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DRI Dietary Reference Intakes Calcium Vitamin D 8 Implications and Special Concerns The last step in the risk assessment process is the step of so-called risk characterization. Its intent is to highlight the nature of the “risks” or public health problems that are relevant to the use of Dietary Reference Intakes (DRIs) and to alert users of the DRI reference values to implications of the assessors’ work and to related special issues. This chapter reflects the risk characterization step of the risk assessment approach and is organized to provide: a brief summary of the assessment; discussions about the implications of the committee’s work for stakeholders; and discussions to highlight population segments and conditions of interest relative to calcium and vitamin D nutriture. SUMMARY OF ASSESSMENT The new DRIs establish, for the first time, an Estimated Average Requirement (EAR) and a Recommended Dietary Allowance (RDA) for calcium and vitamin D. Previously, the DRIs for these nutrients reflected Adequate Intakes (AIs). The ability to set EARs and RDAs rather than AIs enhances the utility of the reference values for national planning and assessment activities. It is important to recognize that these values are intended for the North American population, and also that the requirement for each nutrient is based on the assumption that the requirement for the other nutrient is being met. Considerable effort was made to ensure that an array of indicators was examined as a possible basis for setting requirements, as well as upper levels of intake. The intent was to fully and objectively examine the scientific
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DRI Dietary Reference Intakes Calcium Vitamin D basis for the suggested benefit before drawing conclusions. Despite the many claims of benefit surrounding vitamin D in particular, the evidence did not support a basis for a causal relationship between vitamin D and many of the numerous health outcomes purported to be affected by vitamin D intake. Although the current interest in vitamin D as a nutrient with broad and expanded benefits is understandable, it is not supported by the available evidence. The established function of vitamin D remains that of ensuring bone health, for which causal evidence across the life stages exists and has grown since the 1997 DRIs were established (IOM, 1997). The conclusion that there is not sufficient evidence to establish a relationship between vitamin D and health outcomes other than bone health does not mean that future research will not reveal a compelling relationship between vitamin D and another health outcome. The question is open as to whether other relationships may be revealed in the future. Of great concern recently have been the reports of widespread vitamin D deficiency in the North American population. Based on this committee’s work and as discussed below, the concern is not well founded. In fact, the cut-point values used to define deficiency, or as some have suggested, “insufficiency,” have not been established systematically using data from studies of good quality. Nor have values to be used for such determinations been agreed upon by consensus within the scientific community. When higher cut-point values are used compared with those used in the past, they necessarily result in a larger proportion of the population falling below the cut-point value and thereby defined as deficient. This, in turn, leads to higher estimations of the prevalence of deficiency among the population and possibly to unnecessary intervention incorporating high-dose supplementation in the health care of individuals. National survey data suggest that the serum 25-hydroxyvitamin D (25OHD) levels in the North American population generally exceed the levels identified in this report as sufficient for bone health, underscoring the inability to conclude that there are significant levels of deficiency in the population. Specifically in terms of the new DRIs and challenges for calcium and vitamin D nutriture, several points can be highlighted, within the context of the limitations of estimates of dietary intake, which tend to be underestimates of actual consumption. First, for calcium, adolescent girls continue to be a group at risk for low intakes from food sources. Older women use calcium supplements in greater proportion, and some may be at risk for excess intake as a result of the use of high-dose supplements. If supplements are needed to ensure adequate calcium intake, it would appear that lower dose supplements should be considered. Many older women have baseline calcium intakes that are close to or just below requirements, and therefore the practice of calcium supplementation at high levels may be unnecessary. This is a special concern for calcium supplement use given
