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Is vitamin c and calcium*

Vitamin D and calcium interactions: functional outcomes1 , 2 , 3 , 4

I present the results of published studies and original data and describe the functional outcomes of effects related to the interaction between vitamin D status and calcium intake These effects fall into 3 broad categories: 1) synergistic effects of vitamin D status and calcium intake on calcium absorption; 2) effects of calcium intake on vitamin D status; and 3) largely observational data suggesting an association between calcium and vitamin D status and nonskeletal outcomes, such as cancer To a considerable extent, both vitamin D status and the benefits associated therewith appear to be dependent on, or at least augmented by, calcium intakes at or above currently recommended levels

INTRODUCTION

The charge of this brief review is to consider the functions of vitamin D that involve an interaction with calcium I focus on 3 broad categories of these functions: calcium absorptive effects, the influence of calcium intake on vitamin D status, and a large array of nonskeletal effects suggesting a constructive interaction between calcium and vitamin D The pertinent evidence has been developed largely in adult humans

CALCIUM ABSORPTION

What has not been adequately studied, however, is the quantitative relation between vitamin D status and the efficiency of absorptive transport Such research can only be done at a high level of organization, preferably in intact humans

Quantitative relations between net calcium absorption, calcium intake, and percentage active absorption Calcium intake is shown on the horizontal axis, net absorption (difference between ingested intake and fecal output, which is the nutritionally relevant variable here) on the left vertical axis, and percentage of ingested calcium absorbed by active transport (ie, mediated by vitamin D) on the right axis The diagonal lines represent the relation between net absorption and calcium intake for varying values of active transport (ranging from 0% to 48%) Reproduced with permission from reference 3

In brief, a person needs both calcium and vitamin D to ensure sufficient net absorption of calcium for meeting various body needs from commonly available food sources An inescapable conclusion of these quantitative relations is that, given prevailing intakes of both nutrients, clinical trials or observational studies that fail to take this dual need into consideration will often produce null results, and systematic reviews that fail to weed out such studies will produce misleading conclusions

The several active absorption lines in Figure 1 ⇑ imply both that active absorption is a regulated function and that regulation may be limited by vitamin D status Regulation of active absorption is a well-established fact of endocrine physiology, and the ability of vitamin D to limit active absorption is supported by studies performed in my laboratory and summarized in detail elsewhere (9, 10)

Plateau relation of intestinal calcium absorption fraction (for an ingested calcium load of ≈300 mg) to vitamin D status, expressed as serum 25-hydroxyvitamin D [25(OH)D] Arrows above and below the plateau level represent physiologic regulation unlimited by vitamin D status Reproduced with permission from reference 11

In brief, vitamin D is an enabling agent that, when present in optimal concentrations, has no perceptible effect on calcium absorption in its own right; however, it permits or facilitates flexible physiologic response to varying calcium need This physiologic regulation functions around a unidirectional (ie, gross) absorption fraction of ≈030 At suboptimal levels, vitamin D's availability limits this physiologic control

The reason for this insufficient absorptive response is twofold First, parathyroid hormone increases bone resorption, making some of the needed calcium available from that source (The resulting decrease in bone mass and increase in bone remodeling are the bases for the negative effect of low vitamin D status on bone strengthIn this study, there was a calciumonly arm as well, and the calciumtreated individuals showed a degree of reduction in cancer intermediate between the double placebotreated women and those receiving calcium plus vitamin D.) Second, 25(OH)D appears to augment absorption directly, possibly by the rapid-response binding to membrane receptors described by Norman et al (2) This is shown by the fact that orally administered 25(OH)D increases calcium absorption in typical adult humans without changing serum 1,25(OH)2D concentrations (12), and also by the observation that serum 25(OH)D concentrations correlate with absorptive efficiency in adults but serum 1,25(OH)2D concentrations do not (13, 14) Essentially the same conclusion follows from the recognized fact that calcium absorption is poor in patients with osteomalacia, despite their often normal or high levels of serum 1,25(OH)2D [but always low concentrations of 25(OH)D]

