, than those with higher 25(OH)D levels. The 2 groups receiving vitamin D supplementation had significant improvement in their scores, whereas the placebo group did not.

Less Musculoskeletal Pain. A small descriptive study reported that most patients (93%) with persistent musculoskeletal pain had 25(OH)D values of 20 ng/mL or less. In one RCT, patients with diffuse musculoskeletal pain or osteoarthritis and 25(OH)D values lower than 20 ng/mL were randomized to receive vitamin D or placebo for 3 months. Those given vitamin D had no improvement in their pain compared with baseline or compared with placebo-treated patients. In another double-blind RCT, primary care patients with 25(OH)D levels of 10 to 25 ng/mL were randomized to receive 50,000 IU of vitamin D or placebo weekly for 8 weeks. The treated group showed significantly greater improvement in fibromyalgia assessment scores than the placebo group. Patients with 25(OH)D values lower than 10 ng/mL were treated in an unblinded fashion with 50,000 IU of vitamin D weekly for 8 weeks but had no symptom improvement.

Reduced Risk of Renal Disease. In a subgroup analysis of the NHANES III data set, low 25(OH)D values were associated with a greater risk of kidney failure in African American but not in white participants. However, the opposite trend was observed in whites.

INDICATIONS FOR VITAMIN D TESTING

Measurement of serum 25(OH)D levels is indicated in select circumstances. If clinical symptoms of rickets in children or osteomalacia in adults are present, measurement of 25(OH)D levels will confirm vitamin D deficiency. Such testing would be appropriate in adults or children with bone pain, elevated serum alkaline phosphatase or PTH levels, and low serum calcium or phosphorus levels. Persons of advanced age, those with osteoporosis, or those at increased risk of falls or fractures may also benefit from measurement of 25(OH)D levels. However, one could argue that providing at-risk groups with routine supplementation of adequate doses of vitamin D may make testing for vitamin D insufficiency unnecessary. When to test and how to treat adults with vitamin D deficiency have recently been reviewed in this journal. No evidence shows benefit for screening 25(OH)D levels in the asymptomatic population.

CONCLUSION

Critically evaluating the evidence regarding the purported benefit of vitamin D on a multitude of health outcomes is difficult. The bulk of current data is based on observational, epidemiological studies, which are useful for generating hypotheses but not for proving causality. It is particularly difficult to tease out the effects of confounding variables that relate both to health outcomes and to vitamin D status, such as physical activity, milk intake, and adiposity. Few of the observational associations have been confirmed by RCTs, and many of the interventional studies of vitamin D also included calcium supplementation. Future clinical trials, including a National Institutes of Health–funded 5-year 20,000-participant prospective RCT comparing the effect of supplementation with 2000 IU/d of vitamin D3 or placebo, will help clarify the benefits and risks of vitamin D supplementation in many of the disorders discussed in this review.

On the basis of the current data, it seems prudent for persons older than 60 years to take a vitamin D supplement of 800 to 2000 IU/d to reduce the risk of falls and fractures. These recommendations are consistent with the recently released report of the Institute of Medicine, which recommended that healthy adults take 600 IU/d to maintain skeletal health and also concluded that information about the health benefits beyond bone health could not be considered reliable. Dark-skinned infants who are exclusively breast-fed are at greater risk of rickets and should receive 400 IU/d of supplemental vitamin D. Vitamin D supplementation in these ranges is likely to prevent bone loss, may improve bone density, may reduce fractures, and appears to reduce falls. Although vitamin D intoxication has been associated only with intakes of 50,000 to 1 million IU/d over the course of months or years, the potential risks of kidney stones, vascular disease, and fractures with high-dose vitamin D regimens are unclear. Until more data from RCTs are available, a healthy dose of skepticism should be maintained regarding the other health claims for vitamin D.

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Source: Mayo Clin Proc. 2011 Jan;86(1):50-60. Thacher TD, Clarke BL. Department of Family Medicine, Mayo Clinic, Rochester, MN 55905, USA. thacher.thomas@mayo.edu. http://www.mayoclinicproceedings.com/content/86/1/50.long

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Vitamin D and Your Health: Just How Critical is this "Sunshine Vitamin"?

Posted By Administration, Friday, January 7, 2011
Updated: Friday, April 18, 2014

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By John C. Pittman, MD, and Mark N. Mead, MSc

If you’re like millions of Americans who regularly tune into the news, you probably heard about the vitamin D report issued in November 2010 by the Institute of Medicine’s Food & Nutrition Board (FNB), a committee of 14 medical scientists appointed to assess current data of health outcomes associated with these two nutrients. The FNB report concluded that most North Americans get enough of this “sunshine vitamin” through their diets, and moreover that consuming extra vitamin D is unlikely to help protect the public from cancer, heart disease, diabetes, or other chronic diseases.  Among the report’s other conclusions:

• Raise the recommended daily amount of vitamin D to 600 international units (IU), up from the 200 IU level that had been recommended in 1997.  People over age 70 are advised to get 800 IU daily.  Our response:  Most experts agree that it is virtually impossible to significantly raise your vitamin D levels when supplementing at only 600 to 800 IU/day. Michael Holick, MD, PhD, director of the General Clinical Research Center at Boston University Medical Center and author of numerous scientific reports on vitamin D, has recommended that all adults supplement with 2000 IU daily. Holick himself takes 3000 IU per day and has many patients taking at least that much. Robert Heaney, a professor of medicine at Creighton University in Omaha who has long studied vitamin D’s health benefits, says people should consider taking up to 4,000 IUs a day.

• The risk of harm increases at daily vitamin D intake levels greater than 4000 IU. Our response:  This would suggest that a daily intake of 10,000 IU/day would cause toxicity in humans; however, the FNB report provided no evidence to support this position, citing only one poorly conducted study indicating 20,000 IU/day may cause mild elevations in serum calcium but not clinical toxicity.  Several leading vitamin D researchers have proposed that the new upper tolerable limit should be 10,000 IU, based on extensive observations of adults taking this dose or higher.

• Regarding the serum 25-hydroxyvitamin-D level—the primary indicator of vitamin D status—the FNB report deemed that a level of 20 ng/mL is sufficient for all persons.  Our response:  The most widely used benchmark for sufficiency has been 32 ng/mL, and many experts suggest that higher levels may be needed for specific health outcomes.

The FNB report made headlines across the country, and prompted many people to either cut back on their vitamin D dose or stop supplementing altogether.  However, we see several serious limitations in the FNB’s approach and conclusions.  First, the guidelines are based on the minimum amount of vitamin D needed to ensure bone health and do not address the amount that may affect other health outcomes, such as the prevention of cancer and heart disease, or improvement in muscle and joint health.  Ostensibly, the FNB committee believed that evidence was insufficient to determine the role of vitamin D in the prevention of these other chronic diseases and health outcomes.  However, many leading vitamin D authorities throughout the world would take issue with this perspective.

For example, a comprehensive evidence-based review, published in the November-December 2009 Journal of the American Board of Family Medicine, concluded that, “Low vitamin D levels are associated with increased overall and cardiovascular mortality, cancer incidence and mortality, and autoimmune diseases such as multiple sclerosis.”  Even more recently, an international committee of 25 experts from various medical disciplines proposed clinical guidelines for vitamin D intake.  Their focus was on the vitamin D needs of adult patients with or at risk for fractures, falls, cardiovascular or autoimmune diseases, and cancer.  The expert panel reached strong agreement about the need for vitamin D supplementation in these specific groups of patients and the need for assessing their 25(OH)D serum levels “for optimal clinical care.”  A target range of “at least 30 to 40 ng/mL” was recommended—about twice the level proposed by the FNB report.  These recommendations were published in the September 2010 issue of Autoimmunity Reviews.