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DRI Dietary Reference Intakes Calcium Vitamin D the possibility that total intakes (diet plus supplements) above 2,000 mg/day may increase the risk for kidney stones, and demonstrate no increase in benefits relative to bone health. There is also some limited evidence that the long-term use of calcium supplements may increase the risk for cardiovascular disease. Although no attempt was made to compare systematically the data used for the North American population that is the subject of this report with data from other countries focused on persons who are genetically and environmentally different from those in the United States and Canada, it should be recognized that calcium requirements may be subject to a variety of factors that have not yet been fully elucidated and so therefore cannot yet be integrated into DRI reviews. For vitamin D, the challenges introduced by issues of sun exposure cannot be ignored. This nutrient is unique in that it functions as a prohormone, and the body has the capacity to synthesize the nutrient if sun exposure is adequate. However, concerns about skin cancer risk preclude making recommendations about sun exposure; in any case, there are a number of unknowns surrounding the effects of sun exposure on vitamin D synthesis. At this time, the only solution when DRIs are to be set for vitamin D is to proceed on the basis of an assumption of minimal sun exposure and set a reference value assuming that all of the vitamin D must come from the diet. Moreover, the possibility of risk for persons typically of concern because of reduced synthesis of vitamin D, such as persons with dark skin or older persons in institutions, is minimized given the assumption of minimal sun exposure for the DRIs. One unknown in the process of DRI development for vitamin D is the degree to which waning kidney function with aging may be relevant. It appears that increasing serum 25OHD levels do not typically increase calcitriol levels in aging persons with mild renal insufficiency, and a dietary strategy to address the concern is not evident. Although ensuring adequacy is important, there is now an emerging issue of excess vitamin D intakes. A congruence of diverse data on health outcomes ranging from all-cause mortality to cardiovascular risk suggests that adverse health outcomes may be associated with vitamin D intakes that are much lower than those classically associated with hypervitaminosis D and that appear to occur at serum 25OHD levels achievable through current levels of supplement use. IMPLICATIONS The extensive review of the data required to conduct this study and to determine DRIs for calcium and vitamin D that are consistent with existing scientific understandings has answered many questions. But, the process has also identified or left unanswered other questions due to the limita-
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DRI Dietary Reference Intakes Calcium Vitamin D tions of the available evidence. Because uncertainties exist in the knowledge base related to the role of vitamin D and calcium in health outcomes, it is important to acknowledge that there are uncertainties surrounding these reference values for calcium and vitamin D. The development of any reference value should be viewed as a work in progress, which may be subject to change if there are significant changes in the science base. Further, an important aspect of DRI development is its grounding in public health applications and the concept of distributions of risk. This approach may appear strange to some and may be disconcerting to those with a clinical orientation who are familiar with the medical model in which the goal is to treat the patient in the most efficacious manner to enhance a positive outcome. The interpretation and use of data in the case of DRI development are within the context of the relevant probability distributions of risk; the DRI task focuses on median requirements and the description of risk, whereas the medical model is based on maximizing effects that ensure beneficial outcomes for all persons. This report, therefore in contrast to a medical model approach, determines dose–response relationships by assessing the level at which 50 percent of the population’s needs are met (the EAR) and the level at which approximately 97.5 percent of the population are likely to have their needs met (the RDA). The distribution of dose–response effects is highly relevant to DRI development, compared with information about a maximizing effect for benefit. A difficulty the committee too often faced was studies that included only a placebo or baseline low dose coupled with a relatively large, single supplemental dose, as these are relatively uninformative for DRI development. Discussions below call attention to the uncertainties surrounding the DRI values for calcium and vitamin D and also highlight important conclusions that stem from the process of developing these DRIs. In addition, given that this report is the first effort to develop DRIs since the 2007 IOM workshop that explored lessons learned and new challenges and outlined the risk assessment approach for DRI development (IOM, 2008; Taylor, 2008), comments are offered about the process. Specific research recommendations for the future development of DRIs related to calcium and vitamin D are presented in Chapter 9. Assumption of Minimal Sun Exposure The committee’s assumption of minimal sun exposure is a markedly cautious approach given that the vast majority of North Americans appear to obtain at least some vitamin D from inadvertent or deliberate sun exposure. Currently, there is a lack of information about whether certain levels of sun exposure may be experienced without increased risk of cancer and whether such exposure would be consistent with a contribution of vitamin
