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Creighton University, Omaha, NE 68178
2 To whom correspondence should be addressed. E-mail: rheaney{at}creighton.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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4000 international units (IU) (100 µg) or twice the current tolerable upper intake level (UL). In young individuals, most of this comes from the skin. However, cutaneous vitamin D3 synthesis declines with age, creating a need for increasing oral intake to maintain optimal serum 25-hydroxyvitamin D [25(OH)D] concentrations. Estimates of the population distribution of serum 25(OH)D values, coupled with available dose-response data, indicate that it would require input of an additional 2600 IU/d (65 µg/d) of oral vitamin D3 to ensure that 97.5% of older women have 25(OH)D values at or above desirable levels. The age-related decline in cutaneous input, taken together with the UL, creates a substantial barrier to the deployment of public health strategies to optimize vitamin D status in the elderly.
KEY WORDS: • upper level • vitamin D • serum 25(OH)D
Emerging from the explosion of knowledge about vitamin D that has occurred since the 1997 publication of the dietary reference intakes for calcium and related nutrients (1), there is now general recognition that vitamin D plays a role in the function of many tissues and organs that have no connection with the health of bone and calcium economy (the nutrient's classic function). It had previously been recognized that vitamin D is normally made in the skin by photoconversion of 7-dehydrocholesterol to previtamin D3. More recently, it has become clear that metabolic utilization of vitamin D is on the order of a few thousand international units (IU)/d (2) and that, because oral intake is typically only about one-tenth of that amount, the principal normal source of vitamin D for most of the population must be cutaneous synthesis.
This brief review focuses on barriers that may impede public health efforts to ensure vitamin D adequacy, particularly in the vulnerable elderly population. For these purposes, serum 25-hydroxyvitamin D [25(OH)D] concentrations of 80 nmol/L will be taken as evidence of adequacy. Evidence for use of this figure is discussed extensively elsewhere. In any event, there is quasiconsensus among vitamin D clinical investigators that a serum level of 75–80 nmol/L is optimal (3).
To achieve such levels in the bulk of the population, we must overcome two major barriers: declining cutaneous synthesis of vitamin D with age (4) and the dietary reference intake, specifically the tolerable upper intake level (UL) currently set at 2000 IU/d (50 µg/d) (1).
Decrease in cutaneous cholecalciferol synthesis with age. Older individuals as a group tend to expose less skin to the sun than, for example, adolescents. This is partly because they either work or stay indoors during the midday hours when skin synthesis in response to solar radiation is at its maximum and also because they are more likely to use sunscreens and wear more clothing, thus exposing less skin. This latter point is a particular issue for adult women of all ages whose culture or religion requires more modest dress. In the aggregate, factors contributing to a decline in vitamin D status with age are behavioral in character and, for the most part, can be altered by behavior modification, at least in theory.
However, an intrinsic factor also exists that evidently is not susceptible to modification; that is, the declining capacity of the skin itself to make cholecalciferol with age. Holick et al. (4) had shown a >4-fold difference in the elevation of serum cholecalciferol level induced by standard skin exposure to UVB radiation in individuals aged 62–80 y, as compared with 20- to 30-y-old controls. Further, MacLaughlin and Holick (5) showed a decline of about 50% in skin concentration of 7-dehydrocholesterol from age 20 to age 80 y.
At the same time, it must be noted that, whereas skin synthetic efficiency declines with age, it is not completely eradicated. Even casual exposure to the sun can be useful. A recent report from Japan (at 40° N latitude) contrasted 25(OH)D values in elderly stroke patients in a rehabilitation facility who were taken outdoors frequently with comparable values from controls of similar neurological status who were kept indoors (6). Both groups started with serum 25(OH)D levels below 20 nmol/L. The indoor group deteriorated over the year of the trial, whereas the outdoor group exhibited an increase in serum 25(OH)D to about 50 nmol/L. Whereas this latter level is, itself, probably inadequate (2,6), the response it demonstrates to casual sun exposure is evidence that skin retains appreciable synthetic capacity in the elderly.