 

 

 


Against this backdrop, it’s also important to realize that the FNB’s guidelines have nothing to do with the requirements for optimal functioning and overall health.  Physicians who carefully observe what happens with their individual patients are better able to discern the effects of different doses of vitamin D in the context of specific health situations.  For someone with low blood levels of vitamin D, an initially high supplemental dose—on the order of 5000 to 10,000 IU per day—may result in better mood, increased muscle strength, relief of joint aches, and other clinical benefits.  But one size does not fit all; the same dose of vitamin D is not appropriate for everyone.  This is why individual testing and expert supervision are so important when trying to pinpoint the optimal dose for you personally.

The Sunshine Deficiency

Vitamin D has emerged in recent years as a nutrient with astounding potential for promoting human health. The vitamin’s most recognized function is the enhancement of calcium absorption and bone mineral metabolism. In 2007, the Dietary Supplement Education Alliance estimated that appropriate use of calcium with vitamin D by older adults for five years could lead to the elimination of approximately 776,000 hospitalizations and nursing stays linked to hip fractures, resulting in an annual savings of $16.1 billion. In other words, supplements such as calcium and vitamin D serve as a potent form of “biological insurance” that can help keep the human frame intact. As we explain in a moment, however, the benefits of improving your vitamin D status extend far beyond healthy bones.

Vitamin D is classified as a vitamin, but it’s really a hormone your body generates in response to sunlight. Fair-skinned people can generate 20,000 IU of vitamin D through 20-30 minutes of mid-day sun exposure; in contrast, dark-skinned individuals may require at least four times this level of exposure to attain the same output. (Note that these levels far surpass any amount obtainable through diet alone, which helps explain why the US recommended dietary allowance of vitamin D is set at a mere 200-400 IU for people aged 1-70 years.) 

Your body’s production of vitamin D depends on the amount of skin surface exposed and the quality of sunlight.  Direct-overhead sun exposure provides the strongest stimulus for the skin’s synthesis of vitamin D.  In temperate regions, almost all of this “human photosynthesis” occurs in summertime, because the angle of sunlight largely determines the intensity of ultraviolet radiation, hence the rate of vitamin D production.

Given these facts, it comes as no surprise that most cases of vitamin D deficiency are due to a sunlight deficit, not a dietary one. If you were to totally avoid the sun and regularly took two standard multivitamins every day for several years, each containing 400 IU of vitamin D as your sole source of vitamin D, you would eventually become vitamin D deficient. (Remember, most people meet 90% of their vitamin D needs from very casual sun exposure, like the sunlight that strikes your face, arms and hands when stepping outside for a few minutes in the middle of the day.)

These days, due to fears of developing skin cancer, many people get too little sunshine.  This results in a low or suboptimal blood level of 25-hydroxyvitamin D—the sole measure of one’s vitamin D status.  If this level is low—say, below 50 nanomoles per liter (nmol/L) — research indicates that you may be more prone to developing a host of health problems.  The classical disorder linked with vitamin D deficiency is known as osteomalacia, a painful softening of the bones. In children, the deficiency causes the shafts of leg bones to irreversibly bow or bend, resulting in the grotesque disfigurement known as rickets.  Sunbathing or taking cod liver oil (which contains vitamin D) were eventually found to prevent rickets, which is now extremely rare, thanks mainly to the practice of fortifying dairy products with vitamin D.

But lack of vitamin D can also lead to various other health problems, including osteoporosis, osteopenia, heart disease, hypertension, diabetes, osteoarthritis, joint problems, muscle weakness, chronic muscle pain, fibromyalgia, multiple sclerosis, Type 1 diabetes, depression, mental illness and yes, many types of cancer as well. Let’s take a quick look at what science is telling us about the connections between vitamin D and these various disorders.

Osteoporosis and Osteopenia.  When you’re lacking in vitamin D, you’re more prone to developing osteoporosis, osteopenia, and osteomalacia (as mentioned above), and your risk of experiencing a fracture increases.  Achievement of optimal blood vitamin D levels is essential for boosting bone mineral density and maximizing bone strength, which is why elderly people with osteoporosis—particularly those being treated with bisphosphonates—are advised to boost their intake to at a range of 800 to 2000 IU, along with calcium.  Again, however, if your vitamin D status is poor initially, it’s important to supplement at a higher dosage level in order to truly improve the blood levels of 25(OH)D. Daily supplementation at the right level—again, relative to the blood test result—is especially important for older adults because aging is linked with a reduced capacity to synthesize vitamin D in the skin upon sun exposure.

Cardiovascular Disease and High Blood Pressure. Vitamin D deficiency has been linked with a greater risk of cardiovascular disease and high blood pressure. For example, a meta-analysis of 18 studies found that the lower the serum vitamin D level, the higher the risk of high blood pressure, as reported in the 28 December 2010 Journal of Hypertension. In addition, we know that vitamin D can impact several key mechanisms involved in heart disease, such as inhibiting inflammation as well as vascular muscle proliferation and vascular calcification. To date, however, studies evaluating vitamin D supplementation have not consistently shown a benefit, possibly due to suboptimal levels of vitamin D (no studies have yet looked at doses higher than 2000 IU, even in deficient individuals) or a lack of consideration for other factors that impact cardiovascular health.

Cancer. People living in colder climates not only experience more bone thinning with age but also have higher rates of various cancers. These individuals tend to spend more time indoors, so they get less sun exposure. It’s also interesting to note that cancer mortality rates tend to be lowest in the summer, when vitamin D levels are highest. Laboratory studies indicate that high-dose vitamin D may help block the growth of cancers of the breast, colon, rectum, prostate, lung and head/neck region, as well as lymphoma, leukemia and multiple myeloma. Generally, the lower one’s overall sun exposure and vitamin D intake, the greater the risk of developing and dying from cancer. In a five-year clinical trial conducted out of Creighton University in Nebraska, women who regularly took 2000 IU of vitamin D3 showed a 77% reduction in overall cancer rates compared to women taking a placebo pill, as reported in the June 2007 issue of the American Journal of Clinical Nutrition. This 2000 IU level of vitamin D3 has also been shown to reduce PSA levels in men with prostate cancer.  

One other key application concerns cancer treatment. Vitamin D has a synergistic effect against malignant disease when combined with several kinds of anti-cancer drugs, including the taxanes (Taxol and Taxotere), platinum compounds (e.g., cisplatin), dexamethasone, tamoxifen, and mitoxantrone.  Soy isoflavones, too, seem to synergize with vitamin D in combating cancer. Finally, there’s good evidence that vitamin D can be very effective in slowing down the breakdown of bone and lessening bone pain in patients with advanced cancers. 

Obesity and Metabolic Syndrome. Vitamin D is fat-soluble and therefore stored in fatty tissue. This explains why obese people have a greater capacity to store the vitamin; however, obese people have been shown to produce about half the vitamin D produced by people of a normal weight when exposed to the same amount of sunshine.   Moreover, the vitamin D in those who are lean is more available for the body's metabolic needs than in those who are obese. In a 2007 report for Clinical Nutrition, about half of all morbidly obese individuals were found to be vitamin D deficient. Those with the lowest levels of vitamin D had the greatest risk for the so-called metabolic syndrome. (The latter condition includes the presence or more of the following factors: excess abdominal fat, elevated triglyceride levels, low HDL cholesterol, elevated blood pressure, and elevated fasting glucose and insulin levels.)