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DRI Dietary Reference Intakes Calcium Vitamin D D useful to the body. Therefore, at this time, recommendations concerning sun exposure relative to vitamin D requirements cannot and should not be offered; there are no options other than to base dietary recommendations on the assumption of minimal sun exposure. The evidence to indicate that the synthesis of vitamin D from sun exposure is subject to a feedback loop that precludes toxicity from sun exposure is reassuring and, when coupled with the checks and balances introduced into the DRI development process, makes it very unlikely that consumption of the DRI levels of vitamin D, even if combined with high levels of sun exposure, will be problematic to the general population. However, given that many North Americans appear to obtain at least some vitamin D from inadvertent or deliberate sun exposure, there are implications for the interpretation of intake levels of the vitamin. In short, the intake data for vitamin D cannot stand alone as a basis for public health action on a national population level. Such considerations are consistent with the 2000 IOM report on applications of DRIs in dietary assessment (IOM, 2000), which states: “Whenever possible, the assessment of apparent dietary adequacy should consider biological parameters such as anthropometry, … biochemical indices, … diagnoses, … clinical status, and other factors as well as diet. Dietary adequacy should be assessed and diet plans formulated based on the totality of the evidence, not on dietary intake data alone.” In short, for policy making and decisions about the adequacy of the food supply for the general population at the national level, vitamin D must be considered in the context of measures of serum 25OHD, an established biomarker of exposure from endogenous synthesis as well as diet, including supplements. Although the reported estimates of vitamin D intake appear to be less than needed to meet requirements, the serum 25OHD data available—when coupled with the committee’s assessment of serum 25OHD levels consistent with EAR and RDA values—suggest that average requirements are being met for the DRI age groups nationally in both countries. That is, although mean total intakes of vitamin D generally are lower than the estimated median requirement (the EAR), the available clinical measures do not suggest widespread deficiency states. This underscores the possibility that sun exposure is contributing generally to the maintenance of adequate serum 25OHD concentrations. Uncertainties As discussed in the preceding chapters, there are limited data for many topics of interest in setting DRI values for calcium and vitamin D. Overall, the uncertainties surrounding the DRI values for calcium are less than those for vitamin D, because the evidence base is considerably larger for calcium, and the physiology and metabolism of calcium are better
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DRI Dietary Reference Intakes Calcium Vitamin D understood. The following key issues were identified by the committee as introducing uncertainty into the DRI values for calcium and vitamin D, as based on bone health outcomes: The tendency for study protocols to administer a combination of calcium and vitamin D, reducing the opportunity to ascertain the effects of each nutrient independently; The lack of data examining the responses and health outcomes due to graded doses of calcium or vitamin D intake so as to elucidate dose–response relationships; The interaction between calcium and vitamin D to the extent that it would appear that adequate calcium intake greatly diminishes the need for vitamin D relative to bone health outcomes; The unique situation in which a nutrient (vitamin D) physiologically serves as a prohormone introduced a myriad of variables and feedback loops related to its health effects; The paucity of data and resulting uncertainty concerning sun exposure that confound interpretation of the dose–response relationship between intakes of vitamin D and various health outcomes. This, coupled with the apparent contribution of sun exposure to overall vitamin D nutriture in North American populations, leads to an inability to characterize and integrate sun exposure with intake recommendations as much as may be appropriate, given the concern for skin cancer risk reduction, which must be paramount. Thus, for individuals who do not follow recommendations to avoid sun exposure, the uncertainty of the DRI values is greater than for those who do; The lack of clarity concerning the validity of the serum 25OHD measure as a biomarker of effect; The variability surrounding measures of serum 25OHD concentrations as a result of different methodologies used; A number of findings suggesting a strong role for metabolic adaptations and controls in the case of vitamin D, which complicates estimations of nutrient requirements. These include: the non-linear response of serum 25OHD level to vitamin D intake, which, in turn, suggests that it requires proportionately more vitamin D to continue to increase serum 25OHD levels after a certain serum 25OHD level is reached; the observation that seasonal declines in serum 25OHD level are greater if a person begins the winter season with a higher compared with a lower serum 25OHD level; and the lack of effect of age and body size (other than adiposity) on serum 25OHD levels;