Nevertheless, the decline in intrinsic cutaneous capacity to make vitamin D, coupled with the behavioral factors cited, almost certainly means that assuring normal vitamin D status in the elderly will depend increasingly on some combination of individual supplement use and judicious food fortification (7).
The UL. If, as seems increasingly likely, total daily utilization of vitamin D3 under conditions of vitamin D sufficiency is on the order of 4000 IU (2), it follows that, for individuals with little or no skin synthesis, oral intake will have to supply the entire daily requirement. At this point, the current UL becomes a problem because oral input twice the current UL may be necessary. The evidence behind the 2000 IU figure for the UL has been appropriately and insightfully criticized elsewhere (8,9). The point, however, is that as long as the UL remains at 2000 IU/d, it will be difficult, if not impossible, for public health strategies to effect full normalization of vitamin D status in older population segments.
By contrast, physicians working with individual patients confront much less of a barrier. They can easily give sufficient vitamin D3 to bring patients' serum 25(OH)D levels up to 80 nmol/L, just as they would adjust dosages of various drugs to achieve desired results. Moreover, they could do so only in those patients with measured low vitamin D status. Public health interventions, on the other hand, generally affect equally those who do not need extra nutrients as well as those who do, which is one of the ways the UL becomes a barrier. However, even in individual patient care, physicians could potentially expose themselves to liability by treating patients with dosages above the UL if those patients develop virtually any untoward outcome (whether or not actually related to vitamin D).
Normalizing vitamin D3 status. How likely is it that normalizing vitamin D3 status in North American and European populations would require amounts at or above the UL? We can address this question first by looking at the distribution of serum 25(OH)D values in the population and second by quantification of the equilibrium response of serum 25(OH)D to steady oral vitamin D3 input.
Many recent publications described distribution of serum 25(OH)D values in various population segments (10–14). Despite their diversity, they all share a common feature: major fractions of the individuals measured have 25(OH)D values below desired levels and even below laboratory lower reference levels, which are themselves now increasingly being recognized as too low (12). Perhaps the most representative of these studies was the paper by Looker et al. (10) based on NHANES-III data. Even NHANES, generally representative of the U.S. population for many variables, is not ideal in regard to vitamin D because, for reasons of logistics, the northern tier of states was surveyed in the summer and the southern tier was surveyed in the winter; however, this is probably not a major problem for the older population groups because the amplitude of their seasonal variation in serum 25(OH)D tends to be smaller than in the young. Looker et al. (10) do not provide the parameters of the distributions for various age and ethnic groups because their concern was to show population proportions below certain cutoff values. Nevertheless, if one assumes an approximately normal distribution for the values, one can, from the population fractions to the left of specified cutoff points, back calculate the approximate parameters for the entire distribution. Figure 1 represents an attempt to construct the distribution for non-Hispanic Caucasian women aged 60–79 y. As Looker et al. (10) note, 10% were below the lower reference level for the laboratory method used and, as can be estimated visually, approximately three-fourths of the group had values below 80 nmol/L (shaded zone).
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Figure 2 presents the calculated, original 25(OH)D data distribution (solid line) from NHANES-III and, to its right, the distribution that would result if everyone in the population concerned were to add the UL (2000 IU) to their daily intake. Using a slope value of 0.7 nmol L–1 µg–1/d, it can readily be calculated that a daily input of 2000 IU (50 µg) would raise mean serum 25(OH)D by 35 nmol/L (the dashed line to the right in Fig. 2). Two features of the plots in Figure 2 merit attention. First, whereas 85% of this cohort will have serum 25(OH)D values above 80 nmol/L, about 15% of this group of women receiving an additional 2000 IU/d will still have values below 80 nmol/L; in other words, even the UL would not be sufficient to bring this lowest 15% up to a desired serum 25(OH)D level. Second, in the right tail of the unsupplemented distribution, about 23% of the population were already above 80 nmol/L and hence needed no additional vitamin D at all. Would they have been harmed by getting an extra 2000 IU/d, as might well happen in any population-wide, public health approach? The best answer one can give from the available data is no. As Figure 2 indicates, the upper tail of the right-most distribution is still well below 200 nmol/L. Outdoor workers commonly have values in this range and there is no good evidence of vitamin D toxicity for steady-state vitamin D input producing 25(OH)D levels below 250–300 nmol/L (8).