Autoimmune Diseases. Lack of vitamin D has been linked with multiple sclerosis, rheumatoid arthritis, type I diabetes, lupus, and Crohn’s disease.  For example, babies deficient in vitamin D may have a greatly increased risk of developing type I diabetes by age 30 compared to those who are not deficient. Animal studies suggest that a vitamin D supplement will greatly impede the development of type I diabetes in susceptible individuals. A 2009 report in Arthritis Research & Therapy concluded that vitamin D deficiency is highly prevalent in patients with lupus and rheumatoid arthritis.  However, whether supplementation can help patients with these disorders remains to be proven.

Colds and Flus. Sharply reduced levels of vitamin D, due to the low intensity of solar UV radiation, may have some connection to the increased occurrence of colds and the flu in winter. Scientists have found that people with low vitamin D levels are less capable of fighting off infections, and that supplementing with vitamin D boosts resistance to colds and the flu. In a randomized controlled trial conducted in Japan, researchers gave 1,200 IU/day of vitamin D3 for six months to Japanese 10 year-olds and compared them to children receiving a placebo. As reported in the May 2010 American Journal of Clinical Nutrition, there was a 42% reduction in the incidence of influenza A, along with an 83% reduction in asthma attacks in the vitamin D group compared to the placebo group.  Had those researchers followed the new FNB recommendations and used 400 IU instead of 1,200 IU, it is unlikely that the children would have experienced any benefit at all.

The problems just mentioned are only the tip of the proverbial iceberg.  Low levels of vitamin D also have been linked with mood disorders (e.g., depression), mental illness, autism, muscle weakness, periodontal disease, unexplained bone and muscle pain, infertility, preeclampsia, cystic fibrosis, psoriasis, and age-related cognitive decline.  In some cases, clinical benefits have been seen following vitamin D supplementation—for example, reductions in depressive moods in adults, and improvements in muscle strength and function in children with autism. 

How Much Is Needed?

These days, most of us just don’t get out in the sun as much as our ancestors did. We spend far more time indoors, and yet the sunshine that comes through glass windows will not stimulate vitamin D synthesis. Even if we did get outdoors on a regular basis, we’d then have to reckon with problems associated with getting too much sun—problems such as sunburn, premature aging of the skin, and a heightened risk of skin cancer, especially in fair-skinned people. Older individuals and obese people have more difficulty synthesizing vitamin D, so they would need to be out in the sun longer, thus further increasing the skin cancer risk.

Aside from sunshine, we can get additional vitamin D from foods like fatty fish and fortified milk.  Unfortunately, most fortified dairy products contain synthetic vitamin D, which confers fewer biological benefits than vitamin D3. Moreover, relying on fatty fish may not be a suitable way to get your vitamin D, because you’d have to eat a large amount of fish every day. For many people, vitamin D-rich cod liver oil is a great source, one that has been used in northern regions for well over a century.

This brings us back to vitamin D supplements. Vitamin D in its natural form is called vitamin D3 or cholecalciferol. This form of vitamin D generally has more drawn-out effects and need not be taken daily; in contrast, synthetic forms such as calcitriol need to be taken daily for optimal effectiveness.  Also whereas vitamin D is relatively cheap, calcitriol can be quite expensive – and your insurance company may or may not provide coverage. 

So how much do we really need?  Many of the leading vitamin D authorities say that, if you rarely if ever get any mid-day summertime sun exposure, most adults can benefit by supplementing in the range of  2,000 and 5,000 IU per day.  A recent clinical trial by Dr. Reinhold Vieth confirmed that the 5000 IU amount was safe even for elderly people. For people who do get exposed to 15 or 20 minutes of mid-day sunshine in the spring, summer and fall, the recommended amount is about 2,000 IU per day.  You can also take your week’s worth of vitamin D (say 15,000 to 20,000 IU) all on the same day, once a week.  This makes it much easier to take the vitamin, but there are those individuals who may still have problems absorbing this much Vitamin D at one time, in which case daily dosing is still better. 

The only caveat of taking higher doses of vitamin D is that some individuals may be prone to a condition known as hypercalcemia (excessive calcium in the blood). Symptoms of hypercalcemia include weakness, fatigue, somnolence, headache, anorexia, dry mouth, metallic taste, nausea, vomiting, cramps, diarrhea, muscle pain, bone pain and irritability. If you have cancer and certain other conditions, your physician should monitor you for hypercalcemia in order to safeguard against this problem. If you do happen to become hypercalcemic, your physician will have you discontinue the vitamin D and then check your blood calcium level daily until it has normalized, and then twice weekly on a lower dose of vitamin D.

John Cannell, MD, founding director of the Vitamin D Council, notes that thousands of individuals reading the Council’s newsletter routinely have taken 5,000 IU/day for up to eight years. “Not only have they reported no significant side effects, indeed, they have reported greatly improved health in multiple organ systems,” Dr. Cannell states. “My advice: especially for pregnant women, continue taking 5,000 IU/day until your 25(OH)D is between 50 ng/ml and 80 ng/ml—the vitamin D blood levels obtained by humans who live and work in the sun and the mid-point of the current reference ranges at all American laboratories.” The FNB recommendations are a major disappointment to Cannell and many other proponents of higher vitamin D intake. Given the low cost of vitamin D, as well as the large body of evidence for safety and benefit at intakes well above these recommendations, why not take a chance of achieving those benefits?

John C. Pittman, MD, is the Medical Director of the Carolina Center for Integrative Medicine in Raleigh, NC, and is certified by the American Board of Clinical Metal Toxicology.  Mark N. Mead, MSc, serves as the Center’s Nutrition Educator and Integrative Medicine Research Consultant.

For more information, please visit thier website:  www.carolinacenter.com

 

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What Lies Behind the Vitamin D Revolution?

Posted By Administration, Friday, June 11, 2010
Updated: Friday, April 18, 2014

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by Ronald Hoffman, MD

Generations of medical professionals have been taught to approach vitamin D supplementation with great caution and trepidation. As a fat-soluble vitamin known to enhance calcium absorption, vitamin D taken in excessive amounts was thought to raise the specter of hypercalcemia with its attendant risks of nephrolithiasis and even metastatic calcification. Our understanding of vitamin D's health benefits was limited to its familiar role in maintaining bone strength by means of regulating calcium uptake. But thanks to an explosion in vitamin D research, a broader perspective is rapidly evolving.


Powered by its pervasive influence on myriad physiological processes, vitamin D is staking its claim as "Nutrient of the Decade." We now recognize that vitamin D transcends the definition of a mere vitamin: It is actually a prohormone, and vitamin D receptors are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate gland, and mammary glands. In the digestive tract and parathyroid glands, active vitamin D metabolites are responsible for calcium uptake. Vitamin D receptors are also involved in immune regulation and mediate response to infection and inflammatory processes. Additionally, the nutrient is associated with cell proliferation and differentiation.


Fracture prevention


Vitamin D's traditionally acknowledged role is in bone metabolism. The pathognomonic vitamin D deficiency disease is rickets, but less overt prolonged insufficiency results in osteomalacia. This condition is characterized by softening of the bones and musculoskeletal pain, the result of periosteal traction. Not surprisingly, an association between vitamin D repletion and relief of unexplained body aches has been observed in some studies. 


