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Vitamin D and Health in the 21st Century: an Update |
1 From the Office of Dietary Supplements, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD (PMB, EAY, RLB, and MFP), and the Division of Nutritional Sciences, Cornell University, Ithaca, NY (PMB)
2 The Office of Dietary Supplements, The National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the American Society for Nutrition sponsored the conference. The views and opinions expressed in the articles included in these proceedings do not necessarily reflect those of the sponsoring agencies and organizations. 3 Address reprint requests to MF Picciano, Office of Dietary Supplements, 6100 Executive Boulevard, Room 3B01, MSC 7517, Bethesda, MD 20892-7517. E-mail: piccianm{at}od.nih.gov.
ABSTRACT
We summarize the discussions of a roundtable following the conference "Vitamin D and Health in the 21st Century: an Update." The roundtable participants offered additional information on vitamin D research needs from a critical, impartial, and interdisciplinary perspective. Although the group recognized the progress to date, they found that the available evidence on the relation of 25-hydroxyvitamin D, dietary intake, status, functional health, and adverse outcomes has significant limitations because most studies have been short term, have failed to consider important confounders such as baseline vitamin D status and body mass index, and did not study key populations. To meet these data gaps, the roundtable identified several overarching research needs: 1) long-term, high-quality dose-response studies with relevant outcomes, including bone health, other functional outcomes (such as immune function, autoimmune disorders, and chronic disease prevention), and adverse outcomes (such as hypercalcemia and hypercalcuria), especially in understudied population groups such as dark-skinned individuals, infants, adolescents, reproductive-aged women, and pregnant and lactating women; 2) further research to understand the relation of 25-hydroxyvitamin D threshold values to relevant functional outcomes in each life stage and in racial and ethnic groups; 3) further research to understand the metabolic partitioning, fate, and mobilization of key vitamin D metabolites at recommended and greater than recommended intakes to assess the availability of stored vitamin D, relative contributions of endogenously produced and dietary vitamin D, and impact of important confounders (such as body mass index) on vitamin D status; and 4) further research to define the maximal, long-term vitamin D intake to ensure safety for all humans.
INTRODUCTION
The Office of Dietary Supplements of the National Institutes of Health convened a roundtable discussion after the conference "Vitamin D and Health in the 21st Century: an Update" (1). The roundtable's purpose was to offer additional insights for identifying the vitamin D research needs from an interdisciplinary group of scientists. The charge to the roundtable was to engage in a "critical, impartial, interdisciplinary, and thoughtful discussion among the various perspectives represented by the roundtable participants on relevant scientific issues, the strength of the evidence, the gaps in our knowledge and the research needs. Consensus was neither sought nor required in identifying research needs or gaps of knowledge."
Here, we summarize the discussion from the various perspectives represented by the roundtable participants on the relevant scientific issues, strength of the evidence, gaps in our knowledge, and research needs. The 5 questions addressed by the evidence-based review (EBR) "Effectiveness and Safety of Vitamin D in Relation to Bone Health" (2) sponsored by the Office of Dietary Supplements and the Agency for Healthcare Research and Quality that framed the conference (discussed below) also framed the roundtable discussion. Participants based their discussion on the EBR, the presentations and discussions of the earlier conference, and their expert opinions.
The roundtable discussion chair was Clifford Rosen, Medical Director, Maine Center for Osteoporosis Research, St Joseph Hospital, Bangor, Maine. Roundtable members (who are listed in the front matter to this supplement) provided expertise in nutrition across the life cycle, vitamin D and calcium metabolism, nutritional assessment and toxicology, risk assessment, epidemiology, biostatistics, endocrinology, dermatology, immunology, osteoporosis and bone metabolism, cancer biology and biomarkers, pharmacokinetics, and large-scale nutrition and health intervention trials.
BACKGROUND ON CIRCULATING 25-HYDROXYVITAMIN D AS A BIOMARKER OF VITAMIN D
Before discussing the 5 EBR questions, the roundtable participants considered the usefulness and validity of circulating 25-hydroxyvitamin D [25(OH)D] as an indicator of vitamin D exposure, status, and functional outcomes. Circulating 25(OH)D most strongly reflects exposure to either dietary or endogenous sources of vitamin D, but it also indicates other processes, such as absorption and metabolism.