These observations do not suggest that 1,25(OH)2D is not the active form of the vitamin, but simply underscore that, for optimal absorptive function, it appears that both metabolites of the vitamin must be present and that the mechanism of the absorptive response to vitamin D is more complex than once thought This seems to be an area warranting further investigation

INFLUENCE OF CALCIUM INTAKE ON VITAMIN D STATUS

Extensive clinical experience has shown that serum 25(OH)D concentrations (and hence vitamin D status) vary greatly between individuals, even when cholecalciferol inputs are apparently similar When the vitamin D input is cutaneous, one might expect some variability in status because efficiencies of cutaneous synthesis differ from person to person But even when the input is oral (and therefore accurately known), the variance of serum 25(OH)D responses is still very large

Increments to the maximal concentration (Cmax) for serum 25-hydroxyvitamin D after a single oral dose of 100 000 IUs cholecalciferol to 64 healthy adults The horizontal bar represents the mean rise Copyright Robert P Heaney, 2007 Used with permission

However, not all investigators have found this effect Goussous et al (21), using a calcium supplement of 1000 mg/d for 3 mo, found no difference in 25(OH)D concentrations, but these investigators did not succeed in reducing serum 1,25(OH)2D concentrations appreciably in the experimental group compared with the control group As Clements et al showed, it is the change in serum 1,25(OH)2D concentration that mediates the change in metabolic consumption of 25(OH)D We also know that serum 25(OH)D concentrations and 25(OH)D half-time rise after surgical removal of parathyroid adenomas (18), an effect shown by Clements et al to be due to the postsurgical drop in serum 1,25(OH)2D concentration

Thus, some aspect of the variability in 25(OH)D response to standard vitamin D inputs could be due to interindividual differences in calcium status How much of that variability at prevailing calcium intakes is due to this mechanism is uncertain, and research is needed to shed more light on this relation if we are to optimize vitamin D status in the population

NONSKELETAL EFFECTS OF CALCIUM AND VITAMIN D

Beyond the arena of the skeletal and calcium economies, the connection between calcium and vitamin D becomes more circumstantial and the underlying physiology, to the extent that it might be pertinent, less well elucidated Nevertheless, several recent observations suggest such a connection

Nevertheless, Women's Health Study investigators recently reported a strong parallel, in which risk of breast cancer (particularly in premenopausal women) was inversely associated with both calcium and vitamin D intakes (25) Similarly, the randomized controlled trial of Lappe et al (26) showed a significant reduction in incident all-cancer risk for a combination intervention involving calcium and vitamin D supplementation Principal cancers in this study were breast, colon, lung, and marrow/lymphoma In this study, there was a calcium-only arm as well, and the calcium-treated individuals showed a degree of reduction in cancer intermediate between the double placebo-treated women and those receiving calcium plus vitamin D This finding is suggestive of a contribution of calcium in its own right For colon cancer at least, such a connection would be plausible, because an earlier randomized controlled trial showed reduction in colon adenoma recurrence with calcium supplementation (27), and there is a compelling body of animal data showing that high calcium intakes serve as anti-promoters for colon cancer and thereby reduce experimental colon cancer incidence substantially (28, 29)

From a mechanistic perspective, it would seem important to separate the effects of calcium and vitamin D, but from a more pragmatic perspective, doing so may be less relevant, because the population intakes of both nutrients are recognized to be inadequate and to be in need of improvement (38, 39) Furthermore, an excessively reductionistic approach may be intrinsically inappropriate, because most nutrients act in concert with one another, and the attempt to establish efficacy for one apart from the other, as if they were drugs, may be misguided (40)

Acknowledgments

The author had no conflict of interest

↵ 2 Presented at the National Institutes of Health conference “Vitamin D and Health in the 21st Century: an Update,” held in Bethesda, MD, September 5–6, 2007

↵ 3 Supported by a Creighton University Research Endowment