Chronic vitamin D deficiency can result in secondary hyperparathyroidism with consequent osteoporosis. Vitamin D deficiency in childhood and adolescence impairs attainment of optimal bone mass. Frequently, clinicians neglect to assess vitamin D status and don't consider the treatment option of aggressive repletion when using drugs to manage osteopenia or osteoporosis. A new minimum threshold for vitamin D of 50-75 nmol/L (20-30 ng/mL) was recently proposed to prevent osteoporosis. However, vitamin D receptor polymorphisms modulate skeletal response to vitamin D supplementation even in healthy girls, and individual requirements for bone optimization may vary. A minimal threshold of 40 ng/mL for healthy bone metabolism has also been proposed.


The ultimate goal of osteoporosis treatment is fracture prevention. Considerable evidence suggests vitamin D can support muscle strength and thereby reduce the incidence of falls, particularly in elderly, at-risk patients. In addition, vitamin D arguably has an indirect role in staving off fractures: As a nondrug treatment for osteoporosis, the use of vitamin D reduces polypharmacy with various cardiovascular, anti-inflammatory, and psychiatric medications that can induce nutrient depletions and impair balance in frail seniors. 


Cardiovascular disease


Vitamin D deficiency is associated with increased risk for cardiovascular events and mortality. In the Multi-Ethnic Study of Atherosclerosis, 25-hydroxyvitamin D (25[OH]D)levels were inversely associated with the risk of coronary artery calcification, a measure of coronary atherosclerosis.


Cardiovascular disease (CVD) represents the culmination of an array of predisposing influences, and vitamin D may intervene beneficially in several ways. Studies confirm an association between obesity and vitamin D deficiency, and low vitamin D status is predictive of insulin resistance. Overweight women replete with vitamin D shed pounds more successfully. Moreover, studies have found correlation between suboptimal vitamin D status and both hypertension and diabetes.


In renal disease, characterized by problematic vitamin D metabolism, CVD is rampant—but cardiovascular risk is known to be attenuated by vitamin D administration.


Evidence also indicates that vitamin D deficiency—common in elderly, debilitated patients—plays a role in congestive heart failure, which is mediated by the nutrient's effect on myocyte contractility.



Cancer


Sun exposure is clearly required for vitamin D sufficiency. However, latitude, season, time of day, weather conditions, shade, skin pigmentation, air pollution, clothing, use of sunscreen, and age impact cutaneous vitamin D activation. Below 32º latitude (corresponding to a line stretching from Los Angeles to Columbia, S.C.), sunlight exposure can activate vitamin D year-round. But above 44º north latitude (which extends from the northern tip of California to Boston), no cutaneous activation is possible from November through February.


It has long been noted that colon cancer rates increase with higher geographic latitude. This epidemiologic correlation was initially attributed to Western diet and lifestyle, but subsequent studies controlled for extraneous factors and confirmed the protective role of sunlight. Scientists were then able to establish the biological plausibility for the impact of vitamin D in cancer prevention, recognizing the vitamin's effects on cell proliferation, oncogenesis, and apoptosis. Since then, investigators have explored a putative involvement of vitamin D in both primary and secondary prevention of prostate cancer and breast cancer as well as non-Hodgkin's lymphoma, melanoma, and other malignancies.


Immunity


Cells involved in innate and adaptive immune responses —including macrophages, dendritic cells, T cells, and B cells—express the vitamin D receptor. In the 19th century, before the advent of antibiotics, caregivers recognized that individuals with TB could benefit from sunlight and fresh air during their stays in mountain sanitoria. Research has confirmed that host response to TB is partially mediated by vitamin D, and that vitamin D deficiency is associated with dysregulation of macrophage response. 


The observed seasonal correlation between sunlight exposure and the incidence of viral upper respiratory infections has prompted speculation about the role played by vitamin D. Research confirms that vitamin D dramatically stimulates the expression of potent antimicrobial peptides. These compounds exist in neutrophils, monocytes, natural killer cells, and epithelial cells lining the respiratory tract, where they play a major role in protecting the lung from infection. The action of vitamin D serves as a key link between Toll-like receptor activation and antibacterial responses in innate immunity. An association between vitamin D insufficiency (25[OH]D <40 nmol/L) and acute respiratory tract infection was recently confirmed. As yet, prospective intervention studies are few and small in scale.


Autoimmunity


The incidence of certain autoimmune diseases correlates positively with latitude from the equator, as reflected by the epidemiology of rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, and multiple sclerosis (MS). Studies confirm that patients suffering from autoimmune disease have vitamin D levels below the international norm. There is substantial biological rationale for vitamin D as a cytokine modulator. 


Animal models of autoimmune disease suggest a response effect with vitamin D administration; large human therapeutic trials using vitamin D are still lacking, but the first results of phase I/II studies are promising. Meanwhile, it is now acknowledged that administering vitamin D in patients with autoimmune diseases is justifiable. 


Other conditions


Perhaps the most persuasive rationale for considering vitamin D optimization comes from a study of 3,400 French men, age 50 years and older, correlating vitamin D status with all-cause mortality. Men in the lowest quartile of 25(OH)D levels had a 44% higher death rate. The authors qualified their findings by stating that although the study controlled for lifestyle variables and comorbidities, a possibility exists that low levels of vitamin D are merely reflective, and not causative, of poor health status.


Because of the ubiquity of the nutrient's impact on physiologic processes, some researchers have proposed associations between vitamin D status and incidence of autism, allergic diseases, depression, schizophrenia, cognitive impairment, pre-eclampsia, fibromyalgia, Parkinson disease, polycystic ovary syndrome, and benign prostatic hyperplasia. Athletic trainers, cognizant of research suggesting that vitamin D may augment muscle strength, are increasingly embracing oral supplementation and UV-light exposure for purposes of performance enhancement. 


Of course, a long-observed relationship between sunlight exposure and severity of psoriasis suggests mediation by vitamin D; topical calcipotriene (Dovonex), a synthetic vitamin D analogue, is a standard dermatologic treatment for the condition.


Vitamin D has received renewed interest for its role in pregnancy. Studies suggest that higher levels of vitamin D supplementation than are currently recommended for pregnant women may safeguard offspring from the risks of low birth weight, autism, juvenile diabetes, asthma and allergic rhinitis, and infectious diseases. The Canadian Pediatric Society recently recommended that pregnant women increase their intake of vitamin D to 2,000 IU/day.


 

Pervasiveness of deficiency and risk factors


A number of health authorities now acknowledge that vitamin D deficiency is a pervasive problem in the United States and the developed world. Sun deprivation, already a problem for inhabitants of temperate latitudes, is exacerbated by indoor occupations and recreation and is further encouraged by warnings against sun exposure to prevent skin cancer.


Although overt vitamin D deficiency is no longer common in U.S. children, lesser degrees of vitamin D insufficiency are widespread. Groups at heightened risk for vitamin D deficiency include: the homebound elderly; older individuals overall (due to the declining potential for vitamin D production as the skin ages); darker-skinned individuals (melanin in skin protects the skin from UV radiation but increases the exposure time required for photoactivation of pre-vitamin D in the skin); and members of communities that require their constituents to cover up. Obesity also is associated with vitamin D deficiency, and some evidence indicates that adipose tissue is involved in sequestration of the nutrient.


