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The case for improving vitamin D status
Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 635–641
The case for improving vitamin D status Robert P. Heaney ∗ Creighton University Medical Center, 601 North 30th Street-Suite 4841, Omaha, NE 68131, United States Received 30 November 2006
Abstract Evidence from both physiological experiments and randomized trials demonstrates that elevating vitamin D status above levels prevailing in the North American and European adult populations improves calcium absorption and reduces fall risk and osteoporotic fractures. Additionally observational data suggest that raising vitamin D status protects against various cancers and autoimmune disorders as well. Hence a strong case can be made for immediate improvement in vitamin D status of the general population. © 2006 Elsevier Ltd. All rights reserved. Keywords: Vitamin D; 25(OH)D; Calcium absorption; Fractures; Falls; Cancer
1. Introduction
2. Current status of vitamin D nutriture
In its publication of the dietary reference intakes for the bone-related nutrients in 1997, the Food and Nutrition Board (FNB) of the Institute of Medicine defined serum 25hydroxyvitamin D [25(OH)D] as the functional indicator for vitamin D status [1]. Operationally, therefore, “improving vitamin D status” means raising the serum 25(OH)D level from prevailing values to some putatively more healthful level. In brief the “case” boils down to demonstrating the presence of preventable disease or dysfunction at prevailing levels of 25(OH)D, showing that these can be mitigated or prevented by improving vitamin D status, and finally establishing that doing so would be safe. In making this case I shall focus on the population, rather than the individual patient. A logically secondary, but nevertheless extremely important consideration is the target level for serum 25(OH)D. In what follows I shall use a value of 80 nmol/L as the lower end of the optimal range for serum 25(OH)D, but want to stress that I hold no particular brief for that number beyond the fact that it seems to emerge from a large number of different types of studies. The “case” does not hinge upon the target level, but upon the demonstration of benefit to be reaped by moving up the 25(OH)D continuum.
There is a very large, and still growing, literature documenting current vitamin D status of various age and population groups, both in North America and in other parts of the world [2–14]. Virtually all studies show that substantial fractions of the population have serum 25(OH)D concentrations below various cut-off levels, even in childhood, and for most adult populations, the fraction below 80 nmol/L varies from roughly 65% to essentially 100%. For example, a recent report on hip fracture patients in Finland indicated that 97% had values below 74 nmol/L [15], and of 104 centenarians in northern Italy, 99 had undetectable levels [16]. Fig. 1 is a plot of the distribution of serum 25(OH)D in a population-based sample of 1160 women over age 55 years living in a semi-rural community in eastern Nebraska (41◦ N latitude) [14]. The mean concentration was 71 nmol/L and 66% of the sample were below 80 nmol/L. Fifty-six percent of these women were taking supplements and the median vitamin D intake, overall, was 200 IU/d. This distribution is useful because it already incorporates the effect of prevalent vitamin D supplementation at currently recommended intake levels. It also provides information on the proportion of the population already at or above the optimal level (i.e., those who would not benefit from a universal fortification or supplementation regimen).
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Fig. 1. Frequency distribution of seasonally adjusted values for serum 25(OH)D in a semi-rural female population aged 55 years and older [14]. The solid line is the Gaussian curve fitted to the data. The data are normally distributed with mean = 71 and S.D. = 20 (Copyright Robert P. Heaney, 2006. Used with permission).
3. Evidence of disease/dysfunction at prevailing levels It is well established that serum 25(OH)D levels below 20 nmol/L indicate the presence of rickets or osteomalacia [1], but I shall ignore this extreme deficiency state since most of the population, with the exception of the older elderly, will typically have values above 20 nmol/L, and the case I have been asked to make relates to the bulk of the population, not to those that have outspoken, classical deficiency, for whom vitamin D supplementation is clearly indicated. The evidence falls into two broad categories, that derived from experiments or randomized controlled trials, and that derived from associations found in observational studies. 3.1. Experimental data The experimental data fall into four functional groups: (1) calcium absorption; (2) osteoporotic fractures; (3) falls; (4) response to infection. 3.1.1. Calcium absorption The oldest recognized function of vitamin D is the facilitation of calcium absorption from the intestine, now understood to involve a genomic action whereby 1,25(OH)2 D induces the formation of a calcium transport protein responsible for shuttling calcium ions from the brush border of the mucosal cell to the baso-lateral membrane. While this activity is generally recognized as the mechanism which is deranged in the extreme vitamin D deficiency that results in such disorders as rickets and osteomalacia, there is a paucity of data with respect to the quantities of vitamin D needed to optimize this function at levels above those producing rickets. Fig. 2 presents the data from three studies [17–19] showing a seeming threshold of absorptive performance as a function of vitamin D status. Important for our consideration is the
Fig. 2. Fractional calcium absorption values plotted against serum 25(OH)D from Heaney et al. [17], Barger-Lux and Heaney [18], and Bischoff et al. [19]. Error bars are 1 S.E.M. (Copyright Robert P. Heaney, 2005. Used with permission).
