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Chung M, Balk EM, Brendel M, et al. Vitamin D and Calcium: A Systematic Review of Health Outcomes. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Aug. (Evidence Reports/Technology Assessments, No. 183.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Vitamin D and Calcium: A Systematic Review of Health Outcomes.

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The Food and Nutrition Board of the Institute of Medicine (IOM), with funding from agencies and departments of the US and Canadian governments, recently completed their 10-year development of nutrient reference values entitled Dietary Reference Intakes (DRI).1 In September, 2007, the IOM held a conference to examine the lessons learned and future challenges from the process used to develop the DRI values.2 One improvement identified at that meeting for DRI updating was the use of systematic reviews to enhance the transparency and rigor of the literature review process that is a necessary component in the deliberations of DRI committees. To assess the feasibility of implementing this approach in the DRI updating process, the Office of Dietary Supplements (ODS) of the National Institutes of Health (NIH) through the Agency for Healthcare Research and Quality (AHRQ) requested the Tufts Medical Center Evidence-based Practice Center (Tufts-EPC) perform an exercise to identify the issues and challenges of conducing systematic reviews as a component of the process used to support the development and updating of DRI values. The Tufts-EPC assembled a group of nutrition experts from academic institutions and federal government agencies, led participants in teleconferences and meetings, and conducted exercises in formulating questions that would be amenable to a systematic review of the scientific literature and abstract screening.3 One of the intents of this exercise was to identify limitations, challenges, and unanticipated issues that IOM committees may face prior to actually initiating the use systematic reviews as a routine part of the DRI process.

Following these activities, a working group of US and Canadian government scientists convened to determine whether the scientific literature was sufficient to justify a new review of the vitamin D DRI. To address this issue in May and September of 2007, two conferences were held on the topic of vitamin D and health.4 As a result of these conferences in March of 2008 the IOM convened a working group of US and Canadian government scientists to determine whether significant new and relevant scientific evidence had become available since the 1997 IOM publication of vitamin D DRI to justify initiating a formal review and potential revision of the values.5 The working group reviewed the proceedings of the two conferences and the results from a systematic review commissioned by the ODS on the effectiveness and safety of vitamin D in relation to bone health conducted by the University of Ottawa EPC (Ottawa-EPC).6 They concluded that there was sufficient new data on bone health for several of the lifestage groups, on potential adverse effects, and on dose-response relationships between intakes and circulating 25-hydroxyvitamin D [25(OH)D] concentrations, and between 25(OH)D concentrations and several health outcomes to warrant a formal review and potential revision of the values.5 As a result, the NIH/ODS, Public Health Agency of Canada, Health Canada and FDA commissioned the Tufts-EPC to update the Ottawa-EPC report, and systematically review the data related to vitamin D and calcium with respect to a broader spectrum of health outcomes.

Sources, Metabolism and Functions of Vitamin D

Vitamin D was classified as a vitamin in the early 20th century and in the second half of the 20th century as a prohormone (“conditional” vitamin).7,8 There are two forms of vitamin D, vitamin D3 (cholecalciferol), which is produced from the conversion of 7-dehydrocholesterol in the epidermis and dermis in humans, and vitamin D2 (ergocalciferol) which is produced in mushrooms and yeast. The chemical difference between vitamin D2 and D3 is in the side chain; in contrast to vitamin D3, vitamin D2 has a double bond between carbons 22 and 23 and a methyl group on carbon 24.

The major source of vitamin D for humans is exposure to sunlight. The efficiency of the conversion of 7-dehydrocholesterol to vitamin D3 is dependent on time of day, season of the year, latitude, skin color and age. There is little vitamin D that occurs naturally in the food supply. The major naturally occurring food sources include fatty fish, beef liver and egg yolk. In the U.S. and Canada, the major dietary source of dietary vitamin D is fortified foods, including cow’s milk and, depending on country, other fortified foods and dietary supplements. These sources cannot be relied on in countries other than the U.S. and Canada. Dietary vitamin D is absorbed from the intestine and circulates in plasma bound to a vitamin D binding protein.

