Dietary Reference Intakes for Calcium and Vitamin D.

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 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 theDRI 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 2000IOM 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 withEAR andRDA values—suggest that average requirements are being met for theDRI 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 settingDRI 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 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 theDRI 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;
• 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 forDRI 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 anIOM 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 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 inChapter 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 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 1997IOM 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 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 inChapter 1, theDRI 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 firstDRI 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 process 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 inTaylor, 2008) that is focused on methodologies for approximating dose–response relationships warrants attention, as it is likely thatDRI 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 forDRI 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 inTaylor, 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 ofAI 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 number 4-2³ inTaylor, 2008), because it is not entirely consistent with the statistical approach based on distributions of requirements that underpin the DRIs. Guidelines for the use of AIs would be helpful, both those that exist for other nutrients at this time as well as those that might be specified in the future.

Adiposity

As highlighted inChapter 3, excess adiposity or obesity—defined as a body mass index (BMI) measure of 30 mg/m² or higher—is associated with lower serum 25OHD concentrations (and higher parathyroid hormone levels) than found in non-obese counterparts. This would appear to be due to sequestration of 25OHD by adipose tissue, given that supplementation of obese and lean persons with vitamin D appears to result in no significant difference in response between the two groups (Jones, 2008). Moreover, a few studies of modest weight loss have found circulating 25OHD levels to increase despite no increased intake of vitamin D from diet or sun exposure (Riedt et al., 2005;Reinehr et al., 2007;Zittermann et al., 2009;Tzotzas et al., 2010), suggesting release from adipose stores with adipose depletion. Further, neither season nor ethnicity influences these biochemical parameters (Alemzadeh et al., 2008).

An important concern is whether the lower serum 25OHD levels associated with obesity have meaningful consequences for theDRI indicator of bone health. Evidence for effects of obesity on bone density is mixed. The combined influence of increased weight-bearing activity and endogenous synthesis of estrogen due to outcomes of increased adiposity has long been associated with higher bone density (Reid, 2008). In a population-based study in Finland of perimenopausal and early postmenopausal women,Pesonen et al. (2005) found that increased body weight was a strong predictor of high bone density. Likewise,Morin and Leslie (2009), in a retrospective cohort study, found a strong correlation between higherBMI category and high bone density in postmenopausal women.

Although these and other studies have suggested that total body mass contributes to bone density and would appear to support the role of increased weight-bearing activity as a factor positively influencing bone density (Prentice et al., 1991;Khosla et al., 1996;Wortsman et al., 2000;Finkelstein et al., 2002,2008), more recent studies lead to further questions. The distribution of body fat may influence bone mass, such that excess intra-abdominal fat could adversely affect bone remodeling and even contribute to greater fracture risk (Premaor et al., 2010;Sukumar et al., 2011). One possibility is that intra-abdominal adipose tissue is more biologically active than subcutaneous fat, secreting cytokines and adipokines that negatively affect osteoblast and osteoclast activity (Kawai and Rosen, 2010). Moreover, both lean and fat mass contribute to weight-bearing effects. Because obesity is accompanied by increases in both lean mass and fat mass, at least in younger individuals, it is difficult to attribute the effect on bone density to fat mass as opposed to lean mass. Further, body composition changes with age, even in the obese; in turn, there may be less lean body mass in older individuals.

This complicates the ability to clarify how adiposity may affect bone health. As noted, some studies have suggested that adiposity or increased fat mass itself may be a factor in the development rather than the prevention of osteoporosis, particularly in the elderly.Zhao et al. (2007) observed that when the effect of mechanical loading from high body weight on bone density was statistically controlled, fat mass was inversely correlated with bone mineral content. Further investigation byZhao et al. (2008) suggested that molecular signaling pathways involved in osteoblast differentiation may contribute to the previously identified effect of increased adiposity on decreased bone mineral content, although a mechanism has not been elucidated. However, this science is just emerging and it is premature to speculate on its significance or relevance to bone health and bone density.

At this time, there is the possibility that obesity, at least in older persons, may not be beneficial for bone health and may be demonstrated to be a risk factor, not an advantage, for decreased bone density and, in turn, reduced bone health. There is no evidence that increases in calcium or vitamin D nutriture beyond the requirements specified for non-obese persons can affect this purported outcome.

Persons Living at Upper Latitudes in North America

The question of the impact of latitude on vitamin D nutriture is often a topic of concern or, at least, interest. The issue, however, is set in the context of the inability to specify a safe dose of sunlight that could contribute to vitamin D synthesis while also avoiding the risk of skin cancer. There are also the recognized challenges associated with quantifying the contributions from sun exposure coupled with the limited information on the role of stored vitamin D during seasonal changes. The prevailing assumption about the effect of latitude is that ultraviolet B (UVB) penetration decreases with increasing latitude (i.e., distance from the equator) and this, in turn, causes persons living at higher latitudes in North America to experience little or no UVB exposure, making them at risk for vitamin D deficiency. This assumption may not be entirely accurate. However, the question of latitude may work in tandem with other factors, discussed below, such as limited sun exposure overall or cultural and dietary practices. This section focuses only on the issue of latitude per se.

The relationship betweenUVB penetration and latitude is complex and not merely a function of distance from the equator. Other factors that come into play include the reduced atmosphere at the poles (about 50 percent less than at the equator), more cloud cover at the equator than at the poles, differences in ozone cover, and the duration of sunlight in summer versus winter. Geophysical surveys have indicated that UVB penetration over 24 hours during the summer months at Canadian north latitudes equals or exceeds UVB penetration at the equator (Lubin et al., 1998), suggesting that persons living in the northern latitudes are not necessarily receiving notably less total sunlight during the year. Rather, it suggests that there may be considerable opportunity during the spring, summer, and fall months in the far north for humans to form vitamin D and store it in liver and fat. Likewise, animals living in the same region that are consumed as part of the traditional diet are also rich sources of vitamin D (Keiver et al., 1988;Kenny et al., 2004;Brunborg et al., 2006;Kuhnlein et al., 2006).