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DRI Dietary Reference Intakes Calcium Vitamin D The limited number of long-term clinical trials related to calcium and vitamin D intakes and health outcomes; and The need to set ULs based on limited data in order to ensure public health protection. An important question that will undoubtedly be asked given this committee’s report, is: Why is it that so much information about the positive effects of vitamin D on outcomes such as cancer, diabetes, and immunity is said to exist and is reported almost daily in the press, but this committee found no basis to support these causal relationships? The short answer is that a systematic examination of the evidence, using established guidelines for measuring the strength and quality of studies, revealed that the claimed benefits based on the associations of low or high intakes of vitamin D on non-skeletal health outcomes could not be supported by the studies—the evidence was inconsistent and/or conflicting or did not demonstrate causality. In addition, some effects were not related to setting nutritional requirements for vitamin D. This conclusion, however, does not preclude pursuing investigation of causal relationships. Moreover, a related question that will be asked is: With the advent of newer studies, why is there still so much uncertainty? At least one reason is that most studies were not designed to seek data maximally useful for DRI development, which is well described by others (Yetley et al., 2009). DRI development fundamentally requires elucidation of dose–response relationships and benefits from data of high quality obtained in randomized controlled trials. In making its conclusions about potential indicators other than bone health, the committee noted the findings previously specified by an IOM committee tasked with examining the evolution of evidence for nutrient and disease relationships (IOM, 2002). That committee concluded that evidence about relationships between specific nutrients and a disease or health outcome typically remains elusive for a number of reasons (IOM, 2002). These include the following: Although preliminary evidence, usually from mechanistic studies, experimental animal studies, and observational studies in humans, can generate exciting new hypotheses about nutrient–health relationships, evidence from these studies has limitations. For instance, even in well-designed, large-scale observational studies, it is difficult to isolate the effects of a single nutrient under investigation from the confounding effects of other nutrients and from non-nutrient factors. Scientific advances in understanding relationships between specific nutrients and health outcomes do not necessarily emerge
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DRI Dietary Reference Intakes Calcium Vitamin D within a short time, and progress is often erratic. Some gaps are filled, while others are created. The etiology of disease–health relationships, especially in the case of chronic disease, is commonly multi-factorial. Even if diet has a prominent role, it is extremely unlikely that a single nutrient is directly responsible for a chronic disease or, conversely, that addition of a single nutrient will eliminate disease risk. It is possible that a focus on specific nutrients as risk factors for diseases in relatively homogeneous or diseased populations can lead to a number of spurious associations. Clinical trials, which are generally considered to provide the strongest evidence about the effects of nutrient intake on subsequent disease and health, are complex, expensive, and time-consuming, especially for chronic diseases that develop over decades and are influenced by a host of genetic, physiological, and environmental factors that may also affect risk. The committee found all of the above findings to be the case for non-skeletal health outcomes for vitamin D, as the discussions of the strength, consistency, and causality of the evidence demonstrate in Chapter 4. Finally, an important uncertainty focuses on the issue of excess intake. This is particularly true for vitamin D, which has been hypothesized to confer health benefits at relatively high levels of intake. Although the committee’s decisions for the ULs made use of emerging data concerning a U-shaped (or perhaps reverse-J-shaped) curve for risk, which suggested adverse effects at levels much