In its native form vitamin D is not biologically active, the active form is 1,25(OH)2D. The conversion of vitamin D to 1,25(OH)2D requires two hydroxylation in tandem. Vitamin D is first hydroxylated by the liver to form 25(OH)D, which is then hydroxylated by the kidney to form 1,25(OH)2D. 25(OH)D has low biological activity, but it is the major form of vitamin D that circulates in the blood stream. Serum 25(OH)D concentrations are generally thought to reflect nutritional status.7,8 When adequate amounts of vitamin D are available, the kidney, the major site of 1,25(OH)2D production converts some of the 25(OH)D to alternate hydroxylated metabolites, which have low biological activity (e.g., 24,25(OH)2D or 1,24,25(OH)3D). Renal synthesis of 1,25(OH)2D is tightly regulated by plasma parathyroid hormone, together with serum calcium and phosphorus concentrations. Additional tissues that express the enzyme that catalyses the conversion of 25(OH)D to 1,25(OH)2D, 25-hydroxyvitamin D3-1-α-hydroxylase, include colon, prostate, mammary gland, macrophages, antigen-presenting cells, osteoblasts and keratinocytes.9

Vitamin D has both genomic and nongenomic functions. For the genomic functions, 1,25(OH)2D interacts with nuclear vitamin D receptors to influence gene transcription. Nuclear receptors for 1,25(OH)2D have been identified in over 30 cell types, including bone, intestine, kidney, lung, muscle and skin. For the nongenomic functions, 1,25(OH)2D acts like a steroid hormone, working through activation of signal transduction pathways linked to vitamin D receptors on cell membranes. Major sites of action include intestine, bone, parathyroid, liver and pancreatic beta cells. Biological actions include increases in intestinal calcium absorption, transcellular calcium flux and opening gated calcium channels allowing calcium uptake into cells such as osteoblasts and skeletal muscle.

One of the major biological functions of vitamin D is to maintain calcium homeostasis which impacts on cellular metabolic processes and neuromuscular functions. Vitamin D affects intestinal calcium absorption by increasing the expression of the epithelial calcium channel protein, which in turn enhances the transport of calcium through the cytosol and across the basolateral membrane of the enterocyte. Vitamin D also facilitates the absorption of intestinal phosphate. 1,25(OH)2D indirectly affects bone mineralization by maintaining plasma calcium and phosphorus concentrations, and subsequently extracellular calcium and phosphorus concentrations at the supersaturating range necessary for mineralization. 1,25(OH)2D, in concert with parathyroid hormone, also causes demineralization of bone when calcium concentrations fall to maintain plasma concentrations within a narrow range. It has yet to be determined whether 1,25(OH)2D directly influences bone mineralization.

In addition to intestine and bone, a wide range of other tissues and cells that are influenced by vitamin D. Five biological systems have vitamin D receptors and are responsive to 1,25(OH)2D, as summarized in Figure 1.10 These systems include immune, pancreas, cardiovascular, muscle and brain; and control of cell cycle. The biological effects of 1,25(OH)2D are diverse. For example, as recently noted, 1,25(OH)2D inhibits PTH secretion and promotes insulin secretion, inhibits adaptive immunity and promotes innate immunity, and inhibits cell proliferation and stimulates their differentiation.11 A number of recent reviews have appeared on these topics.10–17

Figure 1. Summary of the vitamin D endocrine system.

Figure 1

Summary of the vitamin D endocrine system. From Norman AW. A vitamin D nutritional cornucopia: new insights concerning the serum 25-hydroxyvitamin D status of the US population.

