Tom D. Thacher, MD, and Bart L. Clarke, MD
Vitamin D deficiency, which classically manifests as bone disease (either rickets or osteomalacia), is characterized by impaired bone mineralization. More recently, the term vitamin D insufficiency has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with other disease outcomes. Reliance on a single cutoff value to define vitamin D deficiency or insufficiency is problematic because of the wide individual variability of the functional effects of vitamin D and interaction with calcium intakes. In adults, vitamin D supplementation reduces the risk of fractures and falls. The evidence for other purported beneficial effects of vitamin D is primarily based on observational studies.
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. Conclusive demonstration of these benefits awaits the outcome of controlled clinical trials.
Mayo Clin Proc. 2011;86(1):50-60
BMD = bone mineral density; CI = confidence interval; 1,25(OH)2D = 1,25-dihydroxyvitamin D; HR = hazard ratio; HRT = hormone replacement therapy; NHANES = National Health and Nutrition Examination Survey; 25(OH)D = 25-hydroxyvitamin D; OR = odds ratio; PTH = parathyroid hormone; RCT = randomized controlled trial; RR = relative risk; WHI = Women's Health Initiative
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.1
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 called ergocalciferol 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. 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 D3,2,3 but with regular daily intake they can be considered bioequivalent.4,5 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.6 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.7
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 subopti-mal 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.
As discussed in detail in recent reviews,8,9 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.10 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.10 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.11 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.12
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.13-15 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.5 In situations of very low calcium intakes, some evidence suggests that the demand for 1,25(OH)2D may be greater.14,16,17 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, Heaney18 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 wom-en.19 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.5,20 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.5 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.21
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.22 Outdoor sun exposure and time spent outdoors are better predictors of serum 25(OH)D values than dietary vitamin D intake.23
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