Conditions that predispose a person to vitamin D deficiency include liver disease, which interferes with the 25 hydroxylation of vitamin D; chronic renal failure, which interferes with 1 hydroxylation; and malabsorption syndromes, which are either iatrogenic (e.g., status after bariatric surgery or in users of fat-sequestering medications such as cholestyramine) or the result of biliary tract disease, cystic fibrosis, celiac disease, inflammatory bowel disease, or similar conditions. Certain drugs, including anti-epileptic medications, deplete vitamin D. To complicate matters, research points to vitamin D receptor polymorphisms, which attenuate end-organ response to circulating levels of vitamin D. 


Routine, modest supplementation is not a reliable bulwark against vitamin D deficiency. Researchers were recently surprised to note the high prevalence of vitamin D deficiency in pregnant women—the very group most likely to be shielded from this problem because of high compliance with prenatal-vitamin regimens. Additionally, living in the sunny, warm regions of the country may raise a person's chances of achieving vitamin D sufficiency, but a recent study of Hispanics in Arizona uncovered a high rate of vitamin D inadequacy.


Dietary sources of vitamin D are limited (Table 1). Milk, which is the only dairy product routinely fortified with the nutrient, supplies a mere 100 IU/cup, which represents only a quarter of the minimal requirement for adults. Human breast milk delivers only 25 IU/L on average. Herring, tuna, eel, and mackerel are all good sources of vitamin D, but many people avoid these foods because they do not like the taste. 


Measurement


The two forms of vitamin D most commonly measured by clinical laboratories are 25(OH)D (calcidiol) and 1,25 hydroxyvitamin D (1,25[OH]2D) (calcitriol). Until recently, health-care providers predominantly relied on the latter for vitamin D assessment, but new findings suggest that its utility is limited (except in renal disease, in which 1 hydroxylation is an issue). Not infrequently, 1,25(OH)2D levels are found to be sufficient or even supra-normal while 25(OH)D levels remain suboptimal. 


Because of its greater reliability, a 25(OH)D level is now favored as the accepted method for determining vitamin D nutritional status. The optimal level of serum 25(OH)D is 35-55 ng/mL (90-140 nmol/L), with some medical scientists advocating for the slightly higher value.


Many reference labs have adopted a classification system that stratifies vitamin D levels as follows (to convert conventional [ng/mL] units to SI [nmol/L] units, multiply by 2.5):


0-14.9 ng/mL = Severely deficient 


15.0-31.9 ng/mL = Mildly deficient 


32.0-100.0 ng/mL = Optimal 


>100.0 ng/mL = Toxicity possible 


Findings of elevated bone isoforms of alkaline phosphorous, elevated parathyroid hormone, or urinary N-telopeptide should prompt suspicion of vitamin D deficiency (to be confirmed by serum measurement of 25[OH]D).


Toxicity


The threshold for vitamin D toxicity is currently being re-evaluated, with most experts now agreeing that previous benchmarks have been unduly conservative (Table 2). This change in thinking stems partially from the realization that a single, minimal erythemal dose of sun exposure promotes synthesis of 10,000 IU of vitamin D. Early reports of vitamin D toxicity with doses as low as 3,600 IU/day have been challenged due to methodologic flaws. It has been reported that human toxicity likely begins to occur after chronic daily vitamin D consumption of approximately 40,000 IU/day. 


A theoretical risk of vitamin D toxicity exists when prolonged sunlight exposure is combined with aggressive supplementation, but feedback inhibition occurs with UV-light activation of vitamin D in the dermis, rendering this possibility less likely.


Clinicians must administer vitamin D cautiously in patients with certain medical conditions. For example, individuals with primary hyperparathyroidism are at risk for hypercalcemia, which might be exacerbated by additional vitamin D. (Conversely, in secondary hyperparathyroidism, correction of the underlying vitamin D deficiency helps normalize elevated calcium).


In sarcoidosis and such malignancies as oat-cell cancer and non-Hodgkin's lymphoma, aberrant conversion of 25(OH)D to calcitriol results in hypercalcemia, offering a relative contraindication to vitamin D administration.


The main symptoms associated with vitamin D toxicity result from hypercalcemia. Anorexia, nausea, and vomiting can develop, followed in some cases by renal failure. The diagnosis can be confirmed through measurement of serum 25(OH)D (typically >140 ng/mL) in the presence of elevated serum calcium.


Treatment involves stopping vitamin D intake. If necessary, the clinician can hydrate the patient with IV normal saline and administer corticosteroids or bisphosphonates (which inhibit bone resorption) to reduce blood calcium levels.


Recommendations for supplementation 


The longtime government recommendation for vitamin D intake in adults and older children was set rather arbitrarily at 400 IU/day. This is thought to derive from the historical precedent that a teaspoon of cod liver oil, a traditional source of supplementation, delivers approximately 400 IU of vitamin D.


For infants younger than age 4 years, the Daily Value (developed by the FDA to help consumers compare the nutrient contents of products within the context of a total diet) is just 200 IU, but in 2008 the American Academy of Pediatrics took the lead in advancing the threshold to 400 IU in light of evidence of the safety and benefits of vitamin D.


The Food and Nutrition Board of the Institute of Medicine is currently re-examining Daily Values for vitamin D and calcium and plans to issue revised guidelines this year. Most nutrition scientists are expecting upward revisions.


Controversy now rages over what constitutes "deficiency" versus "sufficiency." Alternatively, optimal therapeutic levels may be appropriate for various health conditions. Guidelines for prevention of rickets, for example, may be inadequate for prevention or reversal of osteoporosis. Some argue that nutritional support for such autoimmune diseases as MS might call for pharmacologic doses of vitamin D. In a recent study, 16% of 25 MS patients who were given an average of 14,000 IU/day of vitamin D for one year suffered relapses. In contrast, close to 40% of 24 MS patients who took an average of 1,000 IU/day—the stepped-up supplementation belatedly acknowledged to be necessary by many MS specialists—relapsed. 


A clue to the amount of vitamin D needed to optimize serum levels of 25(OH)D in seniors comes from a study of men and women older than age 64 years. The intakes required to maintain serum 25(OH)D concentrations of >15 ng/mL, >20 ng/mL, and >32 ng/mL in 97.5% of the sample were 688 IU/day, 988 IU/day, and 1,548 IU/day, respectively. Note that these levels of supplementation are well above the current Daily Values yet do not even attain what some consider being optimal thresholds for vitamin D.


Vitamin D supplements are available in two forms, D2 (ergocalciferol) and D3 (cholecalciferol). High-dose prescription vitamin D 50,000 IU (Drisdol, Calderol, Calciferol), commonly prescribed for rapid remediation of vitamin D deficiency, is vitamin D2. Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, and vitamin D3 is manufactured by the irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol.


Some argue that vitamin D3 could be more than three times as effective as vitamin D2 in raising serum 25(OH)D concentrations and maintaining those levels for a longer time, and that its metabolites have superior affinity for vitamin D-binding proteins in plasma. Further research is required to compare the clinical efficacy of the two forms.


Most supplements available from health-food stores are vitamin D3. Commonly available doses range from 400 to 5,000 IU, variously delivered in tablet, capsule, and liquid forms. Parenteral forms of vitamin D are also available but are seldom needed to reach target levels outside the settings of chronic renal failure and dialysis.


Suggested treatment of vitamin D deficiency 


Vitamin D deficiency (25[OH]D level <20 ng/mL): Vitamin D 50,000 IU once a week for three months; repeat 25(OH)D level.