Sources, Metabolism, and Functions of Calcium

The major source of dietary calcium in the North American diet, but not necessarily other counties, is dairy products (about 70 percent). Additional sources include commercial white bread made with calcium sulfate, foods made with milk products, leafy greens, canned fish and calcium fortified foods. Oxalic acid impedes the absorption of calcium from many plant foods. Intestinal calcium absorption is regulated by two processes. One route of intestinal calcium absorption is dependent on 1,25(OH)2D. This process occurs primarily in the duodenum and proximal jejunum, is saturable, is energy dependent, and involves a calcium binding protein. The 1,25(OH)2D-dependent absorption of calcium is stimulated by low dietary calcium intakes. The other route of intestinal calcium absorption is independent of 1,25(OH)2D and is termed paracellular. This process is passive (does not depend on carrier proteins or energy) and occurs primarily in the jejunum and ileum. Calcium is absorbed between cells, rather than through cells, and down the concentration gradient. Calcium can be transported in blood bound to albumin and prealbumin, complexed with sulfate, phosphate or citrate, or in a free (ionized) state.

Calcium is transported in blood bound to proteins (~40 percent), primarily albumin and prealbumin, complexed with sulfate, phosphate or citrate (~10 percent), and in the ionized form (~50 percent). Blood calcium concentrations are controlled extracellularly by parathyroid hormone, calcitriol and calcitonin. Intracellular calcium concentrations are maintained at relatively low levels. Increased intracellular calcium concentrations occur in response to second messengers by stimulating release from intracellular sites (endoplasmic reticulum, mitochondria) and hormones by facilitating influx from extracellular sites by transmembrane diffusion or channels.

Calcium balance measures provide information on calcium absorption relative to calcium loss in urine, sweat and endogenous intestinal secretions. During periods of growth, positive calcium balance implies bone mineralization but does not provide an indication of whether the rate of bone mineralization is optimal. During adulthood negative calcium balance implies calcium lost from bone but does not provide an indication of which site(s). Calcium balances measures provide an indication of current but not prior calcium balance. An alternate approach to assessing bone mineralization is by measuring bone mineral density.

Approximately 99 percent of the calcium in the human body is in bone and teeth. In addition to structural roles, calcium has other critical functions. These include serving as a second messenger (e.g., cytosolic calcium, calcium-dependent trigger proteins, removal of calcium stimulus) and protein activator (e.g. phospholipase A2, calpains [calcium dependent proteins that contain calmodulin-like domains], blood clotting enzymes, annexins [calcium and phospholipid binding proteins]). 1,25(OH)2D plays a critical role in regulating plasma calcium concentrations through its role in intestinal calcium absorption, bone resorption and renal calcium resorption. These functions of calcium are frequently classified into the following general categories; bone development and maintenance, blood clotting, transmission of nerve impulses to target cells, muscle contraction and cell metabolism. In addition, calcium may play a role in colon cancer, kidney stones, blood pressure, body weight and lead absorption.

Challenges for the DRI Committees

The following generic challenges must be addressed, preferably in a standardized way, before additional systematic reviews are conducted for use by upcoming DRI committees to ensure the resulting product will yield a maximally useful document.3 Because the potential volume of peer reviewed literature on the biological effects of most essential nutrients is large and continues to grow, rational and well defined eligibility criteria will need to be identified by the committee to manage the workload. Appropriate questions must be formulated so that the answers to those questions can be used to inform the DRI development process, ensure transparency and reproducibility, and serve as the foundation for future updates as new data emerge. Experience has shown that in the absence of unlimited resources, only a limited set of questions can be addressed. Hence, it is critical that the committee prioritize the topics and refine the questions in a way that will address critical issues for development and revision of DRI values.

Age specific intermediate or surrogate outcomes will need to be identified by the committee when few or no studies directly link specific nutrient intakes with clinical outcomes. Preferably, these would include only validated surrogates of the clinical outcome, that is outcomes that are strongly correlated with the clinical outcome (e.g., bone mineral density as a surrogate for fractures in postmenopausal women), and changes in their status reflect corresponding changes in the risk of the clinical outcome (e.g., changes in bone mineral density reflect changes in fracture risk in postmenopausal women).18 In the absence of validated surrogate outcomes, intermediate outcomes must be identified and considered (e.g., absence of anemia as an intermediate outcome for the absence of disease or serum osteocalcin [bone turnover index] as an intermediate marker for fractures). When a nonvalidated intermediate outcome must be considered, the implicit assumption is that they would have the properties of a validated surrogate outcome. Not only should this assumption be made explicit, but the uncertainties involved in applying this assumption should be identified, documented, and discussed by the committee.