ascending limb of the curve, which indicates that absorptive performance improves as vitamin D status rises (for these data, up to a level of ∼80 nmol/L). In other words, below 80 nmol/L, vitamin D status is rate-limiting, whereas above 80 nmol/L other physiological controls become operative. This is not the place to explore how or why, in adults, serum 25(OH)D seems to be a better predictor of absorptive performance than is serum 1,25(OH)2 D [20,21]. My concern here is solely with serum 25(OH)D concentration as an indicator of vitamin D status, and with its relation to absorptive performance. Given prevailing calcium intakes, it seems clear that improved absorptive performance is physiologically beneficial. 3.1.2. Osteoporotic fractures The mechanisms of vitamin D’s action in fracture risk reduction include some combination of improved calcium absorption, reduced fall risk (see below), protection of bone mass, and reduction of excessive bone remodeling. At least four randomized controlled trials have found reduced fracture risk with vitamin D supplementation [22–25]. A formal meta-analysis focusing on hip fracture calculated a significant risk reduction associated with vitamin D doses in the range of 700–800 IU/d or higher, but found no effect for doses as low as 400 IU/d [26]. In at least three of these trials serum 25(OH)D change was measured; the treatment produced an increase from control values of 50–70 nmol/L to treated values of 74–110 indicating in each case that the lower value, though well above the osteomalacia range, was nevertheless associated with preventable fractures. Two of the four trials used calcium in addition to vitamin D and the point estimates of fracture reduction were greater in them. Nevertheless, vitamin D alone was effective in the other two. It may be worth noting that it is arbitrary and artificial to separate calcium from vitamin D in analysis of such studies. Vitamin D and calcium are clearly synergistic, as well as complementary (i.e.,
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vitamin D adequacy permits optimal extraction of calcium from low calcium diets, and high calcium intakes mitigate the reduced absorption of inadequate vitamin D status). Several other trials failed to find a significant effect on fracture risk [27–29]. Aside from the fact that inconclusive trials are always to be expected when investigative power is less than 100%, discernible factors explain at least some of the failure. For example, one large population-based trial using daily oral dosing of 800 IU vitamin D, found no significant effect [27]. Documentable compliance was on the order of 40%, and the rise in serum 25(OH)D produced in the treated subjects did not reach a therapeutic level. By contrast, a second trial, performed in a similar population, used 100,000 IU cholecalciferol every 4 months by mouth (averaging ∼800 IU/d), producing a rise in serum 25(OH)D up into the therapeutic range, and a 33% reduction in all osteoporotic fractures combined [25]. Similarly, the calcium and vitamin D arm of the Women’s Health Initiative (WHI) failed to find a significant fracture reduction by intention-to-treat [29]; however, the vitamin D dose was only 400 IU/d, and at 60% compliance, that fell to only 240 IU/d. 3.1.3. Falls Several trials of vitamin D for falls reduction have been reported, and they, in turn, have been subsequently incorporated into a meta-analysis [30], the conclusion of which was that there was a significant overall effect, with vitamin D reducing fall risk, in some reports substantially. This effect is believed to be due to improved muscle tone and strength, as there are vitamin D receptors in striated muscle, and vitamin D appears to play a role in the signaling that is responsible for muscle protein synthesis. Bischoff et al. [19] demonstrated a 49% reduction in falls in a 12-week trial, in women with average serum 25(OH)D concentrations of 30 nmol/L, and in a reanalysis of another randomized trial (having fracture as the primary endpoint) found a significant, 56% reduction in falls in women, and a 76% reduction in sedentary women [31]. Average 25(OH)D value in this group was 65 nmol/L, substantially higher than found in the women of the earlier study, suggesting continuing benefit up to and above 80 nmol/L. As falls are a major factor in osteoporotic fracture risk, substantial reduction in fall frequency has to be considered an important benefit. 3.1.4. Response to infection It has been recognized for nearly a century that patients with rickets are more prone to various infectious diseases, particularly of the lung, although the mechanism was not well understood. Vitamin D is now recognized to be active in controlling various aspects of the immune response [32,33], and perhaps the best worked out example is found in a recent report on the innate immune system, assessing the response of the system to a standardized challenge resulting in activation of toll-like receptor-2 [34]. In this work human monocytes cultured either in fetal calf serum or in human serum synthesize a bactericidal peptide when toll-like receptor-2 is
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activated. The response, however, depends upon a source of vitamin D. Serum with low concentrations of 25(OH)D elicits only a severely blunted response. A recent randomized controlled trial of vitamin D as adjuvant therapy in patients with pulmonary tuberculosis being treated with standard therapy demonstrated a substantial enhancement of treatment response, with 100% sputum conversion in the vitamin D-treated group by the end of the course of the treatment [as contrasted with a 76% conversion in patients receiving the standard therapy, but no vitamin D] [35]. 3.1.5. Comment In the foregoing four areas, experimental and/or randomized trial data demonstrate decreased disease or dysfunction associated with elevation of vitamin D status from levels prevailing in the populations studied. Except for calcium absorptive performance, none of the available data specifically bears on what may be the optimal level for serum 25(OH)D for that particular outcome. Most of the studies in which change in 25(OH)D was documented resulted in elevations on the order of 20–30 nmol/L (for a vitamin D dosage generally in the range of 700–800 IU/d). Whether greater benefit would have been produced with higher doses and a greater elevation of serum 25(OH)D cannot be determined. Nevertheless, it seems reasonably certain that a population-level elevation of at least 20 nmol/L would have a major, highly beneficial effect on morbidity as it relates both to skeletal health and to response to infections. 3.2. Observational data 3.2.1. The calcium economy The impact of vitamin D on the calcium economy, per se, is expressed mainly as decreased calcium input into the extracellular fluid, both from the intestine and from bone. This low calcium challenge immediately elicits an increase in parathyroid hormone secretion which is sustained so long as the calcium input remains low. Thus, serum PTH and 25(OH)D have been frequently reported to vary inversely [12–14,36]. The relationship has been described as either curvilinear or biphasic, exhibiting an inflection point below which serum PTH rises as serum 25(OH)D falls, but above which, serum PTH remains constant, irrespective of changes in serum 25(OH)D. The location of that inflection point along the serum 25(OH)D continuum has been variously reported from the neighborhood of 45–50 nmol/L up to as high 110–120 nmol/L. The inflection point, itself, is an inverse function of calcium intake in a population. For any given vitamin D level, calcium absorption will vary more or less directly with calcium intake [37]. Thus, high calcium intakes effectively mitigate some of the hypocalcemic challenge that results from vitamin D deficiency. It is in part for this reason that it has been argued that the location of the inflection point is not a very reliable indicator of the lower end of the optimal range for vitamin D status.