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2600 IU/d (65 µg/d). It is important to understand that this is in addition to whatever input the population concerned may have been receiving from food, supplement, and solar sources, and thus is not the total requirement by any means. It should be stressed that the foregoing calculations have to be considered approximations. To begin with, they are based on estimates of the distribution for 25(OH)D in NHANES-III (because the actual values have not yet been published). Also, they apply to everyone a single rate of increase of serum 25(OH)D in response to fixed oral input increments, whereas there will be a range of values for this variable, as well, and that range is not well characterized. Fortunately, for purposes of safety, these dose-response slopes tend to be inversely related to starting 25(OH)D values. This is probably because the 24-hydroxylase and other degradative pathways are up-regulated at higher serum 25(OH)D concentrations. In any event, what that means in the practical sense is that individuals with high starting values will get less of an increase from the same steady-state oral dose than those with lower starting values, a factor that will tend to protect them from toxicity.
Having said this, however, these approximations are probably not far from correct. Our estimate of total body utilization, described earlier (2), had a lower confidence limit of 3520 IU/d, well above the UL; without substantial sun exposure, all of this amount (or more) will have to be provided by oral input. What remains to be more securely established is the safety of those who need no supplementation but who would nevertheless receive extra vitamin D in any public health approach to correct a deficiency in the general population.
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FOOTNOTES |
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. Institute of Medicine. Dietary reference intakes for calcium, magnesium, phosphorus, vitamin D, and fluoride. Food and Nutrition Board. Washington, DC: National Academy Press; 1997.
2. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxy-cholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77:204–10.
3. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int. 2005;16:713–6.
4. Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet. 1989;ii:1104–5.
5. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76:1536–8.[Medline]
6. Sato Y, Metoki N, Iwamoto J, Satoh K. Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure in stroke patients. Neurology. 2003;61:338–42.
7. Newmark HL, Heaney RP, Lachance PA. Should calcium and vitamin D be added to the current enrichment program for cereal-grain products? Am J Clin Nutr. 2004;80:264–70.
8. Vieth R. The mechanisms of vitamin D toxicity. Bone Miner. 1990;11:267–72.[Medline]
9. Vieth R. Critique of the considerations for establishing tolerable upper intake levels for vitamin D. J Nutr. 2006;136:1117–22.
10. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone. 2002;30:771–7.[Medline]
11. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical patients. N Engl J Med. 1998;338:777–83.
12. Fleming JK, Hoefner DM, Sharp M, Brown MP. Proposed cut-points for 25-hydroxy vitamin D; an induced epidemic or existing condition of hypovitaminosis D? Clin Chem. 2006; in press.
13. Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT, Petruschke RA, Chen E, de Papp AE. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. 2005;90:3215–24.
14. Passeri G, Pini G, Troiano L, Vescovini R, Sansoni P, Passeri M, Gueresi P, Delsignore R, Pedrazzoni M, Franceschi C. Low vitamin D status, high bone turnover, and bone fractures in centenarians. J Clin Endocrinol Metab. 2003;88:5109–15.
15. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. Br Med J. 2003;326:469–74.
16. Heaney RP, Barger-Lux MJ, Dowell MS, Chen TC, Holick MF. Calcium absorptive effects of vitamin D and its major metabolites. J Clin Endocrinol Metab. 1997;82:4111–6.
17. Mocanu V, Stitt PA, Costan AR, Zbranca E, Luca V, Vieth R. Long term efficacy and safety of high vitamin D intakes as fortified bread. FASEB J. 2005; 19(4):A59, Part 1 Suppl. S. March 4.
18. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med. 1992;327:1637–42.[Abstract]
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