lower than those associated with hypervitaminosis D, the lack of data on the safety of higher intakes of vitamin D when used chronically is very concerning. Byers (2010), in a recent editorial commenting on the outcomes of a pooling study focused on vitamin D and six types of cancer in which the only association observed was a doubling of the risk for pancreatic cancer for those in the highest quintile of circulating serum 25OHD levels, offered the following observation: “We have learned some hard lessons…. and we now know that taking vitamins in supernutritional doses can cause serious harm.” Conclusions About Vitamin D Deficiency in the United States and Canada Serum 25OHD levels have been used as a “measure of adequacy” for vitamin D, as they reflect intake from the diet coupled with the amount contributed by cutaneous synthesis. The cut-point levels of serum 25OHD intended to specify deficiency and sufficiency for the purposes of interpreting laboratory analyses and for use in clinical practice are not specifically
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DRI Dietary Reference Intakes Calcium Vitamin D within the charge to this committee. However, the committee notes with some concern that serum 25OHD cut-points defined as indicative of deficiency (or as reported by some, “insufficient”) for vitamin D have been subject to a wide variation in specification without a systematic, evidence-based consensus development process. In order to ensure clarity, the discussion in this section expresses serum 25OHD levels in both nmol/L and ng/mL measures. From this committee’s perspective, a considerable over-estimation of the levels of vitamin D deficiency in the North American population now exists due to the use by some of cut-points for serum 25OHD levels that greatly exceed the levels identified in this report as consistent with the available data. The 1997 IOM report (IOM, 1997) specified a serum 25OHD concentration of 27.5 nmol/L (11 ng/mL) and above as an indicator of vitamin D adequacy from birth through 18 years of age, and a concentration of 30 nmol/L (12 ng/mL) and above as an indicator of vitamin D adequacy for adults. This level (27.5 nmol/L for children, and 30.0 nmol/L for adults) remains a level below which frank deficiency including rickets and osteomalacia may be expected to occur. In recent years, others have suggested different cut-point values as determinants of deficiency (or “insufficiency”). These include values ranging from less than 50 nmol/L (20 ng/mL) to values above 125 nmol/L (50 ng/mL). Based on this committee’s deliberations, the vitamin D–related bone health needs of approximately one-half of the population may be expected to be met at serum 25OHD concentrations between 30 and 40 nmol/L (12 and 16 ng/mL); most of the remaining members of the population are likely to have vitamin D needs met when serum concentrations between 40 and 50 nmol/L (16 and 20 ng/mL) are achieved. Failure to achieve such serum concentrations place persons at greater risk for less than desirable bone health as manifested by, depending upon age, increased rates of bone accretion, bone mineral density, and fractures. Use of higher than appropriate cut-points for serum 25OHD levels would be expected to artificially increase the estimates of the prevalence of vitamin D deficiency. The specification of cut-point values for serum 25OHD levels has serious ramifications not only for the conclusions about vitamin D nutriture and nutrition public policy, but also for clinical practice. At this time, there is no central body that is responsible for establishing such values for clinical use. This committee’s review of data suggests that persons are at risk of deficiency at serum 25OHD levels of below 30 nmol/L (12 ng/mL). Some, but not all, persons are potentially at risk for inadequacy at serum 25OHD levels from 30 up to 50 nmol/L (12 to < 20 ng/mL). Practically all persons are sufficient at levels of 50 nmol/L (20 ng/mL) and above. Serum concentrations of 25OHD above 75 nmol/L (30 ng/mL) are not associated with increased benefit. There may be reason
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DRI Dietary Reference Intakes Calcium Vitamin D for concern at serum 25OHD levels above 125 nmol/L (50 ng/mL). Given the concern about high serum 25OHD levels as well as the desirability of avoiding mis-classification of vitamin D deficiency, there is a critical public health and clinical practice need for consensus cut-points for serum 25OHD. The current lack of evidence-based consensus guidelines is problematic and of concern because individuals with levels of 25OHD serum above 50 nmol/L (20 ng/mL) may at times be diagnosed as deficient and treated with high-dose supplements of vitamin D containing many times the levels of intake outlined in this report. Decisions Regarding Levels of Calcium and Vitamin D to Be Administered in Controlled Clinical Trials Although this report identifies upper levels of intake below which adverse effects are not expected to arise, ULs are intended to serve as a lifetime public health measure for a free-living, unmonitored population. Those