If >20 ng/mL but <30ng/mL, change the vitamin D supplement to 5,000 IU/day until levels of 40-50 ng/mL are attained.


If still <20 ng/mL, advance vitamin D to 50,000 IU twice a week, or consider giving it more frequently. (In certain clinical situations, especially those involving malabsorption syndromes, up to 50,000 IU three times a week may be needed.) 


Vitamin D insufficiency (25[OH]D level 20-30 ng/mL): Administer vitamin D 5,000 IU daily for three months, repeat 25(OH)D level.


If <30 ng/mL, advance vitamin D to 50,000 IU once a week or more frequently if needed.


Once 25(OH)D levels are restored to >40 ng/mL, administer maintenance supplementation of 2,000-5,000 IU/day. 


For reasons that are not yet completely clear, considerable variability in response to vitamin D supplementation exists among patients. Clinicians should monitor a patient's 25(OH)D levels frequently to assess reaction to therapy until stable levels are achieved, subject to seasonal variations and changes in health status.


- Ronald Hoffman, MD

Dr. Hoffman is founder and Medical Director of the Hoffman Center in New York City. The author has no relationships to disclose relating to the content of this article.


Read on


  • Arabi A, Zahed L, Mahfoud Z, et al. Vitamin D receptor gene polymorphisms modulate the skeletal response to vitamin D supplementation in healthy girls. Bone. 2009;45:1091-1097.

  • Lips P, Bouillon R, van Schoor NM, et al. Reducing fracture risk with calcium and vitamin D. Clin Endocrinol (Oxf). 2009; September 10 (published online ahead of print).

  • Stechschulte SA, Kirsner RS, Federman DG. Vitamin D: bone and beyond, rationale and recommendations for supplementation. Am J Med. 2009;122:793-802. 

  • Janssens W, Lehouck A, Carremans C, et al. Vitamin D beyond bones in chronic obstructive pulmonary disease: time to act. Am J Respir Crit Care Med. 2009;179:630-636.

  • Holick MF. The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action. Mol Aspects Med. 2008;29:361-368.

  • Rovner AJ, O'Brien KO. Hypovitaminosis D among healthy children in the United States: a review of the current evidence. Arch Pediatr Adolesc Med. 2008;162:513-519. 
  • Cannell JJ, Hollis BW. Use of vitamin D in clinical practice. Altern Med Rev. 2008;1:6-20.

  • Autier P, Gandini S. Vitamin D supplementation and total mortality: 
a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;10:167:1730-1737. 
  • Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis. 2007;66:1137-1142.

  • Holick MF. Medical Progress: vitamin D deficiency. N Engl J Med. 2007;357:266-281. 
  • Niino M, Fukazawa T, Kikuchi S, Sasaki H. Therapeutic potential of vitamin D for multiple sclerosis. Curr Med Chem. 2008;15:499-505.

  • Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: global perspective. Ann Epidemiol. 2009;19:468-483.

  • de Boer IH, Kestenbaum B, Shoben AB, et al. 25-hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification. J Am Soc Nephrol. 2009;20:1805-1812. 

  • Cannell JJ, Zasloff M, Garland CF, et al. On the epidemiology of influenza. Virol J. 2008;5:29.
  • Laaksi I, Ruohola J-P, Tuohimaa P, et al. An association of serum vitamin D concentrations <40 nmol/L with acute respiratory tract infection in young Finnish men. Am J Clin Nutr. 2007;86:714-717. 
  • Szulc P, Claustrat B, Delmas PD. Serum concentrations of 17beta-E2 and 25-hydroxycholecalciferol (25[OH]D) in relation to all-cause mortality in older men—the MINOS study. Clin Endocrinol (Oxf). 2009;71:594-602.

  • Cashman, KD, Wallace J MW, Horigan G, et al. Estimation of the dietary requirement for vitamin D in free-living adults >64 y of age. Am J Clin Nutr. 2009;89:1366-1374.


All electronic documents accessed February 10, 2010.


Published March 1, 2010. The Clinical Advisor. What Lies Behind the Vitamin D Revolution. By Ronald Hoffman, MD.

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Vitamin D Deficiency and Tooth Decay

Posted By Administration, Tuesday, April 8, 2008
Updated: Friday, April 18, 2014

By Gina Nick, NMD

Here is yet another reason to consider getting tested for, and supplementing with Vitamin D3…I am re-printing a report released by the Orthomolecular Medical Society that discusses the connection between how much vitamin D3 you have in your body, and tooth decay, Alzheimer’s disease, respiratory infections, cancer, heart disease, diabetes and other ailments.  This is one of many essential nutrients that the body needs to function properly.   And it happens to be an inexpensive therapy that helps to prevent and  treat some of the most expensive diseases of our time like heart disease, cancer and diabetes. Vitamin D3 works synergistically with vitamin K and calcium to increase bone mineral density in women with osteoporosis. Some whole food sources include organic egg yolks, raw, organic butter (preferably from goat rather then cow), and cod liver oil.

-Dr. G

Vitamin Deficiency Underlies Tooth Decay
Malnutrition Causes Much More than Dental Disease

Cavities and gum diseases are not often regarded as serious diseases, yet they are epidemic throughout our society, from the youngest of children to the oldest of senior citizens. Research more than suggests that the same good nutrition that prevents cavities and gum diseases may also prevent other illnesses.

Dental caries and gum pathology are frequently associated with serious chronic health problems. Multiple independent studies published after 1990 document this. Cavities are associated with poor mental health [1-4]. Elderly individuals with dementia or Alzheimer’s disease had an average of 7.8 teeth with fillings vs. an average of only 2.7 fillings for elderly individuals without dementia [1]. It is likely that the toxic heavy metal mercury, which makes up half of every amalgam filling, is a contributing factor.

A recent authoritative review showed a clear association between cavities and heart diseases [5]. More importantly, this same study showed that people with poor oral health, on average, lead shorter lives. The association between cavities and diabetes is also a subject of active, ongoing research [6-8]. Connections between heart disease, diabetes, and dental decay have been suspected for decades. Many of the scientists who called attention to this have proposed that diets high in sugar and refined carbohydrates were the common cause of these diseases [9-15].

Dental diseases, mental diseases, heart disease, infectious respiratory diseases, and heart disease are all at least partially caused by common failures in metabolism. Such failures are inevitable when there is a deficiency of essential nutrients, particularly vitamins D, C, and niacin.

There is especially strong evidence for a relationship between vitamin D deficiency and cavities. Dozens of studies were conducted in the 1930’s and 1940’s [16-27]. More than 90% of the studies concluded that supplementing children with vitamin D prevents cavities. Particularly impressive was a study published in 1941 demonstrated the preventative affect of “massive” doses of vitamin D [28]. And yet no subsequent studies in the scientific literature suggested a need to follow up and repeat this work.

Vitamin D deficiency is linked to respiratory infections, cancer, heart disease, diabetes and other ailments [29]. The evidence for vitamin C was reviewed by Linus Pauling [15], and the evidence for niacin was reviewed by Abram Hoffer [30].

Obtaining vitamins in sufficient doses to help prevent dental disease is safe and easily accomplished. Between 5,000 and 15,000 IU of vitamin D may be obtained from modest exposure to sunshine in the middle of the day. Recommending that people regularly use the capacity of their skin to make vitamin D is common sense. Certainly 1,000 to 2,000 IU per day of vitamin D in supplemental form is safe. 2,000 milligrams per day of vitamin C, and hundreds of milligrams per day of niacin, help prevent tooth and mouth troubles. Sick individuals, and those who are prone to cavities, will typically benefit by starting with higher doses of vitamin D, vitamin C, and niacin under the supervision of an orthomolecular physician.