Key limitations in using 25(OH)D to define vitamin D status include 1) the nature of vitamin D as a prohormone, rather than as a nutrient per se; 2) its variability due to many nonnutritional factors (eg, season, geographic latitude, clothing, institutionalization, use of sunscreen) and physiologic state of the individual [eg, body mass index (BMI), extracellular volume, and vitamin D binding protein (DBP) concentration and affinity]; and 3) our lack of understanding of 25(OH)D economy in the body. We know that 99% of 25(OH)D circulates bound to DBP, but we do not understand how and to what extent 25(OH)D or other metabolites are mobilized from lipid storage pools to enter the circulation. Contributing to these major limitations of 25(OH)D as a status biomarker are the unknown extent of storage of vitamin D, potential dangers of its accumulation in adipose tissue, regulation of its mobilization from these stores, and the consequences of the saturation of this storage.
Furthermore, the strength of the relation of 25(OH)D to functional outcomes varies according to outcome and life or reproductive stage. Researchers have studied dose-response relations among vitamin D intakes, serum 25(OH)D concentrations, and functional health outcomes for bone but not for other outcomes. The emerging roles of vitamin D in immune function, autoimmune disorders, cancer, and other chronic diseases (such as diabetes) make the relation of these other functional health outcomes to 25(OH)D concentrations important to understand. Thus, the strongest evidence supports the use of 25(OH)D concentrations as a biomarker of exposure to dietary and endogenous vitamin D; its usefulness as an indicator of functional outcome at all life stages is less clear.
QUESTION 1: ARE SPECIFIC SERUM 25(OH)D CONCENTRATIONS ASSOCIATED WITH BONE HEALTH OUTCOMES IN CHILDREN, PREGNANT OR LACTATING WOMEN, OR IN OLDER MEN AND POSTMENOPAUSAL WOMEN?
Background
As a prelude to answering question 1, the roundtable participants discussed the relation of parathyroid hormone (PTH) and 25(OH)D concentrations across the life cycle. They noted that the parathyroid gland is a target for 1,25-dihydroxyvitamin D [1,25(OH)2D]. However, responses of PTH to vitamin D status vary across the life cycle. For example, the rise in PTH is important in adults because it signals ongoing bone loss, particularly in elderly women. In infants and children, the relation of PTH and 25(OH)D is similar to that in adults but its interpretation is different because PTH regulates normal bone growth. The roundtable participants noted that 4 y of National Health and Nutrition Examination Survey data for circulating concentrations of PTH and 25(OH)D will be available soon and researchers will need to analyze these data to inform our understanding of this relation for various ages, sexes, and physiologic states.
Nature of the concerns
The relation of 25(OH)D to bone health outcomes or relevant indicators of calcium status and metabolism varies among populations and at different life stages. For example, African American children absorb more calcium than do white children despite having 
50% lower circulating 25(OH)D concentrations. In addition, calcium absorption as a functional outcome of 25(OH)D is very different for children and reproducing women than for other adults. Therefore, the use of a single inflection point as a threshold for the entire population could be an oversimplification. However, what is not known is the concentration of 25(OH)D that might provide insufficient substrate for extra-renal production of the active metabolite 1,25(OH)2D.
The roundtable participants discussed the importance of understanding the role of vitamin D status in bone health in reproducing women and their infants and in postmenopausal women. For example, a low maternal vitamin D status during pregnancy has a negative impact on the infant's bones. In women of reproductive age and postmenopausal women, fair evidence [defined by the EBR (2) as "sufficient evidence of an association that is limited by consistency of results or lack of one ‘good’ quality study"] shows that serum 25(OH)D concentrations correlate with changes in bone mineral density (BMD). Results from the Women's Health Initiative (3) show a relation between serum 25(OH)D concentration and risk of hip fracture. The roundtable participants noted that factors regulating DBP can vary in different individuals. For example, estrogen therapy and the use of oral contraceptive pills change DBP by as much as a factor of 2 and increase the total amount of 1,25(OH)2D but not of free vitamin D. Moreover, interpretation based on circulating free versus bound vitamin D compounds may be questionable because the absence of DBP in null mutant mice does not influence the function of vitamin D. For these reasons, we need interpretative guidelines that are specific to reproductive states. Interpretative guidelines need to consider the relation of 25(OH)D to both status and functional outcomes.