responsible for determining the appropriate dosages of nutrients to be studied in carefully controlled experimental trials conducted with appropriate adverse event and safety monitoring have the opportunity to bring other considerations into play when deciding on the levels of nutrients that are acceptable and appropriate for subjects taking part and being monitored in such studies. Research using intakes higher than those specified in the ULs can be justified under a number of circumstances after careful review of the literature and through the use of appropriate study protocols. Indeed, such studies are likely to be informative to the understanding of dose–response relationships and the health benefits or risks associated with calcium and vitamin D intakes. The DRI Development Process As described in Chapter 1, the DRI development process has recently been subjected to a review as well as targeted discussions about the process and ways to enhance it (IOM, 2008). As an overall result of these discussions, DRI development is now placed more clearly in the context of the risk assessment approach—that is, an organizing framework for conducting evaluations with public health implications often made with evidentiary uncertainties. There is also a series of existing “gap issues”—specifically, needed methodologies and guidelines—that have been identified as important to improving and enhancing the process for developing DRIs and would benefit from targeted efforts to resolve the gaps (Taylor, 2008). The report of this committee is the first DRI report to be completed subsequent to the 2004 to 2008 evaluation of the DRI development process. It has been structured to be consistent with the risk assessment pro-
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DRI Dietary Reference Intakes Calcium Vitamin D cess with the intent of enhancing its transparency, especially in the face of uncertainties. Although this committee was mindful of the identified methodological gaps for enhancing the DRI process, it was not tasked with addressing them; in any case, virtually all of the relevant issues are complex and suggest a need to convene groups of individuals with specific expertise germane to the question at hand. Because this DRI report is an initial effort to set DRI development on the path of a risk assessment approach, its experience points to the importance of addressing several gap issues. Specifically: The identification of dose–response relationships for calcium and vitamin D relative to health outcomes was a major challenge. The gap issue1 (number 5-5 in Taylor, 2008) that is focused on methodologies for approximating dose–response relationships warrants attention, as it is likely that DRI efforts in the future will face the same challenges. With the exception of the inclusion of osteoporosis within the bone health measures, the existing data precluded the use of a chronic disease such as cancer or heart disease as an indicator for DRI development. However, had it been possible, this DRI process would have benefited from guidelines specifying what, if any, differences may apply to using chronic disease endpoints versus other types of endpoints for DRI development (gap issue number 4-42 in Taylor, 2008). In the committee’s judgment, sufficient new data were available to allow the development of EARs and RDAs, and it was no longer necessary to make use of AI estimates for calcium and vitamin D, except for infants. The AI is useful in that it allows the specification of some type of a reference value for use in public health settings—which is better than the absence of any value. However, it presents challenges in public health applications (gap issue num- 1 “New methodologies—many from other fields of study—are emerging and can be useful for examining and approximating dose–response relationships when available data are limited. These should be more closely examined and incorporated into the DRI process as appropriate” (Taylor, 2008). 2 “There is considerable interest—as well as more than 10 years of experience—surrounding the inclusion of chronic disease indicators within DRI development. A variety of perspectives were put forward. There is a need for focused discussions about how to include chronic disease indicators in the DRI process, including specific approaches for addressing their confounders, identification of appropriate biomarkers, and quantifying their effects” (Taylor, 2008).