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Nevertheless the fact that PTH begins to rise at 25(OH)D levels that are substantially above the osteomalacic range is an indicator of physiological compensation for inadequate vitamin D-mediated calcium input, and thus constitutes presumptive evidence of physiological compromise as a result of low vitamin D status. Aside from physiological optimization, it is perhaps more relevant to note that parathyroid hormone is the principal determinant of the quantity of bone remodeling in the skeleton. It is now recognized that remodeling is a more important determinant of fracture risk than is bone mass [38–40]. For this reason alone, PTH levels above those that would occur with full vitamin D repletion have to be considered a fracture risk factor. 3.2.2. Skeletal status Numerous reports indicate that bone mineral density varies directly with serum 25(OH)D. Perhaps most pertinent to a North American population are the data from NHANES-III [41], analyzed by Bischoff-Ferrari et al., showing a continuous positive relationship between BMD at the hip and serum 25(OH)D in whites, blacks, and Hispanics, out to 25(OH)D levels well in excess of 100 nmol/L. In this national, population-based dataset, the rise in BMD on 25(OH)D was steepest below 40 nmol/L, but continued to be positive throughout the range of 25(OH)D values observed in U.S. adults. Other things being equal, more massive bones are more fracture resistant. 3.2.3. Neuromuscular status Neuromuscular status is a predictor of fall risk and hence has been the subject of numerous investigations. In general, instability, slowness of gait, sway, and similar indices of lower extremity function have been found to be inversely associated with 25(OH)D levels. Once again, using the data assembled by NHANES-III, Bischoff-Ferrari et al. were able to show that performance of elderly individuals on timed 8-foot walks and time to rise from a chair improved as 25(OH)D status improved, throughout the entire range of values observed in the population concerned [42]. As with BMD, the largest improvement was observed at the low end of the 25(OH)D continuum, but performance continued to improve even at values above 100 nmol/L. Comparable data have recently been presented from the Amsterdam Longitudinal Aging Study [43], some of the data of which are presented in Fig. 3. In this study lower extremity performance was assessed on a 12 point scale. As the figure shows, performance improved as serum 25(OH)D rose. There was not only a significant trend upward, but a significant difference step-by-step. The highest grouping was demarcated at 75 nmol/L and it is thus impossible to decide whether higher levels of 25(OH)D would have been associated with still better performance. 3.2.4. Cancer The literature on the relationship between vitamin D status and cancer risk and/or cancer mortality is too vast to summarize even superficially in this context. The available
Fig. 3. Performance scores in elderly individuals from the Amsterdam Longitudinal Aging Study, plotted by 25 nmol steps for serum 25(OH)D. Adapted from Wicherts et al. [43].
data are essentially all observational in character. First of all, it has long been recognized that cancer mortality varies directly with latitude (and hence inversely with sun exposure) [32,33,44]. Several large databases now contain information on antecedent measurements of serum 25(OH)D, from which prospective risk of cancer can be assessed. Ahonen et al. [45], for example, reported that men with serum 25(OH)D values below the median for the population had a 70% greater risk of incident prostate cancer than individuals above the median, with the risk declining by 25(OH)D quartile. In the Nurses’ Health Study risk of colorectal cancer declined as serum 25(OH)D rose, with values in the range of 75–80 nmol/L carrying a cancer risk roughly half that of individuals in the lowest quartile [46]. Gorham et al. [47], pulling together several reports of colorectal cancer risk, found a clear inverse relationship between serum 25(OH)D level and relative risk of incident colorectal cancer. They estimate that, at a serum 25(OH)D of 80 nmol/L, colorectal cancer risk is reduced by 50%. Even WHI, which ostensibly reported no benefit from a calcium-vitamin D intervention, nevertheless observed a highly significant inverse relationship between baseline serum 25(OH)D and incident colorectal cancer risk [48]. Those in the lowest quartile of serum 25(OH)D had an incident cancer rate 2.5× that of those in the highest quartile. Breast cancer risk, also, shows an inverse association both with UV-B exposure [45] and with serum 25(OH)D [49–51]; and there are at least two reports indicating that mammographic densities, recognized to be a risk factor for breast cancer, vary inversely with serum 25(OH)D status, with the lowest risk being found at or above serum 25(OH)D levels of 80 nmol/L [52,53]. For all of these studies, risk drops as serum 25(OH)D rises up to at least levels of 80 nmol/L. However, since large num-
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bers of individuals with still higher values are not commonly found in the populations at risk for the cancers concerned, it is not possible to estimate whether the trend lessens above 80 nmol/L, or whether higher values might have been associated with even lower cancer risk. 3.2.5. Other diseases There is a substantial body of evidence indicating an inverse relationship between vitamin D status (or UV-B exposure) and risk of Type I diabetes, various arthritides, multiple sclerosis, periodontal disease, and other chronic disorders [32,33]. For example, in NHANES-III, Scragg et al. [54] showed that the likelihood that blood sugar values (either fasting or following a standard glucose challenge) would fall in the diabetic range was an inverse function of serum 25(OH)D status. In another study, employing a standard glucose tolerance test, blood sugar values at various time points during the test were an inverse function of 25(OH)D status, with blood sugar exhibiting an inflection type of behavior similar to that observed for PTH [55]. The data are too sparse to permit a precise estimate of the location of the inflection point, but the point estimates from available data would place that inflection at somewhere in the range of 110–120 nmol/L. These and other studies, too numerous to mention, complement the information available from randomized trials or physiological experiments. Thus, the neuromuscular functional relationship complements the data on fall reduction from controlled trials of vitamin D supplementation, and the BMD and PTH data complement the data on fracture risk reduction with vitamin D treatment. There are no randomized trials of cancer prevention using vitamin D as the primary intervention, but there is a large body of animal data clearly establishing several biological mechanisms for enhanced oncogenesis in the face of moderate to severe vitamin D deficiency. The extreme difficulty associated with performing randomized trials of, for example, cancer prevention makes it doubtful that we shall soon see so-called “level I” evidence with respect to certain of these disease endpoints. Nevertheless, if population level vitamin D status is raised to levels that optimize skeletal status and minimize fracture risk, it may well be that evidence of efficacy for the other disease endpoints summarized superficially in this section will come, not from controlled trials, but from public health statistics, documenting a fall in disease incidence, just as occurred with dental caries following water fluoridation, or with pellagra, following niacin fortification of wheat flour. In any event, the possibility that some of the diseases briefly discussed might benefit from improving vitamin D status adds a level of urgency to the case that can be made for those diseases for which level I evidence is available.