Reliable indicators of exposure (or biomarkers) need to be identified by the panel. A reliable biomarker should accurately reflect the degree of biological exposure to the nutrient of interest and fulfill the classic risk assessment model (e.g., exhibit a dose-response relationship). To that extent, the measurement of biological exposure should be independent and free from any interaction with the self-estimated intake of the nutrient of interest. It is important for the DRI committee to recognize that use of a biomarker to evaluate the strength of downstream associations requires that the biomarker concentrations be back translated into levels of nutrient intake and that if an association is found between a given biomarker concentration and risk of a clinical outcome, an estimate of the nutrient intake that corresponds to the clinical outcome will likewise be necessary.

Additional challenges for the DRI committees with respect to the conduct of systematic review include defining relevance of studied populations with respect to nutrient distributions and health risks to those for which reference values are being established, generalizability of well-controlled experiments with few subjects, generalizability of studies of subjects having narrow eligibility criteria, applicability for findings of animal studies to humans when data in humans are nonexistent, generalizability of early studies that used methodologies not considered state of the art or directly comparable with contemporary methods (e.g., change in analytical techniques or standardization), appropriate approaches to evaluating, interpreting and integrating data from observational studies with interventional data, and approaches to factor contemporary issues into the process, such as the role of genomics and nutrient fortification into the systematic review.

Key Questions Addressed in this Report

The aim of this report is to answer specific questions formulated to support the review and updating of DRI values by the DRI committee. The primary purpose of this report is to summarize all existing literature of vitamin D and calcium, and clinical outcomes in a way that will facilitate the deliberations of the IOM committee commissioned to review and potentially revise the DRI values for these nutrients. Specific clinical, surrogate and intermediate outcomes that are relating to vitamin D or calcium functions were selected by a technical expert panel. Detailed methods and analytic frameworks are described in Chapter 2. The intent of this report is not to make recommendations on specific outcomes nor specific values for DRI to be based upon, the intent of this report is to provide information for use during the deliberations of the IOM committee. The federal agencies of the US and Canadian governments involved in the DRI process formulated the key questions listed below based on the generic analytic framework as recently described (Figure 2).3 The key questions are:

Figure 2. Generic analytic framework to assist formulation of key questions for the development of DRIs.

Figure 2

Generic analytic framework to assist formulation of key questions for the development of DRIs. Arrow 1: Association of exposure with clinical outcomes of interest. Arrow 2: Association of exposure with surrogate or intermediate outcomes (with good or (more...)

  • What is the effect of exposures on functional or clinical outcomes? (Arrow 1)
  • What is the effect of exposures on indicators of functional or clinical outcomes? (Arrow 2)
  • What is the effect of indicators of exposure or body stores on functional or clinical outcomes? (Arrow 3)
  • What is the effect of exposures on indicators of exposure? (Arrow 4)
  • What is the effect of indicators of exposure or body stores and intermediate indicators of outcomes? (Arrow 5)
  • What is the effect of intermediate indicators of outcomes and functional or clinical outcomes? (Arrow 6)

For each of these questions, the mandate was to also address factors that affect these relationships.

The focus of this evidence report is on the relationship of vitamin D only, calcium only, and combinations of vitamin D and calcium to relevant health outcomes. Serum 25(OH)D concentration was used as an indicator of vitamin D status and calcium intake (dietary and supplement) as an indicator of calcium status. Evidence was sought for the life stages as defined in the DRI process. For the above questions, information relevant to benefit (efficacy) and safety (adverse effects) were considered. The questions were refined with input from a committee of vitamin D and calcium experts, discussed in the Methods chapter.


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