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DRI Dietary Reference Intakes Calcium Vitamin D 1996). Among clinical trials and observational evidence examining the effects of OCs on bone density from the past two decades, results have been mixed and, when considered in total, are inconclusive. A systematic review of 75 studies of varied design, including 11 randomized controlled trials, examined outcomes of OC use and bone density in healthy premenopausal, amenorrheic premenopausal, anorexic premenopausal, and perimenopausal women (Liu and Lebrun, 2006). A meta-analysis was not done; however, the review found good evidence for a positive effect of OCs on bone density in perimenopausal women, fair evidence for an effect in amenorrheic premenopausal women, and limited evidence for an effect in anorexic and healthy premenopausal women. Observational studies published since Liu and Lebrun (2006) also suggest mixed results from studies on OC use and bone density that may be related to the population group studied. A small study on OC use and bone density and bone size in a young white female cohort found that OC use had a significant negative effect on bone density at the spine and heel and resulted in a non-significant decrease in hip bone density (Ruffing et al., 2007). Similarly, Hartard et al. (2007), in a cross–sectional analysis of young white women taking OCs, also suggested a negative effect of OCs on bone density. Women who had ever used OCs had significantly lower bone densities at the tibial shaft and femoral neck compared with those who had never used OCs. In premenopausal and postmenopausal women no significant difference was found between OCs users and never users in another cross–sectional study of the effects of OCs on bone density and bone markers (Allali et al., 2009). Randomized trials of estrogen treatment with and without vitamin D and calcium supplementation suggest a positive effect on bone density in postmenopausal women. Recker et al. (1999) tested vitamin D and calcium supplementation with and without low-dose hormone replacement therapy for effectiveness in maintaining bone density in postmenopausal women more than 65 years of age. Although this study did not differentiate between hormone replacement therapy alone and therapy combined with vitamin D and calcium supplementation, it did suggest an effect of increasing bone density and bone markers in older women who received the combination therapy compared with those who received vitamin D and calcium supplementation alone. A randomized, double-blind, placebo-controlled trial of OC therapy either alone or combined with calcitriol therapy found a significant increase in bone density and reduction in bone resorption at the hip compared with OC therapy alone in postmenopausal women (ages 65 to 77 years) who had normal bone density for their age (Gallagher et al., 2001). Another prospective randomized trial in postmenopausal women (ages 53 to 79 years) treated with hormone replacement therapy alone or with calcitriol also found a significant increase in bone density, at multiple
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DRI Dietary Reference Intakes Calcium Vitamin D sites and total body, for the combined therapy compared with hormone replacement alone (Gutteridge et al., 2003). Given the variability in all the study outcomes reviewed by the committee and the unresolved question of the effect of age and endogenous estrogen status on the ability of OCs to preserve bone density or prevent bone resorption, specific recommendations to address the impact of OCs with or without vitamin D and calcium supplementation for both premenopausal and postmenopausal women cannot be offered at this time. Premature Infants Premature infants are a clinical population and thus outside the scope of this committee’s task, which is focused on the normal, healthy population. However, because premature infants are a highly vulnerable group and do raise special concerns relative to calcium and vitamin D nutriture, this group is discussed here briefly. The minerals in human milk, especially calcium and phosphorus, do not fully meet the needs of rapidly growing premature infants who rely primarily on passive intestinal absorption of calcium, therefore “this and other factors place premature infants at high risk for nutritional rickets” (Abrams, 2005). “The recent addition of various forms of mineral salts and/or mineral fortifiers to human milk and the use of specialized preterm infant formulas with high calcium content have been reported to enhance the amount of calcium and other minerals retained from the diet, to increase the bone mineral content of the infants and to decrease the incidence of osteopenia and frank rickets in preterm infants (Schanler et al., 1988; Schanler and Abrams, 1995; Schanler, 1998)… The bioavailability of the calcium in these fortifiers may be a key aspect of their adequacy. Using a commercially available human milk fortifier, Schanler and Abrams (1995) reported that net calcium retention was 104 ± 36 mg/kg body weight per day in premature infants, a value approximating the in utero accretion rate during the third trimester. These retention values are well above those achieved using earlier human milk fortifiers (Schanler et al., 1988)” (Abrams, 2005). “Of interest is that calcium absorption from both fortified human milk and specialized preterm formula averages 50 to 65 percent in many studies (Abrams et al., 1991; Bronner et al., 1992). This constancy of absorptive fraction in premature infants suggests that much of the calcium absorption by premature infants and newborn full-term infants is not vitamin D dependent…” (Abrams, 2005), which is the conclusion of a review of more than 100 balance studies by Bronner et al. (1992). How much vitamin D is needed by premature infants is more difficult to determine. Unfortunately, there are no studies using modern isotope