We believe that individuals taking these nutrients, along with good dental care, will have dramatically fewer cavities and gum operations than individuals just getting good dental care. This idea is easily tested, and the time has come to do so.

References:

[1] B Ellefsen; P Holm-Pedersen; D E Morse; M. Schroll; B. Andersen; G. Waldemar. Caries Prevalence in Older Persons with and without Dementia. Journal of the American Geriatrics Society, Volume 56, Number 1, January 2008, 59-67(9).
[2] J M Chalmers, K D Carter, A J Spencer. Caries incidence and increments in community-living older adults with and without dementia. Australian Research Center for Population Oral Health, Dental School, The University of Adelaide, Adelaide 5005, Australia. Gerodontology Volume 19 Issue 2, 80 - 94.
[3] Friedlander, A.H.; Mahler, M.E. Major depressive disorder psychopathology, medical management and dental implications. Graduate Medical Education, Veterans Affairs Greater Los Angeles Healthcare System (14), Los Angeles, CA, USA. Journal of the American Dental Association (2001), 132(5), 629-638.
[4] Stewart, R.; et. al. Oral Health and Cognitive Function in the Third National Health and Nutrition Examination Survey (NHANES III), Psychosomatic Medicine 70:936-941 (2008).
[5] Meurman, J.H.; Sanz, M.;Janket, S. Oral infection and vascular disease. Institute of Dentistry, University of Helsinki, Finland. Vascular Disease Prevention (2007), 4(4), 260-267.
[6] Touger-Decker R, Sirois D A, Vernillo A T. Diabetes mellitus: Nutrition and oral health relationships. Department of Primary Care, School of Health-Related Professions, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA. Editor(s): Touger-Decker, Riva. Nutrition and Oral Medicine (2005), 185-204.
[7] Diaz-Romero, R.; Casanova-Roman, R.; Beltran-Zuniga, M; Belmont-Padilla, J.; Mendez, J.; Avila-Rosas, H.. Oral Infections and Glycemic Control in Pregnant Type 2 Diabetics. Instituto Nacional de Perinatologia, Mexico City, Mex. Archives of Medical Research (2005), 36(1), 42-48.
[8] Twetman, S.; Johansson, I.; Birkhed, D.; Nederfors, T. Caries incidence in young type 1 diabetes mellitus patients in relation to metabolic control and caries-associated risk factors. Caries Research (2002), 36(1), 31-35.
[9] Bommer, S. Diseases of civilization and nutrition. Ernaehrungsforschung (1963), 7 598-612.
[10] Miler-Sosnkowska, M. Role of dietary carbohydrates in relation to their metabolism. Inst. Zywienia Czlowieka, Akad. Roln., Warsaw, Pol. Postepy Higieny i Medycyny Doswiadczalnej (1975), 29(4), 537-55.
[11] Cremer, H.D.; Eyer, H. Carbohydrates. Inst. Ernaehrungswiss. I, Univ. Giessen, Giessen, Fed. Rep. Ger. Ernaehrungs-Umschau (1975), 22(10), 291-3.
[12] Newberne, P.M.. Nutrition: summary of evidence. Sweeteners: Issues, uncertainties. Acad. Forum, 4th (1975), 76-85, 252-3.
[13] Heraud, G. Sucrose and nutritional pathology. Sucrerie Francaise (1979), 120(24), 21-6.
[14] Nuttall, F.Q.; Gannon, M.C.. Sucrose and disease. Diabetes Care (1981), 4(2), 305-10.
[15] Pauling, L. “How to Live Longer and Feel Better.” W.H. Freeman and Company, 1986. Revised 2006, Oregon State University Press. http://oregonstate.edu/dept/press/g-h/LiveLonger.html
[16] Tisdall, F.F. The effect of nutrition on the primary teeth. Child Development (1937) 8(1), 102-4.
[17] McBeath, E.C. Nutrition and diet in relation to preventive dentistry. NY J. Dentistry (1938) 8; 17-21.
[17] McBeath, E.C.; Zucker, T.F. Role of vitamin D in the control of dental caries in children. Journal of Nutrition (1938) 15; 547-64.
[19] East, B. R. Nutrition and dental caries. American Journal of Public Health 1938. 28; 72-6.
[20] Mellanby, M. The role of nutrition as a factor in resistance to dental caries. British Dental Journal (1937), 62; 241-52.
[21] His Majesty’s Stationery Office, London. The influence of diet on caries in children’s teeth. Report of the Committee for the Investigation of Dental Disease (1936).
[22] McBeath, F.C. Vitamin D studies, 1933-1934. American Journal of Public Health (1934), 24 1028-30.
[23] Anderson, P. G.; Williams, C. H. M.; Halderson, H.; Summerfeldt, C.; Agnew, R. Influence of vitamin D in the prevention of dental caries. Journal of the American Dental Association (1934) 21; 1349-66.
[24] Day, C. D.; Sedwick, H. J. Fat-soluble vitamins and dental caries in children. Journal of Nutrition (1934) 8; 309-28.
[25] Agnew, M. C.; Agnew, R. G.; Tisdall, F. F. The production and prevention of dental caries. Journal of the American Dental Association, JADA (1933) 20; 193-212.
[26] Bennett, N. G.; et al. The influence of diet on caries in children’s teeth. Special Report Series - Medical Research Council, UK (1931) No. 159, 19.
[27] Mellanby, M.; Pattison, C. L. The influence of a cereal-free diet rich in vitamin D and calcium on dental caries in children. British Medical Journal (1932) I 507-10.
[28] Brodsky, R. H.; Schick, B.; Vollmer, H.. Prevention of dental caries by massive doses of vitamin D. American Journal of Diseases of Children (1941) 62; 1183-7.
[29] http://www.vitamindcouncil.org/
[30] Hoffer A, Saul AW. Orthomolecular Medicine for Everyone. Laguna Beach, California, Basic Health Pub, 2008. http://www.doctoryourself.com/orthomolecular.html

Tags:  dentistry  vitamin D 

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Vitamin D Therapy Halts Cancer Growth and Supports Immune Function

Posted By Administration, Sunday, January 27, 2008
Updated: Friday, April 18, 2014

Gina Nick, PhD, NMD

An excellent summary of the research supporting the use of Vitamin D3 therapyas a treatment for specific cancers and for compromised immune function was recently released by the Orthomolecular Medicine Society. I am including the report in full below.  Take note of the historical use of this simple, inexpensive nutrient and of the recent research also supporting its use.  Sometimes the simple treatments are the most profound. I test the blood for Vitamin D3 levels and almost always find low levels associated with cancer and chronic fatigue syndrome.  In general I recommend 3,000 IU of Vitamin D3 per day to support optimal immune function. Exposure to sunshine every day is one of the best ways to keep your vitamin D levels in a healthyrange however, practicing in Laguna Beach, CAwhere there are more sunny days than not, I still find that the majority of my patients are deficient in this nutrient/hormone, even those that are outside for at least 30 minutes per day.