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ing the issue in such distributional terms helps focus on two critical questions: (1) how much additional vitamin D input would be required to ensure that 97.5% of the target population would be above the lower limit of desirable normal (e.g., 80 nmol/L); and (2) for those already at or above this target value, what effect would the same level of supplementation have on their values, and what would be the risk to them of vitamin D toxicity? In a dose-ranging experiment we have shown that serum 25(OH)D rises by 0.7 nmol/L for every microgram (40 IU) of cholecalciferol given as a continuous daily oral input [56]. That means that an individual with a baseline value of 50 nmol/L, in whom one wished to achieve a value of 80 nmol/L, would require (80 − 50)/0.7 = 1714 IU/d, continuously, in addition to all existing inputs (diet, supplement, and solar exposure). Most published reports of the elevation of serum 25(OH)D by varying doses of cholecalciferol produce slope values in the range we have observed (i.e., 0.6–1.2 nmol/L/g/d). Both to ease calculation and to take a conservative figure, we may use a value of 1.0 nmol/L/g/d to estimate the dose required to shift the population by any specified amount. Thus, taking the distribution presented in Fig. 1, with 2.5% being at or below 31 nmol/L, one can calculate that it would take ∼2000 IU/d of additional input for everyone to raise that 2.5th percentile to 80 nmol/L. (If the rate of rise is closer to the number we measured, i.e., 0.7 nmol/L/g/d, then it would take proportionately more (i.e., ∼2900 IU/d) to ensure that no more than 2.5% of the population were below 80 nmol/L.) Corresponding calculations can be made for those at the upper end of the distribution. In the population presented in Fig. 1, the 97.5th percentile was at 112 nmol/L; and using the conservative slope value of 1.0 nmol/L/g/d, the 2000 IU/d dose needed to raise the 2.5th percentile up to 80 would elevate individuals at the 97.5th percentile to 162 nmol/L. As there are no credible estimates of toxicity from vitamin D at serum 25(OH)D levels below 250 nmol/L, this level of supplementation/fortification would still carry a substantial margin of safety even for those individuals already at the high end of the 25(OH)D distribution. More to the point, values as high as 200 nmol/L are found not infrequently in light-skinned outdoor workers at end of summer [18,57]. In this connection, there is probably an additional margin of safety, inasmuch as the 1.0 nmol/L/g/d factor is a higher value than any observed for dose response at the high end of the 25(OH)D continuum, and the figure we derived (0.7 nmol/L/g/d) is probably closer to the reality. Using a lower value for slope necessarily results in a smaller increment for those who are already high, and thus there may be even less basis for concern about safety.
3.3. Improving vitamin D status
4. Research needs
Improving vitamin D status at a population level means shifting the distribution of 25(OH)D values to the right. Pos-
Although the research opportunities in the field of vitamin D biology seem nearly limitless, two very practical needs are
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evident from this brief analysis. These are the need to provide a firm determination of the lower end of the physiological range of vitamin D status, taking into consideration all relevant system endpoints, not simply the calcium economy. Second is the need to define more precisely the variation in response of individuals to given vitamin D inputs. The foregoing calculations, although taking into consideration the wide variation in vitamin D status, assumed a fairly uniform response at a population level to additional vitamin D inputs. That is almost surely not the case, and we shall need a firmer estimate of individual variability in response before we can have confidence that a given supplementation/fortification regimen would produce the desired results.
5. Comment This presentation has focused on the case for improvement in vitamin D status, and has largely ignored the logistics issues that may be associated with achieving such a result. The successful nutritional interventions of the past have come about largely because of fortification of foods widely consumed by various population sectors (e.g., cereal grains). Wheat flour, for example, was the vehicle used to improve iron and B vitamin status, and cereal grains, folate status. The addition of iodine to salt (mandated in some nations, but optional in the U.S.) has largely eradicated endemic thyroid goiter where implemented, and the addition of fluoride to drinking water has had a similar impact on the prevalence of dental caries. The optimal route of improvement of vitamin D status of the populations of the industrialized nations remains to be determined, but it will likely involve some level of fortification of one or more foods. It would seem important for the nutrition community to focus on this issue soon, as the lag time between reaching a firm conclusion and implementation in practice is discouragingly long. It is sobering to recall that the Food and Nutrition Board of the National Academy of Sciences first petitioned the U.S. Food and Drug Administration for folate fortification of cereal grains in 1974, and it was an additional 24 years before the current, modest level of fortification was mandated. One hopes that the time course for vitamin D will be substantially shorter.
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[42] H.A. Bischoff-Ferrari, T. Dietrich, E.J. Orav, F.B. Hu, Y. Zhang, E.W. Karlson, B. Dawson-Hughes, Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged ≥ 60 y, Am. J. Clin. Nutr. 80 (2004) 752– 758. [43] I.S. Wicherts, N.M. Van Schoor, A.J.P. Boeke, P. Lips, Vitamin D deficiency and neuromuscular performance in the Longitudinal Aging Study Amsterdam (LASA), J. Bone Miner. Res. 20 (Suppl. 1) (2005) S35. [44] W.B. Grant, An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation, Cancer 94 (2002) 1867–1875. [45] M.H. Ahonen, L. Tenkanen, L. Teppo, M. Hakama, P. Tuohimaa, Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland), Cancer Causes Control 11 (2000) 847– 852. [46] D. Feskanich, J. Ma, C.S. Fuchs, G.J. Kirkner, S.E. Hankinson, B.W. Hollis, E.L. Giovannucci, Plasma vitamin D metabolites and risk of colorectal cancer in women, Cancer Epidemiol. Biomarkers Prev. 13 (2004) 1501–1508. [47] E.D. Gorham, C.F. Garland, F.C. Garland, W.M. Grant, S.B. Mohr, M. Lipkin, H.L. Newmark, E. Giovannucci, M. Wei, M.F. Holick, Vitamin D and prevention of colorectal cancer, J. Steroid Biochem. Mol. Biol. 97 (2005) 179–194. [48] J. Wactawski-Wende, J.M. Kotchen, G.L. Anderson, A.R. Assaf, R.L. Brunner, et al., Calcium plus vitamin D supplementation and the risk of colorectal cancer, N. Engl. J. Med. 354 (2006) 684–696. [49] E.R. Bertone-Johnson, W.Y. Chen, M.F. Holick, B.W. Hollis, G.A. Colditz, W.C. Willett, S.E. Hankinson, Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol, Biomarkers Prev. 14 (2005) 1991–1997. [50] E.R. Bertone-Johnson, S.E. Hankinson, A. Bendich, S.R. Johnson, W.C. Willett, J.E. Manson, Calcium and vitamin D