The most widely recognized consequence of vitamin D deficiency in infants and children is rickets. However, rickets is a multifactorial disease stemming from several distinct etiologies, including insufficient vitamin D, calcium, and phosphorus. On a global basis, deficiencies of calcium, rather than of vitamin D, may be responsible for a large percentage of rickets cases, whereas in the United States, vitamin D deficiency is responsible for most cases of rickets. Therefore, data on rickets from other countries might not be relevant to the situation in the United States.
Even when the vitamin D concentration is low, the relation between threshold concentrations of serum 25(OH)D and rickets in infants and children is unclear. We lack good-quality data from population subgroups known to be at risk of vitamin D deficiency, such as dark-skinned and exclusively breastfed infants. Investigators have observed mean 25(OH)D concentrations of <25 nmol/L in white breastfed infants who do not exhibit signs of rickets, whereas this concentration in African American infants who have insufficient sun exposure is associated with rickets. In older children, no relation exists between 25(OH)D concentration and calcium absorption. Vitamin D–deficient rat pups are not rachitic and do not develop rickets while nursing because their calcium absorption is not dependent on vitamin D.
Despite these inconsistencies and complexities, the roundtable recognized that the 25(OH)D concentration has broad-based clinical utility in that clinicians can use it to identify individuals at risk of adverse bone outcomes. The clinical utility of serum 25(OH)D is greatest at the extremes of toxicity and deficiency, and it is less predictive in the middle range.
Research needs
The roundtable participants identified several research needs with respect to the relation between 25(OH)D concentrations and bone health outcomes in individuals of different life stages, racial groups, and ethnicities. The scientific community needs the following:
-hydroxylase knockout mice. This could improve our understanding of functional outcomes beyond bone health outcomes, such as immune function, autoimmune disorders (eg, diabetes), and cancer. QUESTION 2: DOES DIETARY INTAKE OR ENDOGENOUS PRODUCTION AFFECT CIRCULATING 25(OH)D CONCENTRATIONS?
Background
Given our current state of knowledge, 25(OH)D remains the best available marker of dietary and ultraviolet (UV) exposure. However, in using this as a marker of vitamin D status, scientists need to have a clear understanding of how processes other than UV and dietary exposures affect serum 25(OH)D concentrations.
Nature of the concerns
Given the variability of and confounding factors affecting 25(OH)D discussed above, assessing 25(OH)D at a single point in time and trying to relate that concentration to outcomes is problematic and imprecise. However, that is what many studies to date have done. In addition, the difficulty of measuring vitamin D content in foods and supplements makes assessing dietary exposure a challenge.
Research needs
The roundtable participants identified several research needs with respect to dietary intake or endogenous production that affects circulating 25(OH)D concentrations. The scientific community needs the following:
QUESTION 3: WHAT IS THE EVIDENCE FOR EFFICACY OF SUPPLEMENTARY DOSES OF VITAMIN D ON BONE MINERAL DENSITY, FRACTURES, OR FALL RISKS IN REPRODUCTIVE-AGED AND POSTMENOPAUSAL WOMEN AND ELDERLY MEN?
Background
Supplementary vitamin D increases serum 25(OH)D concentrations. Some researchers have suggested that 2.5 µg (100 IU) raises serum 25(OH)D concentration by 1–2 nmol/L but the supplementation dose needed to increase the serum 25(OH)D concentration varies greatly. The source of vitamin D (food versus supplement), for example, affects the magnitude of the increase in serum 25(OH)D concentration.