In health,

-Dr. G

Vitamin D Stops Cancer; Cuts Risk In Half American Cancer Society Drags its Feet

(OMNS, October 2, 2008) A new study of 3,299 persons has shown that those with higher levels of vitamin D cut their risk of dying from cancer in half. (1) Another recent study shows that ample intake of vitamin D, about 2,000 IU per day, can cut breast cancer incidence by half. (2) Still more research found that inadequate Vitamin D is “associated with high incidence rates of colorectal cancer” and specifically urges that “prompt public health action is needed to increase intake of Vitamin D-3 to 1000 IU/day.” (3)

Vitamin D’s anticancer properties are so evident, and so important, that the Canadian Cancer Society now recommends supplementation with 1,000 IU of Vitamin D per day for all adults in winter, and year-round for persons at risk. (4)

The American Cancer Society, however, is dragging its feet, still maintaining that “More research is needed to define the best levels of intake and blood levels of vitamin D for cancer risk reduction.” (5)

What is taking them so long?

Researchers in 2006 noted that “The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects.” (6)

If you search the US National Institutes of Health’s Medline online database for “cancer vitamin D,” you will find over five thousand papers. . . some dating back nearly 60 years.

It’s true: physician reports on vitamin D stopping cancer have been ignored for decades. In 1951, T. Desmonts reported that vitamin D treatment was effective against Hodgkin’s disease (a cancer of the lymphatic system). (7) That same year, 57 years ago, massive doses of vitamin D were also observed to improve epithelioma. ( 8) In 1955, skin cancer was again reported as cured with vitamin D treatment. (9) In 1963, there was a promising investigation done on vitamin D and breast cancer. (10) Then, in 1964, vitamin D was found to be effective against lymph nodal reticulosarcoma, a non-Hodgkin’s lymphatic cancer. (11)

The American Cancer Society has been obsessed with finding a drug cure for cancer. Pharmaceutical researchers are not looking for a vitamin cure. And when one is presented, as independent investigators and physicians have continuously been doing since 1951, it is ignored.

No longer. Michael Holick, MD, Boston University Professor of Medicine, has come right out and said it: “We can reduce cancer risk by 30 to 50% by increasing vitamin D. We gave mice colon cancer, and followed them for 20 days. Tumor growth was markedly reduced simply by having vitamin D in the diet. There was a 40% reduction in tumor size. And, casual sun exposure actually decreases your risk of melanoma. Everyone needs 1,000 IU of vitamin D3 each day.” (12)

What about safety? Yes, it is possible to get too much vitamin D, but it is not easy. “One man took one million IU of vitamin D per day, orally, for six months, “says Dr Holick. “Of course, he had the symptoms of severe vitamin D intoxication. His treatment was hydration (lots of water), and no more vitamin D or sunshine for a while. He’s perfectly happy and healthy. This was published in the New England Journal of Medicine.(13) I have no experience of anyone dying from vitamin exposure. In thirty years, I’ve never seen it.”

There are, of course, some reasonable cautions with its use. Persons with hyperparathyroidism, lymphoma, lupus erythematosus, tuberculosis, sarcoidosis, kidney disease, or those taking digitalis, calcium channel-blockers, or thiazide diuretics, should have physician supervision before and while taking extra vitamin D. And when employing large doses of vitamin D, periodic testing is advisable.

But 1,000 IU per day of vitamin D is simple and safe. Some authorities recommend much more. (14, 15) The American Cancer Society recommends less.

What a shame.

References:

(1) Pilz S, Dobnig H, Winklhofer-Roob B et al. Low serum levels of 25-hydroxyvitamin D predict fatal cancer in patients referred to coronary angiography. Cancer Epidemiol Biomarkers Prev. 2008 May;17(5):1228-33. Epub 2008 May 7.

(2) Garland CF, Gorham ED, Mohr SB et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol, 2007. Mar;103(3-5):708-11.

(3) Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, Newmark HL, Giovannucci E, Wei M, Holick MF. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):179-94.

(4) http://www.cancer.ca/Canada-wide/About%20us/Media%20centre/CW-Media%20releases/CW-2007/Canadian%20Cancer%20Society%20Announces%20Vitamin%20D%20Recommendation.aspx?sc_lang=en

(5) http://www.cancer.org/docroot/PED/content/PED_3_2X_Diet_and_Activity_Factors_That_Affect_Risks.aspAccessed Aug 29, 2008.

(6) Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. The role of vitamin D in cancer prevention. Am J Public Health. 2006 Feb;96(2):252-61.

(7) Desmonts T, Duclos M, Dalmau. [Favorable effect of vitamin D on the evolution of a case of Hodgkin's disease.] Sang. 1951;22(1):74-5. And: DESMONTS T. [Favorable action of vitamin D in leukemic erythroderma and Hodgkin's disease.] Pathol Gen. 1951 Mar;51(326):161-4. Also: VACCARI R. [Vitamin D2 and experimental carcinogenesis.] Boll Soc Ital Biol Sper. 1952 Aug-Oct;28(8-10):1567-9.

( 8) Sainz de Aja Ea. [Case of an epithelioma in a patient treated with massive doses of vitamin D.] Actas Dermosifiliogr. 1951 Nov;43(2):169-70.

(9) Linser P. [Spontaneous cure of skin carcinoma by vitamin D treatment.] Dermatol Wochenschr. 1955;132(40):1072-3. German.

(10) Gordan GS, Schachter D. Vitamin D activity of normal and neoplastic human breast tissue. Proc Soc Exp Biol Med. 1963 Jul;113:760-1.

(11) Desmonts T, Blin J. [Action of Vitamin D3 on the course of a lymph nodal reticulosarcoma.] Rev Pathol Gen Physiol Clin. 1964 Mar;64:137. French.

(12) Andrew W. Saul Interviews Michael F. Holick, MD, PhD. http://www.doctoryourself.com/holick.html

(13) Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associated with an over-the-counter supplement. N Engl J Med. 2001 Jul 5;345(1):66-7.

(14) Vitamin D Boosts Health, Cuts Cancer Risk in Half. Orthomolecular Medicine News Service, October 3, 2007. http://orthomolecular.org/resources/omns/v03n06.shtml

(15) Doctors Say, Raise the RDAs Now. Orthomolecular Medicine News Service, October 30, 2007. http://orthomolecular.org/resources/omns/v03n10.shtml

For more information:

Saul AW. Vitamin D: Deficiency, diversity and dosage. J Orthomolecular Med, 2003. Vol 18, No 3 and 4, p 194-204. http://www.doctoryourself.com/dvitamin.htm

Online access to free archive of nutritionalmedicine journal papers: http://orthomolecular.org/library/jom/

A free, non-commercial vitamin D newsletter is available from John Cannell, M.D., and the Vitamin D Council: http://www.vitamindcouncil.org

Sunlight, Nutrition And Health Research Center: http://www.sunarc.org

 

Nutritional Medicine is Orthomolecular Medicine

Orthomolecular medicine uses safe, effective nutritional therapy to fight illness. For more information: http://www.orthomolecular.org

The peer-reviewed OrthomolecularMedicine News Service is a non-profit and non-commercial informational resource.

Editorial Review Board:

Damien Downing, M.D.
Harold D. Foster, Ph.D.
Steve Hickey, Ph.D.
Abram Hoffer, M.D., Ph.D.
James A. Jackson, PhD
Bo H. Jonsson, MD, Ph.D
Thomas Levy, M.D., J.D.
Erik Paterson, M.D.
Gert E. Shuitemaker, Ph.D.

Andrew W. Saul, Ph.D., Editor and contact person. Email:omns@orthomolecular.org

© Dr Gina Nic

 

Tags:  cancer  immune function  vitamin D 

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