intake and risk of incident premenstrual syndrome, Arch. Intern. Med. 13 (2005) 1246–1252. [51] L.C. Lowe, M. Guy, J.L. Mansi, C. Peckitt, J. Bliss, R.G. Wilson, K.W. Colston, Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population, Eur. J. Cancer 41 (2005) 1164–1169. [52] S. Berube, C. Diorio, W. Verhoek-Oftedahl, J. Brisson, Vitamin D, calcium, and mammographic breast densities, Cancer Epidemiol. Biomarkers Prev. 13 (2004) 1466–1472. [53] S. Berube, C. Diorio, B. Masse, N. Hebert-Croteau, C. Byrne, G. Cote, M. Pollak, M. Yaffe, J. Brisson, Vitamin D and calcium intakes from food or supplements and mammographic breast density, Cancer Epidemiol. Biomarkers Prev. 14 (2005) 1653–1659. [54] R. Scragg, M.F. Sowers, C. Bell, Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the third National Health and Nutrition Examination Survey, Diabetes Care 27 (2004) 2813–2818. [55] K.C. Chiu, A. Chu, V.L.W. Go, M.F. Saad, Hypovitaminosis D is associated with insulin resistance and  cell dysfunction, Am. J. Clin. Nutr. 79 (2004) 820–825. [56] R.P. Heaney, K.M. Davies, T.C. Chen, M.F. Holick, M.J. BargerLux, Human serum 25-hydroxy-cholecalciferol response to extended oral dosing with cholecalciferol, Am. J. Clin. Nutr. 77 (2003) 204– 210. [57] R. Vieth, Vitamin D supplementation, 25-hydroxyvitamin D levels, and safety, Am. J. Clin. Nutr. 69 (1999) 842–856.
The case for improving vitamin D status Robert P. Heaney ∗ Creighton University Medical Center, 601 North 30th Street-Suite 4841, Omaha, NE 68131, United States Received 30 November 2006
Abstract Evidence from both physiological experiments and randomized trials demonstrates that elevating vitamin D status above levels prevailing in the North American and European adult populations improves calcium absorption and reduces fall risk and osteoporotic fractures. Additionally observational data suggest that raising vitamin D status protects against various cancers and autoimmune disorders as well. Hence a strong case can be made for immediate improvement in vitamin D status of the general population. © 2006 Elsevier Ltd. All rights reserved. Keywords: Vitamin D; 25(OH)D; Calcium absorption; Fractures; Falls; Cancer
1. Introduction
2. Current status of vitamin D nutriture
In its publication of the dietary reference intakes for the bone-related nutrients in 1997, the Food and Nutrition Board (FNB) of the Institute of Medicine defined serum 25hydroxyvitamin D [25(OH)D] as the functional indicator for vitamin D status [1]. Operationally, therefore, “improving vitamin D status” means raising the serum 25(OH)D level from prevailing values to some putatively more healthful level. In brief the “case” boils down to demonstrating the presence of preventable disease or dysfunction at prevailing levels of 25(OH)D, showing that these can be mitigated or prevented by improving vitamin D status, and finally establishing that doing so would be safe. In making this case I shall focus on the population, rather than the individual patient. A logically secondary, but nevertheless extremely important consideration is the target level for serum 25(OH)D. In what follows I shall use a value of 80 nmol/L as the lower end of the optimal range for serum 25(OH)D, but want to stress that I hold no particular brief for that number beyond the fact that it seems to emerge from a large number of different types of studies. The “case” does not hinge upon the target level, but upon the demonstration of benefit to be reaped by moving up the 25(OH)D continuum.
There is a very large, and still growing, literature documenting current vitamin D status of various age and population groups, both in North America and in other parts of the world [2–14]. Virtually all studies show that substantial fractions of the population have serum 25(OH)D concentrations below various cut-off levels, even in childhood, and for most adult populations, the fraction below 80 nmol/L varies from roughly 65% to essentially 100%. For example, a recent report on hip fracture patients in Finland indicated that 97% had values below 74 nmol/L [15], and of 104 centenarians in northern Italy, 99 had undetectable levels [16]. Fig. 1 is a plot of the distribution of serum 25(OH)D in a population-based sample of 1160 women over age 55 years living in a semi-rural community in eastern Nebraska (41◦ N latitude) [14]. The mean concentration was 71 nmol/L and 66% of the sample were below 80 nmol/L. Fifty-six percent of these women were taking supplements and the median vitamin D intake, overall, was 200 IU/d. This distribution is useful because it already incorporates the effect of prevalent vitamin D supplementation at currently recommended intake levels. It also provides information on the proportion of the population already at or above the optimal level (i.e., those who would not benefit from a universal fortification or supplementation regimen).
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Fig. 1. Frequency distribution of seasonally adjusted values for serum 25(OH)D in a semi-rural female population aged 55 years and older [14]. The solid line is the Gaussian curve fitted to the data. The data are normally distributed with mean = 71 and S.D. = 20 (Copyright Robert P. Heaney, 2006. Used with permission).
3. Evidence of disease/dysfunction at prevailing levels It is well established that serum 25(OH)D levels below 20 nmol/L indicate the presence of rickets or osteomalacia [1], but I shall ignore this extreme deficiency state since most of the population, with the exception of the older elderly, will typically have values above 20 nmol/L, and the case I have been asked to make relates to the bulk of the population, not to those that have outspoken, classical deficiency, for whom vitamin D supplementation is clearly indicated. The evidence falls into two broad categories, that derived from experiments or randomized controlled trials, and that derived from associations found in observational studies. 3.1. Experimental data The experimental data fall into four functional groups: (1) calcium absorption; (2) osteoporotic fractures; (3) falls; (4) response to infection. 3.1.1. Calcium absorption The oldest recognized function of vitamin D is the facilitation of calcium absorption from the intestine, now understood to involve a genomic action whereby 1,25(OH)2 D induces the formation of a calcium transport protein responsible for shuttling calcium ions from the brush border of the mucosal cell to the baso-lateral membrane. While this activity is generally recognized as the mechanism which is deranged in the extreme vitamin D deficiency that results in such disorders as rickets and osteomalacia, there is a paucity of data with respect to the quantities of vitamin D needed to optimize this function at levels above those producing rickets. Fig. 2 presents the data from three studies [17–19] showing a seeming threshold of absorptive performance as a function of vitamin D status. Important for our consideration is the
Fig. 2. Fractional calcium absorption values plotted against serum 25(OH)D from Heaney et al. [17], Barger-Lux and Heaney [18], and Bischoff et al. [19]. Error bars are 1 S.E.M. (Copyright Robert P. Heaney, 2005. Used with permission).