Other issues that also limit our understanding of supplementation's effects on 25(OH)D concentration and the functional outcomes of the 25(OH)D response include: 1) the potential contribution of 25(OH)D from foods, which the US food-composition tables do not currently include; 2) the contribution of stored 25(OH)D and other metabolites to serum 25(OH)D concentrations; and 3) whether population groups such as reproducing women and racially diverse individuals have differential responses to supplementation. Indeed, evidence exists to suggest that 25(OH)D concentrations in African American women do not increase in response to supplemental vitamin D.
Researchers also need to consider other factors that could influence the response of 25(OH)D concentrations to supplemental vitamin D, such as fortification of foods other than milk or orange juice, bioavailability in various populations, and the impact of food production methods on exposure levels. For example, wild-caught salmon is a good source of vitamin D, whereas the amount of vitamin D in farm-raised salmon varies widely depending on the specific farming practices. Investigations, especially dose-response studies, in laboratory animals and megadose studies in livestock could inform our understanding of these other factors that influence supplementation responses.
Nature of the concerns
No good evidence (defined by the EBR as "consistent results across studies with at least one study judged to be of ‘good’ quality") exists on the effects of supplemental vitamin D independent of supplemental calcium, phosphate, magnesium, and other nutrients on BMD. Trials assessing the outcomes of vitamin D supplementation differ from drug trials in that the vitamin D intake of the control or placebo group comes from a normal diet and endogenous production, rather than no exposure as in a drug trial. As a result, vitamin D–supplemented treatment group members usually consume supplements in the context of a calcium-replete diet that includes reasonable amounts of vitamin D. Supplemental trials do not typically assess or report the background dietary intakes of vitamin D and calcium. To further complicate the results of these trials, the baseline vitamin D concentration affects a person's response to supplements, but studies do not always determine or report the baseline vitamin D concentration. Such inherent variability can be reduced by using animal data, particularly for dose-response studies.
Even with these limitations, less hip bone loss occurs with vitamin D supplementation (typically in combination with calcium) in postmenopausal women and elderly men, but the effects of supplementation on other bone sites, bone mass, and bone mineralization are less clear. Whether the effects of vitamin D persist after supplementation ends is also unclear because the small increase that occurred was not maintained when participants no longer received supplementation. Researchers typically use dual-energy X-ray absorptiometry (DXA) to evaluate BMD, but DXA does not assess morphologic changes, which could also be important. Loss of bone mass with aging could reflect compartmentally specific rather than general structural changes. Imaging techniques might advance our knowledge of vitamin D supplementation's effects on bone beyond what we can determine using DXA or other traditional BMD measures. Vitamin D could enhance osteoblast differentiation, which could play an important role in determining vitamin D's effects on BMD.
Most studies on the effect of vitamin D supplementation on BMD and other outcomes do not adequately consider several confounders across the life cycle. For example, BMD is not a good measure of vitamin D supplementation outcome in children. In postmenopausal women, the hormonal milieu drives bone balance, at least with the doses studied to date. As noted earlier, investigators studying the outcomes of vitamin D supplementation need to consider baseline vitamin D status, calcium status, and BMI. Furthermore, supplementation studies have not included some population groups, such as women of reproductive age, Hispanics, and pregnant and lactating women. Despite these limitations and the confounders in existing studies, we know that vitamin D supplementation affects bone density to some extent in postmenopausal women and elderly men.
In general, the evidence on the interventional effect of calcium combined with vitamin D or vitamin D alone is inconclusive and conflicting with respect to fractures and risk of fractures in all life stages. Authors have reported that supplemental calcium and vitamin D combined reduced fracture risk in a study of older adults with low vitamin D status and stress fracture risk in a study of female military personnel. However, we do not know whether vitamin D alone would produce such a reduction. These inconsistencies in results might reflect differences in compliance rates with supplementation or vulnerable population subgroups that respond differently from the general population. In the Women's Health Initiative (3), only a small subsample out of the entire study population of postmenopausal women from 40 Women's Health Initiative centers benefited from supplementation with calcium and vitamin D. If compliance rates are different in vulnerable populations, targeting these groups in research or public health programs could be important. Researchers studying the outcomes of supplementation also need to consider muscle quality with respect to fracture risk because of its contribution to falls and subsequent fractures.