These factors help to explain why latitude alone does not appear to predict serum 25OHD concentrations in humans. In a Finnish study, healthy subjects living above the Arctic Circle (latitude 66°N) did not have lower serum 25OHD levels than subjects living in southern Finland; in fact, the group living above the Arctic Circle had higher levels. Both groups achieved mean serum 25OHD levels above 90 nmol/L during the summer, whereas the mean serum 25OHD level at the winter nadir was 56 nmol/L in the south and 68 nmol/L in those living above the Arctic Circle (Lamberg-Allardt et al., 1983).

Persons Experiencing Reduced Vitamin D Synthesis from Sun Exposure

The DRIs for vitamin D established in this report are based on the assumption of minimal sun exposure. Therefore, they are regarded as adequate for persons who may be experiencing a reduced synthesis of vitamin D from sun exposure. Assuming that some population groups may be consuming less than the currentDRI values for vitamin D, the question is to what extent are these persons at risk for vitamin D deficiency, or, conversely, to what extent can inadvertent sun exposure be expected to compensate for lower intakes for these persons?

Alternative Diets or Changes in Dietary Patterns

Use of Calcium Supplements

The forms and nature of calcium supplements have been discussed inChapter 2, and their possible role in kidney stone formation as well as the emerging data regarding possible adverse cardiovascular effects have been outlined inChapter 6. The mechanisms for differential effects of food sources and supplement forms of calcium on kidney stone formation are complex and may relate to the timing of calcium administration. Approximately 80 percent of kidney stones contain calcium combined with oxalate or, less often, phosphate (Park and Pearle, 2007).Calcium in food or in supplements taken with food is believed to bind to dietary oxalate in the digestive tract, reducing the absorption and subsequent urinary excretion of oxalate and thus risk for kidney stones (urinary oxalate may be more critical than urinary calcium with respect to calcium oxalate crystallization) (Curhan et al., 1997). When calcium supplements are not taken with food, dietary oxalate is absorbed unopposed and thus is more available for stone formation. Although dairy foods, which are the major source of calcium in much of North America, have been suggested to contain an unidentified protective compound not found in supplements (Curhan et al., 1997), this possibility has not been well studied. Obtaining sufficient calcium via dietary sources is the preferred strategy—and it remains uncertain as to whether taking calcium supplements with food may reduce the likelihood of stone formation associated with supplement use. Head-to-head comparisons of different calcium supplement formulations with respect to risk for kidney stone formation are also lacking. In any case, given the desirability of not surpassing theUL for calcium intake and given that even those not meeting their requirement for calcium are nonetheless consuming some calcium from dietary sources that range from breads to dairy products, care must be taken in selecting a calcium supplement that when combined with dietary intake does not result in a total intake above the UL. The UL for a sizable proportion of the population, including groups that commonly consume calcium supplements, is 2,000 mg/day, which is relatively close to theEAR andRDA values. For these more vulnerable groups, supplements containing amounts less than the RDA may be appropriate given that their diet is likely to contain at least some calcium. Further, until better information is available to clarify the possible link between supplement use and kidney stone formation, taking calcium supplements with foods is advisable.

Moreover, in the case of persons prone to developing kidney stones who cannot get adequate calcium from diet (e.g., due to lactose intolerance), there is limited evidence from small, short-term trials suggesting that supplemental calcium in moderate doses may not increase risk for stone recurrence (Levine et al., 1994;Williams et al., 2001;Lewandowski and Rodgers, 2004). Again, taking supplements with food is desirable.

The ULs are defined for the healthy, general population. Nonetheless, gray areas are acknowledged to exist between healthy people and those with medical conditions; for some persons in these gray areas a calcium intake as high as theUL may no longer be considered without any risk. The effect of calcium intake in situations of hypercalciuria is not fully understood, but conditions leading to hypercalciuria (which may be exacerbated by adding extra vitamin D to an already high calcium intake) may warrant a more cautious approach to ULs for calcium in the future. In older adults experiencing illness or decline, hypercalciuria may develop. For pregnant women experiencing absorptive hypercalciuria and therefore at higher risk of renal stone formation, keeping calcium intake below the UL may also be most appropriate. Similarly, as lactation drives bone resorption, urinary calcium excretion decreases, the ionized serum calcium concentration rises slightly, intravascular volume is contracted and occasionally women become hypercalcemic. Under these and similar conditions, ensuring a calcium intake below the UL may be most appropriate. Greater surveillance of urinary calcium excretion in future studies may shed more light on the relationship between higher levels of total calcium intake and risk of hypercalciuria or hypercalcemia under special conditions.

Oral Contraceptive Use

The use of ethinyl estradiol oral contraceptives (OCs) has been hypothesized to reduce bone resorption and preserve bone density in premenopausal and postmenopausal women. This concept was based on clinical and observational evidence that ethinyl estrogen–based hormone replacement therapy reduced risk for osteoporosis in postmenopausal women (Zittermann, 2000). A non-systematic review of clinical trials carried out before 1994 indicated that the evidence at that time largely supported positive effects of OCs on bone density in postmenopausal women, although a number of trials in the review showed no effects (DeCherney, 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 ofOC 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 sinceLiu and Lebrun (2006) also suggest mixed results from studies onOC 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 ofOC 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 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 thein 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 byBronner 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 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 160IU/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 related 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 end-points 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 inTable 8-1.

TABLE 8-1

Drugs and Their Effect on Vitamin D Metabolism.