ascending limb of the curve, which indicates that absorptive performance improves as vitamin D status rises (for these data, up to a level of ∼80 nmol/L). In other words, below 80 nmol/L, vitamin D status is rate-limiting, whereas above 80 nmol/L other physiological controls become operative. This is not the place to explore how or why, in adults, serum 25(OH)D seems to be a better predictor of absorptive performance than is serum 1,25(OH)2 D [20,21]. My concern here is solely with serum 25(OH)D concentration as an indicator of vitamin D status, and with its relation to absorptive performance. Given prevailing calcium intakes, it seems clear that improved absorptive performance is physiologically beneficial. 3.1.2. Osteoporotic fractures The mechanisms of vitamin D’s action in fracture risk reduction include some combination of improved calcium absorption, reduced fall risk (see below), protection of bone mass, and reduction of excessive bone remodeling. At least four randomized controlled trials have found reduced fracture risk with vitamin D supplementation [22–25]. A formal meta-analysis focusing on hip fracture calculated a significant risk reduction associated with vitamin D doses in the range of 700–800 IU/d or higher, but found no effect for doses as low as 400 IU/d [26]. In at least three of these trials serum 25(OH)D change was measured; the treatment produced an increase from control values of 50–70 nmol/L to treated values of 74–110 indicating in each case that the lower value, though well above the osteomalacia range, was nevertheless associated with preventable fractures. Two of the four trials used calcium in addition to vitamin D and the point estimates of fracture reduction were greater in them. Nevertheless, vitamin D alone was effective in the other two. It may be worth noting that it is arbitrary and artificial to separate calcium from vitamin D in analysis of such studies. Vitamin D and calcium are clearly synergistic, as well as complementary (i.e.,
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vitamin D adequacy permits optimal extraction of calcium from low calcium diets, and high calcium intakes mitigate the reduced absorption of inadequate vitamin D status). Several other trials failed to find a significant effect on fracture risk [27–29]. Aside from the fact that inconclusive trials are always to be expected when investigative power is less than 100%, discernible factors explain at least some of the failure. For example, one large population-based trial using daily oral dosing of 800 IU vitamin D, found no significant effect [27]. Documentable compliance was on the order of 40%, and the rise in serum 25(OH)D produced in the treated subjects did not reach a therapeutic level. By contrast, a second trial, performed in a similar population, used 100,000 IU cholecalciferol every 4 months by mouth (averaging ∼800 IU/d), producing a rise in serum 25(OH)D up into the therapeutic range, and a 33% reduction in all osteoporotic fractures combined [25]. Similarly, the calcium and vitamin D arm of the Women’s Health Initiative (WHI) failed to find a significant fracture reduction by intention-to-treat [29]; however, the vitamin D dose was only 400 IU/d, and at 60% compliance, that fell to only 240 IU/d. 3.1.3. Falls Several trials of vitamin D for falls reduction have been reported, and they, in turn, have been subsequently incorporated into a meta-analysis [30], the conclusion of which was that there was a significant overall effect, with vitamin D reducing fall risk, in some reports substantially. This effect is believed to be due to improved muscle tone and strength, as there are vitamin D receptors in striated muscle, and vitamin D appears to play a role in the signaling that is responsible for muscle protein synthesis. Bischoff et al. [19] demonstrated a 49% reduction in falls in a 12-week trial, in women with average serum 25(OH)D concentrations of 30 nmol/L, and in a reanalysis of another randomized trial (having fracture as the primary endpoint) found a significant, 56% reduction in falls in women, and a 76% reduction in sedentary women [31]. Average 25(OH)D value in this group was 65 nmol/L, substantially higher than found in the women of the earlier study, suggesting continuing benefit up to and above 80 nmol/L. As falls are a major factor in osteoporotic fracture risk, substantial reduction in fall frequency has to be considered an important benefit. 3.1.4. Response to infection It has been recognized for nearly a century that patients with rickets are more prone to various infectious diseases, particularly of the lung, although the mechanism was not well understood. Vitamin D is now recognized to be active in controlling various aspects of the immune response [32,33], and perhaps the best worked out example is found in a recent report on the innate immune system, assessing the response of the system to a standardized challenge resulting in activation of toll-like receptor-2 [34]. In this work human monocytes cultured either in fetal calf serum or in human serum synthesize a bactericidal peptide when toll-like receptor-2 is
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activated. The response, however, depends upon a source of vitamin D. Serum with low concentrations of 25(OH)D elicits only a severely blunted response. A recent randomized controlled trial of vitamin D as adjuvant therapy in patients with pulmonary tuberculosis being treated with standard therapy demonstrated a substantial enhancement of treatment response, with 100% sputum conversion in the vitamin D-treated group by the end of the course of the treatment [as contrasted with a 76% conversion in patients receiving the standard therapy, but no vitamin D] [35]. 3.1.5. Comment In the foregoing four areas, experimental and/or randomized trial data demonstrate decreased disease or dysfunction associated with elevation of vitamin D status from levels prevailing in the populations studied. Except for calcium absorptive performance, none of the available data specifically bears on what may be the optimal level for serum 25(OH)D for that particular outcome. Most of the studies in which change in 25(OH)D was documented resulted in elevations on the order of 20–30 nmol/L (for a vitamin D dosage generally in the range of 700–800 IU/d). Whether greater benefit would have been produced with higher doses and a greater elevation of serum 25(OH)D cannot be determined. Nevertheless, it seems reasonably certain that a population-level elevation of at least 20 nmol/L would have a major, highly beneficial effect on morbidity as it relates both to skeletal health and to response to infections. 3.2. Observational data 3.2.1. The calcium economy The impact of vitamin D on the calcium economy, per se, is expressed mainly as decreased calcium input into the extracellular fluid, both from the intestine and from bone. This low calcium challenge immediately elicits an increase in parathyroid hormone secretion which is sustained so long as the calcium input remains low. Thus, serum PTH and 25(OH)D have been frequently reported to vary inversely [12–14,36]. The relationship has been described as either curvilinear or biphasic, exhibiting an inflection point below which serum PTH rises as serum 25(OH)D falls, but above which, serum PTH remains constant, irrespective of changes in serum 25(OH)D. The location of that inflection point along the serum 25(OH)D continuum has been variously reported from the neighborhood of 45–50 nmol/L up to as high 110–120 nmol/L. The inflection point, itself, is an inverse function of calcium intake in a population. For any given vitamin D level, calcium absorption will vary more or less directly with calcium intake [37]. Thus, high calcium intakes effectively mitigate some of the hypocalcemic challenge that results from vitamin D deficiency. It is in part for this reason that it has been argued that the location of the inflection point is not a very reliable indicator of the lower end of the optimal range for vitamin D status.