Vitamin D alone or combined with calcium reduces fall risk by 20% in the elderly—and even more in institutionalized individuals—and this potential reduction could have a significant public health impact. PTH might mediate vitamin D's effect on falls. Muscle type might also be important; muscle power is a key component in a calcium-transport-dependent mechanism. For example, the muscle weakness in vitamin D–deficient rats is due to consequent phosphate deficiency, and the decreased muscle strength in older adults might be due to the effect of vitamin D on insulin and glucose transport. Confounding factors such as physical activity, balance, and vision also affect risk of falls, so researchers need to consider and control these factors in studies of vitamin D and falls.
Research needs
The roundtable participants identified 2 major research needs with respect to the efficacy of supplementary doses of vitamin D in increasing BMD and reducing the risk of fractures and falls in reproductive-aged and postmenopausal women and elderly men. The scientific community needs the following:
QUESTION 4: IS THERE A LEVEL OF SUN EXPOSURE THAT IS SUFFICIENT TO MAINTAIN ADEQUATE VITAMIN D LEVELS BUT DOES NOT INCREASE THE RISK OF SKIN CANCER?
Background
Skin cancer is the most common cancer in the world. Good evidence relates DNA damage to UV light exposure and demonstrates a clear relation between any UVA or UVB exposure and skin cancer risk. The risk of skin cancer increases with exposure to any UV dose, even a low dose. Currently, limiting exposure to UV light is the most effective means to control skin cancer. Melanomas are on the rise, although this is not entirely related to UV exposure. Nonmelanoma skin cancers in older adults may be caused by early lifetime UV exposures.
Nature of the concerns
A key question is whether a UV exposure level exists that would provide the benefits of adequate vitamin D status without increasing the risk of skin cancer. The fact that neither sunscreen nor vitamin D supplements are available to all populations highlights the usefulness of such information. Can we find a compromise between the current viewpoint that no safe dose of UV radiation exists and the suggestion by some that a level of sun (UVB) exposure exists—possibly with concurrent use of sunscreen—that is sufficient to produce the necessary vitamin D without increasing the risk of skin cancer?
When evaluating the relation between sun exposure and cutaneous production of vitamin D, the relevant factor to consider is skin pigmentation rather than race because skin pigmentation per se is the primary determinant of vitamin D production. Researchers can best evaluate skin pigmentation by using the Fitzpatrick scale (4), which has a range of 1 (always burns) to 6 (never burns).
A potentially important aspect of endogenously produced vitamin D economy may be its initial difference in metabolic partitioning; endogenously produced vitamin D enters the peripheral circulation and then binds to DBP, which transports it to the liver for further metabolism. In contrast, dietary vitamin D enters the peripheral circulation through the lymph bound to chylomicrons and is transported to the liver in remnant particles after peripheral metabolism.
Research needs
The roundtable participants identified 2 research needs with respect to the level of sun exposure that can maintain adequate vitamin D levels without increasing skin cancer risk. The scientific community needs to:
QUESTION 5: DOES INTAKE OF VITAMIN D ABOVE RECOMMENDATIONS LEAD TO TOXICITY?
Background
The roundtable participants characterized the current evidence on the safety of vitamin D as very limited, which underscores the need for extensive investigation in this area. Although the authors of the EBR (2) only identified a few adverse events in the studies included in their review, mainly in the Women's Health Initiative, with 10 µg (400 IU) of vitamin D per day in combination with 1000 mg Ca/d, the data reviewed in the EBR are generally not adequate to make a conclusion about vitamin D's toxicity. In addition, the roundtable participants suggested that the evidence used by the Food and Nutrition Board of the Institute of Medicine in 1997 to establish the tolerable upper level (UL) at 50 µg (2000 IU) of vitamin D per day (5) is also limited and of low quality.