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DRI Dietary Reference Intakes Calcium Vitamin D TABLE 8-1 Drugs and Their Effect on Vitamin D Metabolism Drug Name/Category 25OHD Calcitriol 24,25-Dihydroxyvitamin D Aluminum Not changed Increase/decrease — Anticonvulsants (phenobarbital, Dilantin, Tegretol) Decrease Not changed Decrease Antituberculosis Decrease Decrease — Bisphosphonates Not changed Increase/decrease/not changed Increase Cimetidine Decrease Not changed Not changed Corticosteroids Decrease/not changed Decrease/not changed Not changed Ethanol Increase Decrease — Heparin Not changed Decrease Not changed Hypolipidemic agents Decrease/not changed Not changed — Immunosuppressives Not changed Not changed — Ketoconazole Not changed Decrease Decrease Lithium Not changed Not changed — Rifabutin (anti-HIV) Decrease Not changed — Thiazides Increase Decrease Increase NOTE: — indicates that no information has been reported; HIV = human immunodeficiency virus. SOURCES: Hahn et al. (1972); Favus et al. (1973); Avioli (1975); Compston and Thompson (1977); Compston and Horton (1978); Bell et al. (1979); Alfrey et al. (1980); Palmer et al. (1980); Adams et al. (1981); Williams et al. (1985); Feldman (1986); Lalor et al. (1986); Lawson-Matthew et al. (1988); Dobs et al. (1991); Katz et al. (1994); Bolland et al. (2008). techniques of the effects of vitamin D on calcium absorption in premature infants, nor could such studies be possible practically or ethically. One study with oral vitamin D intakes as low as 160 IU/day (Koo et al., 1995) and multiple studies with intakes of 200 to 400 IU/day (Cooke et al., 1990; Pittard et al., 1991; Backstrom et al., 1999a) “demonstrated adequate serum 25OHD concentrations and clinical outcomes with oral vitamin D intakes as low as 160 IU/day (Koo et al., 1995). In addition, studies have generally failed to show any clinical benefit to increasing vitamin D intake above 400 IU/day in preterm infants (Backstrom et al., 1999b)” (Abrams, 2005). Routine measurement of serum 25OHD levels in premature infants is not supported by currently available clinical research. No studies have re-
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DRI Dietary Reference Intakes Calcium Vitamin D lated serum 25OHD level in these infants to specific clinical outcomes, and extremely few data suggest a dose–response relationship between serum 25OHD levels and other outcomes. A normal level at different gestational ages or postnatal ages is not available for 25OHD in serum based on endpoints such as calcium absorption or bone mineral content. However, in the presence of a likely impairment of 25-hydroxylation, such as might be present in an infant with cholestasis, measurement of serum 25OHD level might be considered, especially to ensure a level at or above 50 nmol/L (20 ng/mL). “The effects of other formula components on mineral absorption have also been considered. A study using a triple lumen perfusion technique demonstrated that calcium absorption was greater using a solution that included a glucose polymer rather than lactose (Stathos et al., 1996). As glucose polymers are widely used in preterm formulas, this effect may be clinically important. Altering the fat blend of infant formula to more closely resemble that of human milk may also enhance mineral absorption in premature infants (Carnielli et al., 1995; Lucas et al., 1997)” (Abrams, 2005). Interactions Between Vitamin D and Prescription Drugs Although clinical practice and related guidelines are outside this committee’s purview, it is useful to acknowledge that measures of the various forms of vitamin D can be affected by prescription drugs and related medications. A brief listing of key interactions can be found in Table 8-1. REFERENCES Abrams, S. A., N. V. Esteban, N. E. Vieira and A. L. Yergey. 1991. Dual tracer stable isotopic assessment of calcium absorption and endogenous fecal excretion in low birth weight infants. Pediatric Research 29(6): 615-8. Abrams, S. A. 2005. Chapter 49: Vitamin D deficiency and calcium absorption during infancy and childhood. In Vitamin D, 2nd Edition, edited by D. Feldman, J. W. Pike and F. Glorieux. London: Elsevier Academic Press. Adams, J. S., T. O. Wahl and B. P. Lukert. 1981. Effects of hydrochlorothiazide and dietary sodium restriction on calcium metabolism in corticosteroid treated patients. Metabolism 30(3): 217-21. Alemzadeh, R., J. Kichler, G. Babar and M. Calhoun. 2008. Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism 57(2): 183-91. Alfrey, A. C., A. Hegg and P. Craswell. 1980. Metabolism and toxicity of aluminum in renal failure. American Journal of Clinical Nutrition 33(7): 1509-16. Allali, F., L. El Mansouri, F. Abourazzak, L. Ichchou, H. Khazzani, L. Bennani, R. Abouqal and N. Hajjaj-Hassouni. 2009. The effect of past use of oral contraceptive on bone mineral density, bone biochemical markers and muscle strength in healthy pre and post menopausal women. BMC Women’s Health 9: 31.
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