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Nevertheless the fact that PTH begins to rise at 25(OH)D levels that are substantially above the osteomalacic range is an indicator of physiological compensation for inadequate vitamin D-mediated calcium input, and thus constitutes presumptive evidence of physiological compromise as a result of low vitamin D status. Aside from physiological optimization, it is perhaps more relevant to note that parathyroid hormone is the principal determinant of the quantity of bone remodeling in the skeleton. It is now recognized that remodeling is a more important determinant of fracture risk than is bone mass [38–40]. For this reason alone, PTH levels above those that would occur with full vitamin D repletion have to be considered a fracture risk factor. 3.2.2. Skeletal status Numerous reports indicate that bone mineral density varies directly with serum 25(OH)D. Perhaps most pertinent to a North American population are the data from NHANES-III [41], analyzed by Bischoff-Ferrari et al., showing a continuous positive relationship between BMD at the hip and serum 25(OH)D in whites, blacks, and Hispanics, out to 25(OH)D levels well in excess of 100 nmol/L. In this national, population-based dataset, the rise in BMD on 25(OH)D was steepest below 40 nmol/L, but continued to be positive throughout the range of 25(OH)D values observed in U.S. adults. Other things being equal, more massive bones are more fracture resistant. 3.2.3. Neuromuscular status Neuromuscular status is a predictor of fall risk and hence has been the subject of numerous investigations. In general, instability, slowness of gait, sway, and similar indices of lower extremity function have been found to be inversely associated with 25(OH)D levels. Once again, using the data assembled by NHANES-III, Bischoff-Ferrari et al. were able to show that performance of elderly individuals on timed 8-foot walks and time to rise from a chair improved as 25(OH)D status improved, throughout the entire range of values observed in the population concerned [42]. As with BMD, the largest improvement was observed at the low end of the 25(OH)D continuum, but performance continued to improve even at values above 100 nmol/L. Comparable data have recently been presented from the Amsterdam Longitudinal Aging Study [43], some of the data of which are presented in Fig. 3. In this study lower extremity performance was assessed on a 12 point scale. As the figure shows, performance improved as serum 25(OH)D rose. There was not only a significant trend upward, but a significant difference step-by-step. The highest grouping was demarcated at 75 nmol/L and it is thus impossible to decide whether higher levels of 25(OH)D would have been associated with still better performance. 3.2.4. Cancer The literature on the relationship between vitamin D status and cancer risk and/or cancer mortality is too vast to summarize even superficially in this context. The available
Fig. 3. Performance scores in elderly individuals from the Amsterdam Longitudinal Aging Study, plotted by 25 nmol steps for serum 25(OH)D. Adapted from Wicherts et al. [43].
data are essentially all observational in character. First of all, it has long been recognized that cancer mortality varies directly with latitude (and hence inversely with sun exposure) [32,33,44]. Several large databases now contain information on antecedent measurements of serum 25(OH)D, from which prospective risk of cancer can be assessed. Ahonen et al. [45], for example, reported that men with serum 25(OH)D values below the median for the population had a 70% greater risk of incident prostate cancer than individuals above the median, with the risk declining by 25(OH)D quartile. In the Nurses’ Health Study risk of colorectal cancer declined as serum 25(OH)D rose, with values in the range of 75–80 nmol/L carrying a cancer risk roughly half that of individuals in the lowest quartile [46]. Gorham et al. [47], pulling together several reports of colorectal cancer risk, found a clear inverse relationship between serum 25(OH)D level and relative risk of incident colorectal cancer. They estimate that, at a serum 25(OH)D of 80 nmol/L, colorectal cancer risk is reduced by 50%. Even WHI, which ostensibly reported no benefit from a calcium-vitamin D intervention, nevertheless observed a highly significant inverse relationship between baseline serum 25(OH)D and incident colorectal cancer risk [48]. Those in the lowest quartile of serum 25(OH)D had an incident cancer rate 2.5× that of those in the highest quartile. Breast cancer risk, also, shows an inverse association both with UV-B exposure [45] and with serum 25(OH)D [49–51]; and there are at least two reports indicating that mammographic densities, recognized to be a risk factor for breast cancer, vary inversely with serum 25(OH)D status, with the lowest risk being found at or above serum 25(OH)D levels of 80 nmol/L [52,53]. For all of these studies, risk drops as serum 25(OH)D rises up to at least levels of 80 nmol/L. However, since large num-
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bers of individuals with still higher values are not commonly found in the populations at risk for the cancers concerned, it is not possible to estimate whether the trend lessens above 80 nmol/L, or whether higher values might have been associated with even lower cancer risk. 3.2.5. Other diseases There is a substantial body of evidence indicating an inverse relationship between vitamin D status (or UV-B exposure) and risk of Type I diabetes, various arthritides, multiple sclerosis, periodontal disease, and other chronic disorders [32,33]. For example, in NHANES-III, Scragg et al. [54] showed that the likelihood that blood sugar values (either fasting or following a standard glucose challenge) would fall in the diabetic range was an inverse function of serum 25(OH)D status. In another study, employing a standard glucose tolerance test, blood sugar values at various time points during the test were an inverse function of 25(OH)D status, with blood sugar exhibiting an inflection type of behavior similar to that observed for PTH [55]. The data are too sparse to permit a precise estimate of the location of the inflection point, but the point estimates from available data would place that inflection at somewhere in the range of 110–120 nmol/L. These and other studies, too numerous to mention, complement the information available from randomized trials or physiological experiments. Thus, the neuromuscular functional relationship complements the data on fall reduction from controlled trials of vitamin D supplementation, and the BMD and PTH data complement the data on fracture risk reduction with vitamin D treatment. There are no randomized trials of cancer prevention using vitamin D as the primary intervention, but there is a large body of animal data clearly establishing several biological mechanisms for enhanced oncogenesis in the face of moderate to severe vitamin D deficiency. The extreme difficulty associated with performing randomized trials of, for example, cancer prevention makes it doubtful that we shall soon see so-called “level I” evidence with respect to certain of these disease endpoints. Nevertheless, if population level vitamin D status is raised to levels that optimize skeletal status and minimize fracture risk, it may well be that evidence of efficacy for the other disease endpoints summarized superficially in this section will come, not from controlled trials, but from public health statistics, documenting a fall in disease incidence, just as occurred with dental caries following water fluoridation, or with pellagra, following niacin fortification of wheat flour. In any event, the possibility that some of the diseases briefly discussed might benefit from improving vitamin D status adds a level of urgency to the case that can be made for those diseases for which level I evidence is available.
