Clinically, the level of 25-OH vitamin D is assessed because it is the major form of the vitamin and is readily converted to the active form, 1,25 [OH]2 vitamin D (also called vitamin D3 or calcitriol) by CYP27B1, primarily in the kidney. A quick scan of PubMed and internet health sites makes clear that there are wide-ranging opinions about how much vitamin D is enough to maintain growth and skeletal health and the role of vitamin D in a broad spectrum of diseases from the common cold and flu to cancer.
Mechanistic research on actions of vitamin D in simple cell systems and rodents provides ample evidence of roles for vitamin D in gene regulation; thus, we know that vitamin D can modulate proliferation, differentiation, and apoptosis of many cell types (e.g., Anet al., 2010; Eganet al., 2010), and have effects on immune function, among others. The precise roles of vitamin D in human health, especially those effects not associated with calcium metabolism, and concentration-response curves of the effects in humans are, however, harder to define, especially since well-controlled, randomized in vivo studies in humans are difficult and expensive.
The non-calcemic effects of vitamin D may occur along different concentration-dependence curves and require a re-evaluation of what defines adequate daily intake (Bikle, 2010). At present, however, much of what we think about vitamin D requirements and effects in humans is based on epidemiologic data.
How much vitamin D does a human need every day? The answer is not clear, although most current suggestions agree within a factor of ~3-4. As with many dietary components, and especially for vitamin D, which the human body can make upon exposure to sunlight, serum levels vary widely, probably reflecting genetic background, diet, latitude, time spent out-of-doors, body size, developmental stage, and state of health, as well as plasma levels of vitamin D binding protein.
The actions of vitamin D could also vary with the expression of various isoforms of the vitamin D receptor and of the activating and inactivating CYPs, and with the presence of various nuclear co-activators. Because rigorous and well-controlled dietary studies are often lacking in humans, recommended daily intakes for vitamins are sometimes as much matters of opinion as of fact, or are extrapolated from studies in model systems.
In practice, most urban dwellers do not get much exposure to sunlight and diet generally does not supply sufficient amounts of vitamin D: a serving of fish may contain 200-500 IU; a cup of a fortified dairy product (cow’s milk, yogurt, soy milk) supplies 100 IU. Thus, for many of us, supplementation is required.
The range of scientific opinion favoring increased vitamin D supplementation is well represented by two papers from a 2009 symposium-in-print: Garland et al. (Garland et al., 2009) used epidemiologic data to argue for increasing the average serum levels of vitamin D to 40-60 ng/ml (100-150 nM), a level that they suggest could be achieved by an intake of 2000 IU/day (50 µg/day) and which might decrease the rate of a number of cancers. Vieth (Vieth, 2009) argues that any benefit of vitamin D needs to be balanced by consideration of the toxicity of vitamin D and the related hypercalcemia, that 2000-4000 IU/day is generally satisfactory, and that toxicity should not be expected below 10,000 IU/day.
A prominent proponent of increasing vitamin D intake is Dr. Michael Holick, an endocrinologist at Boston University Medical Center. Holick summarizes his views and research in a recent review (Holick, 2011) and a book (Holick, 2010). To quote from his review:
“Vitamin D deficiency and insufficiency have been defined as a 25-hydroxyvitamin D <20 ng/ml and 21-29 ng/ml respectively. For every 100 IU of vitamin D ingested the blood level of 25-hydroxyvitamin D, the measure vitamin D status, increases by 1 ng/ml. It is estimated that children need at least 400-1000 IU of vitamin D a day while teenagers and adults need at least 2000 IU of vitamin D a day to satisfy their body’s vitamin D requirement.” (Holick, 2011)
Endocrinology Clinics of North America recently published a compendium of articles by researchers who work on aspects of vitamin D metabolism and action (Multiple Authors, 2010). In general, these authors recommend maintenance of plasma levels of 25-OH-D ≥30 ng/mL, requiring a daily intake of ≥1000 IU for most children and adults, and twice that for pregnant and lactating women. Others argue that in special cases, such as that of pregnant women, up to 6000 IU/day are needed (Hollis, 2007).
The recommendations of the Institute of Medicine fall short of the values advanced by these proponents, but do advise higher daily intakes than previously indicated for both calcium and vitamin D, as discussed below. Thus, the recommended daily allowance of vitamin D will continue to be controversial; happily, proponents of greater increases in vitamin D intake generally recommend an amount at or below what the IOM considers the upper limit of 4000 IU/day.
The Linus Pauling Institute at Oregon State University maintains a well-informed website on vitamin D (Higdon and Drake, 2010).
A report issued on 30 November 2010 by the Institute of Medicine (IOM) of the National Academy of Sciences provides new guidelines for daily vitamin D and calcium supplementation (Institute of Medicine, 2011). These recommendations, referred to as Dietary Reference Intakes (DRIs) are the reference values used for nutrition standards for school meals, food labeling, and are widely employed for assessing vitamin D and calcium sufficiency. These values are more commonly known as the Recommended Dietary Allowance (RDA). The recommendations, new and previous, are shown in Table1.