Nature of the concerns
The roundtable participants discussed the need to identify the form of vitamin D most likely to produce toxic effects. They suggested that 25(OH)D might be more toxic than is vitamin D.
The roundtable participants were particularly concerned about the need to evaluate the safety of vitamin D within the context of long-term exposures, because we need intake recommendations for exposures throughout the life span. The 5-y timeframe of most National Institutes of Health grants is not sufficient to assess safety across a lifetime. Most currently available evidence is based on short-term exposure (
6 mo), so generalizations from these data to long-term exposures are problematic. In addition, most current evidence is limited to adult populations, and few data are available on infants, children, and other potentially vulnerable groups.
Traditionally, clinical trials may lack systematic procedures and protocols for collecting and reporting information on adverse effects. As a result, safety evaluations based on trial data might be biased against finding adverse effects. We can and should considerably improve the collection of information on adverse events in ongoing and future vitamin D trials.
Another concern expressed by the roundtable participants is the need for more data on potential nonskeletal effects of long-term, high doses of vitamin D. Bone-focused approaches to toxicity evaluations might be short-sighted, given the host of other potential adverse outcomes, such as aortic calcification. Many studies have not rigorously examined soft tissue calcification and other adverse outcomes.
Animal studies can provide valuable information on potential long-term safety concerns if these models have relevance to humans. Researchers could complete long-term toxicity studies that are not feasible in humans by using animal models. In addition, animal data could be useful for examining the homeostatic processes associated with high doses of vitamin D.
Finally, the roundtable participants identified concerns related to the absence of data on the relative toxicity of different sources of exposure, such as dietary intakes from foods versus supplements (with and without calcium). They also noted the paucity of data on a range of life stage groups and vulnerable populations. For example, obese persons have lower circulating 25(OH)D concentrations than do their leaner counterparts, which underscores the need to understand better the vitamin D kinetics in adipose tissues. The roundtable participants expressed concern about the excessive focus on 25(OH)D concentrations, which do not indicate whether vitamin D is entering and leaving the tissues. For example, clinicians often prescribe vitamin D to bariatric patients before bypass surgery but as they lose weight, their 25(OH)D concentrations increase. As discussed earlier, we do not understand the dynamics of the relation between 25(OH)D and the mobilization of its stores, which could have relevance to excessive exposure in some physiologic conditions.
Research needs
The roundtable participants identified several research needs with respect to the toxicity of high levels of vitamin D. The scientific community needs the following:
SUMMARY AND CONCLUSIONS
Despite considerable progress in recent years, the available evidence on vitamin D and health is incomplete. The roundtable participants identified several limitations in this evidence. Many studies to date have been short in duration and have failed to consider important confounders, such as baseline vitamin D status, BMI, and other important factors. Furthermore, most studies did not address key population groups, such as dark-skinned individuals; reproductive-age, pregnant, and lactating women; infants; and adolescents.
To fill these data gaps, the roundtable identified the following overarching research needs in addition to the question-specific research needs discussed above. The scientific community needs the following:
ACKNOWLEDGMENTS
The contributions of the authors were as follows—PMB, EAY, and MFP contributed equally to the development, drafting, and revision of this article; RLB contributed to the research, development, and revision of this article. None of the authors had a conflict of interest.
REFERENCES
This article has been cited by other articles:
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E. A Yetley, D. Brule, M. C Cheney, C. D Davis, K. A Esslinger, P. W. Fischer, K. E Friedl, L. S Greene-Finestone, P. M Guenther, D. M Klurfeld, et al. Dietary Reference Intakes for vitamin D: justification for a review of the 1997 values Am. J. Clinical Nutrition, March 1, 2009; 89(3): 719 - 727. [Abstract] [Full Text] [PDF]
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P. M Brannon, E. A Yetley, R. L Bailey, and M. F. Picciano Overview of the conference "Vitamin D and Health in the 21st Century: an Update" Am. J. Clinical Nutrition, August 1, 2008; 88(2): 483S - 490S. [Abstract] [Full Text] [PDF]
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