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ing the issue in such distributional terms helps focus on two critical questions: (1) how much additional vitamin D input would be required to ensure that 97.5% of the target population would be above the lower limit of desirable normal (e.g., 80 nmol/L); and (2) for those already at or above this target value, what effect would the same level of supplementation have on their values, and what would be the risk to them of vitamin D toxicity? In a dose-ranging experiment we have shown that serum 25(OH)D rises by 0.7 nmol/L for every microgram (40 IU) of cholecalciferol given as a continuous daily oral input [56]. That means that an individual with a baseline value of 50 nmol/L, in whom one wished to achieve a value of 80 nmol/L, would require (80 − 50)/0.7 = 1714 IU/d, continuously, in addition to all existing inputs (diet, supplement, and solar exposure). Most published reports of the elevation of serum 25(OH)D by varying doses of cholecalciferol produce slope values in the range we have observed (i.e., 0.6–1.2 nmol/L/g/d). Both to ease calculation and to take a conservative figure, we may use a value of 1.0 nmol/L/g/d to estimate the dose required to shift the population by any specified amount. Thus, taking the distribution presented in Fig. 1, with 2.5% being at or below 31 nmol/L, one can calculate that it would take ∼2000 IU/d of additional input for everyone to raise that 2.5th percentile to 80 nmol/L. (If the rate of rise is closer to the number we measured, i.e., 0.7 nmol/L/g/d, then it would take proportionately more (i.e., ∼2900 IU/d) to ensure that no more than 2.5% of the population were below 80 nmol/L.) Corresponding calculations can be made for those at the upper end of the distribution. In the population presented in Fig. 1, the 97.5th percentile was at 112 nmol/L; and using the conservative slope value of 1.0 nmol/L/g/d, the 2000 IU/d dose needed to raise the 2.5th percentile up to 80 would elevate individuals at the 97.5th percentile to 162 nmol/L. As there are no credible estimates of toxicity from vitamin D at serum 25(OH)D levels below 250 nmol/L, this level of supplementation/fortification would still carry a substantial margin of safety even for those individuals already at the high end of the 25(OH)D distribution. More to the point, values as high as 200 nmol/L are found not infrequently in light-skinned outdoor workers at end of summer [18,57]. In this connection, there is probably an additional margin of safety, inasmuch as the 1.0 nmol/L/g/d factor is a higher value than any observed for dose response at the high end of the 25(OH)D continuum, and the figure we derived (0.7 nmol/L/g/d) is probably closer to the reality. Using a lower value for slope necessarily results in a smaller increment for those who are already high, and thus there may be even less basis for concern about safety.
3.3. Improving vitamin D status
4. Research needs
Improving vitamin D status at a population level means shifting the distribution of 25(OH)D values to the right. Pos-
Although the research opportunities in the field of vitamin D biology seem nearly limitless, two very practical needs are
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evident from this brief analysis. These are the need to provide a firm determination of the lower end of the physiological range of vitamin D status, taking into consideration all relevant system endpoints, not simply the calcium economy. Second is the need to define more precisely the variation in response of individuals to given vitamin D inputs. The foregoing calculations, although taking into consideration the wide variation in vitamin D status, assumed a fairly uniform response at a population level to additional vitamin D inputs. That is almost surely not the case, and we shall need a firmer estimate of individual variability in response before we can have confidence that a given supplementation/fortification regimen would produce the desired results.
5. Comment This presentation has focused on the case for improvement in vitamin D status, and has largely ignored the logistics issues that may be associated with achieving such a result. The successful nutritional interventions of the past have come about largely because of fortification of foods widely consumed by various population sectors (e.g., cereal grains). Wheat flour, for example, was the vehicle used to improve iron and B vitamin status, and cereal grains, folate status. The addition of iodine to salt (mandated in some nations, but optional in the U.S.) has largely eradicated endemic thyroid goiter where implemented, and the addition of fluoride to drinking water has had a similar impact on the prevalence of dental caries. The optimal route of improvement of vitamin D status of the populations of the industrialized nations remains to be determined, but it will likely involve some level of fortification of one or more foods. It would seem important for the nutrition community to focus on this issue soon, as the lag time between reaching a firm conclusion and implementation in practice is discouragingly long. It is sobering to recall that the Food and Nutrition Board of the National Academy of Sciences first petitioned the U.S. Food and Drug Administration for folate fortification of cereal grains in 1974, and it was an additional 24 years before the current, modest level of fortification was mandated. One hopes that the time course for vitamin D will be substantially shorter.
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