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Active level of vitamin D are not indicated by standard blood tests - Sept 2012

Dose Response to Vitamin D Supplementation in Postmenopausal Women

TO THE EDITOR: I read the recent article by Gallagher and colleagues (1) with interest. Although it correctly stated that there was a relationship between the scrum 25-hydroxyviramin D (25-[OH]D) intermediate metabolite and the oral dose, there are some other important points to consider. It is important to note that, contrary to popular opinion, the level of circulating 25-(OH)D should not be considered an appropriate indicator of true vitamin D sufficiency or insufficiency. Because the total body load of any of the vitamin D metabolites has yet to be quantitatively assessed, there is no way of knowing whether there is a deficiency; what relationship, if any, exists between blood levels and total body storage; or what the relationship between active and inactive metabolites might be. These are key points that need to be addressed.

The popular, and probably wrong, interpretation of low serum 25-(OH)D level is that it reflects a vitamin D deficiency. Because there is no way to measure actual total body stores of serum 25-(OH)D or 1,25-dihydroxyvitamin D (l,25-|OH]2D), this is only an assumption. For all practical purposes, 25-(OH)D is inactive, and measurements of this metabolite are of questionable physiologic significance. The extrapolations of indirect data on which some of the basic assumptions have been made are, at best, supposition and cannot be considered proof of what clinical decisions should be made. In hyperphosphatemic tumoral calcinosis, for example, serum 25-(OH)D levels are very low, serum l,25-(OH)2D levels are very high, and there is markedly enhanced calcium absorption.

Serum 25-(OH)D is an intermediate metabolite that is the result of 25-hydroxylation of calciferol in the liver. It is no more an index of total body vitamin D status, or even of 25-(OH)D status, than low serum sodium levels arc of total bodv sodium stores in edema or low serum potassium levels are of intracellular potassium stores until there is profound depletion. Total stores of vitamin D can be high because it is a fat-soluble vitamin, and serum level can be low if the 25-hvdroxvlase is relatively inactive. Stores can be low and the circulating 25-(OH)D level high if the 25-hydroxyIase has been stimulated. This is but one set of examples. There are, of course, several other scenarios, such as the previously mentioned tumoral calcinosis, in which there is a less-than-acceptable correlation.

Only some suggestive evidence has been found for noncalcium activity for 25-(OH)D, so it must still be considered physiologically inactive for all practical purposes. Another key point to remember is that despite the strength of a statistical correlation, it does not infer causality. These points suggest that a critical, and even skeptical, approach must be taken to the study presented before any clinical actions are taken based on the data. These views are mv own and not necessarily of any organization with which I am affiliated.

Arthur B. Chausmer, MD, PhD
Johns Hopkins University School of Medicine
Baltimore, MD 21224

Potential Conflicts of Interest; None disclosed.

384 © 2012 American College of Physicians
I. Gallagher JC Sai A, Tempi in T 2nd, Smith L.
Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med. 2012; 156:425-37. [PMID: 22431675]


We disagree with Dr. Chausmer's suggestion that measuring serum 25-(OH)D levels has no value. Serum 25-(OH)D is a valid indicator of total bodv vitamin D level because there is no other biomarker, and it is the substrate for l,25-(OH)2D, the main regulatory hormone in calcium and vitamin D metabolism. Whether 25-(OH)D has an independent physiologic action on the vitamin D receptor is unknown because l,25-(OH)2D is always present. Because 25-(OH)D circulates in blood at a concentration 1000 times higher than l,25-(OH)2D, it could play a role in nonphysiologic situations (for example, renal failure).

Serum l,25-(OH)2D levels usually do not decrease unless there is renal failure or a decrease in substrate serum 25-(OH)D less than 25 nmol/L (1); however, serum l,25-(OH)2D level: probably decrease at a higher serum 25-{OH)D level between 80 nmol/mL were it not for the development of secondary hyperparathyroidism (2). When serum 25-(OH)D level is less than 50 nmol/L, bone resorption markers and hip fracture increase (2). These are just some of the reasons why the Institute of Medicine selected a serum 25-(OH)D level less than 50 nmol/L as a definition of insufficiency and why it is clinically important to measure it (3). In addition, our data apply to a worldwide population in which serum 25-(OH)D levels are often less than 25 nmol/L, increasing the incidence of osteomalacia (4).

Dr. Chausmer describes a special disease, hyperphosphatemic tumoral calcinosis, that leads to abnormal vitamin D metabolism and is irrelevant to a discussion of vitamin D insufficiency. Mutations in fibroblast growth factor 23 and other genes decrease renal phosphate excretion, stimulate 24-hydroxylase that converts 25-(OH)D and l,25-(OH)2D into inactive metabolites causing secondary hyperparathyroidism, stimulating l,25-(OH)2D and calcium absorption.

Sunlight is responsible for producing 80% of the nutritional supply of vitamin D in the body and maximizes serum 25-(OH)D levels in summer and autumn. During winter, there is a 50% decrease in serum 25-{OH)D levels, secondary hyperparathyroidism, and minimal change in serum l,25-(OH)2D levels. Storage of vitamin D in fat must be minimal, otherwise one would expect these stores to buffer the lack of vitamin D input from sunlight in the autumn and winter (2). Data in Figure 3 in our article show a difference of 17.5 nmol/L in serum 25-(OH)D levels in persons with a body mass index greater than 30 kg/m2 versus those with a normal body mass index (<25 kg/m2), suggesting that fat is not a significant storage site for vitamin D. The difference in obese versus thin people could be related to extracellular volume dilution.

We suggest that measuring and maintaining a serum 25-(OH)D level greater than 50 nmol/L in the population is highly advisable because numerous studies show poor clinical health outcomes and increased mortality below that level (3). Whether it is a marker of disease or causation is still uncertain. In our discussion, we point out that in defining a Recommended Dietary Allowance for vitamin D sufficiency (that is, serum 25-(OH)D levels <50 nmol/L), there should be a clinical outcome. All of the evidence suggests that serum 25-(OH)D has biological significance and there is no other substitute for nutritional assessment of vitamin D.

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There are many other instances where the active level of vitamin D is not associated with the inactive level

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