The IOM evaluation focused on three central issues:
- the health outcomes influenced by vitamin D and calcium;
- the vitamin D and calcium requirements to achieve the desirable health outcomes;
- adverse actions arising from over medication.
Background for IOM Study
Increasing medical and public interest over the last 10 years focused on claims of enhanced benefits of vitamin D and calcium on human health. It is also commonly believed that there is negligible risk associated with taking vitamin D and calcium supplements, which are widely available in North America. Scientific research suggested relationships between vitamin D intake and cancer prevention, increased immunity; and possible roles in preventing diabetes or preeclampsia.
These findings come on a background of clinical findings that many adults and children may be deficient in vitamin D. Based on this array of issues and several preceding comprehensive reviews (Cranney et al., 2007) [summarized in (Cranney et al., 2008)] and (Chung et al., 2009), the IOM was approached by the U.S. and Canadian governments to conduct a review of data pertaining to calcium and vitamin D requirements and to identify DRIs based on current scientific evidence about the roles of calcium and vitamin D in human health. Health outcomes considered bone and skeletal health, physical performance and falls, cancer and site-specific neoplasms (breast, colorectal, prostate), cardiovascular diseases and hypertension, type 2 diabetes and metabolic syndrome (obesity), falls, immune disorders and infectious diseases, neuropsychological functioning (autism, cognition, and depression), and disorders of pregnancy (preeclampsia).
Summary of IOM Findings
Using an evidence-based approach, the review committee found compelling support favoring a role for calcium and vitamin D in sustaining skeletal health. This, along with analysis of parameters regulating mineral ion homeostasis were used to generate the new DRIs. Evidence for a role of supplemental vitamin D or calcium on non-skeletal outcomes was inconclusive.
The IOM determined that the extent of vitamin D deficiency among the North American population has been overestimated because of inflated cut-points for serum 25(OH) vitamin D. The IOM recommendations now suggest that persons are at risk of deficiency at serum 25(OH) vitamin D levels below 30 nmol/L (12 ng/mL). Some, but not all, persons are potentially at risk for inadequacy at serum 25(OH) vitamin D levels between 30 and 50 nmol/L (12 and 20 ng/mL). Practically all persons are sufficient at serum 25(OH) vitamin D levels of at least 50 nmol/L (20 ng/mL). Serum 25 (OH) vitamin D concentrations above 75 nmol/L (30 ng/mL) are not consistently associated with increased benefit. Serum 25-OH D levels above 125 nmol/L (50 ng/mL) are a cause for concern.
Potential toxicities of vitamin D and calcium were also assessed and revised Upper Limits (UL) for daily supplementation were issued. The UL is the level above which the risk for adverse actions begins to increase. The UL is the highest average daily nutrient intake level likely to pose no risk of adverse health effects for nearly all people in a particular group. The revised ULs are based on increased fortification of foods with nutrients and the use of larger doses of dietary supplements. In general, the risk of adverse effects for vitamin D begins when intake surpasses 4,000 IUs per day. The risk of harm for calcium begins when intake surpasses 2,000 milligrams per day. Side effects of excess vitamin D or calcium most immediately include hypercalcemia and hypercalciuria.
Serum calcium levels are tightly regulated at 2.2-2.6 mmol/L (9-10.5 mg/dL) for total calcium and 1.1-1.4 mmol/L (4.5-5.6 mg/dL) for ionized calcium. When serum calcium falls, parathyroid hormone (PTH) secretion increases. PTH exerts direct effects on the kidney to retain calcium and on bone, where it mobilizes calcium. PTH also induces the expression of renal 1α vitamin D hydroxylase (CYP1α), which converts 25(OH) vitamin D to its active form, 1,25[OH]2 vitamin D (calcitriol). Vitamin D, in turn, stimulates intestinal calcium absorption.
The major therapeutic uses of vitamin D include treatment of nutritional or metabolic rickets; osteomalacia, particularly in the setting of chronic renal failure; hypoparathyroidism; and osteoporosis. Vitamin D supplementation may help prevent fractures, but the relationship between blood vitamin D concentrations and fracture risk is unclear (Cauley et al., 2008). The IOM investigation failed to find evidence indicating a significant reduction in risk of falls that was related to vitamin D intake or blood levels (Institute of Medicine, 2011). Calcium is used in the treatment of calcium deficiency states and as a dietary supplement. The role of supplemental calcium in supporting skeletal integrity is controversial.
Gender, age, diet, and health impact the requirements for calcium and Vitamin D. Milk, yogurt, cheese, and foods and juices fortified with calcium and vitamin D remain the best dietary sources of calcium and vitamin D. If these do not provide the desired RDA, supplements can be used to supply the balance of recommended daily amounts. A one-cup serving of most dairy products contains 200-300 mg of calcium.
By: Peter A. Friedman; Laurence L. Brunton
AccessMedicine from McGraw-Hill © 2011 The McGraw-Hill Companies
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