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D
Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium

The purpose of this systematic evidence-based review, referred to as AHRQ-Tufts,1 requested by the Office of Dietary Supplements/National Institutes of Health, the Public Health Agency of Canada, Health Canada, and the Food and Drug Administration and conducted by the Tufts Evidence-based Practice Center (EPC), was to answer key scientific questions on how dietary vitamin D and calcium intake effect health outcomes. The key questions addressed in the AHRQ-Tufts reports are as follows:


Key Question 1. What is the effect of vitamin D, calcium, or combined vitamin D and calcium intakes on clinical outcomes, including growth, cardiovascular diseases, body weight outcomes, cancer, immune function, pregnancy or birth outcomes, mortality, fracture, renal outcomes, and soft tissue calcification?


Key Question 2. What is the effect of vitamin D, calcium, or combined vitamin D and calcium intakes on surrogate or intermediate outcomes, such as hypertension, blood pressure, and bone mineral density?

1

Chung, M., E. M. Balk, M. Brendel, S. Ip, J. Lau, J. Lee, A. Lichtenstein, K. Patel, G. Raman, A. Tatsioni, T. Terasawa and T. A. Trikalinos. 2009. Vitamin D and Calcium: A Systematic Review of Health Outcomes. Evidence Report No. 183. (Prepared by the Tufts Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-I.) AHRQ Publication No. 09-E015. Rockville, MD: Agency for Healthcare Research and Quality.



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D Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium The purpose of this systematic evidence-based review, referred to as AHRQ-Tufts,1 requested by the Office of Dietary Supplements/National Institutes of Health, the Public Health Agency of Canada, Health Canada, and the Food and Drug Administration and conducted by the Tufts Evi- dence-based Practice Center (EPC), was to answer key scientific questions on how dietary vitamin D and calcium intake effect health outcomes. The key questions addressed in the AHRQ-Tufts reports are as follows: Key Question 1. What is the effect of vitamin D, calcium, or combined vitamin D and calcium intakes on clinical outcomes, including growth, cardiovascular diseases, body weight outcomes, cancer, immune function, pregnancy or birth outcomes, mortality, fracture, renal outcomes, and soft tissue calcification? Key Question 2. What is the effect of vitamin D, calcium, or combined vita- min D and calcium intakes on surrogate or intermediate outcomes, such as hypertension, blood pressure, and bone mineral density? 1 Chung, M., E. M. Balk, M. Brendel, S. Ip, J. Lau, J. Lee, A. Lichtenstein, K. Patel, G. Raman, A. Tatsioni, T. Terasawa and T. A. Trikalinos. 2009. Vitamin D and Calcium: A Systematic Review of Health Outcomes. Evidence Report No. 183. (Prepared by the Tufts Evidence- based Practice Center under Contract No. HHSA 290-2007-10055-I.) AHRQ Publication No. 09-E015. Rockville, MD: Agency for Healthcare Research and Quality. 725

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726 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D Key Question 3. What is the association between serum 25(OH)D concentra- tions or calcium balance and clinical outcomes? Key Question 4. What is the effect of vitamin D or combined vitamin D and calcium intakes on serum 25(OH)D concentrations? Key Question 5. What is the association between serum 25(OH)D concentra- tions and surrogate or intermediate outcomes? The review focused on electronic searches of the medical literature (1969–April 2009) to identify publications addressing the aforementioned questions. One hundred and sixty-five primary articles and 11 systematic reviews that incorporated more than 200 additional primary articles were systematically reviewed, and each was rated on quality and used to assess the strength of evidence for each outcome. The methods and results chapters of the AHRQ-Tufts evidence re- view are reprinted below. The report in its entirety, including appendices and evidence tables, can be accessed and viewed at http://www.ahrq.gov/ clinic/tp/vitadcaltp.htm.

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727 APPENDIX D Chapter 2. Methods Overview This report is based on a systematic review of key questions on the relationships between vitamin D [either 25(OH)D concentrations or supplements] or dietary calcium intake, and health outcomes. The methodologies employed in this evidence report generally follow the methods outlined in the AHRQ Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews (http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf). The initial questions identified by the federal sponsors of this report were refined with input from a Technical Expert Panel (TEP). This report does not make clinical or policy recommendations. The report is being made available to an IOM committee charged with updating vitamin D and calcium DRIs. A description of roles and responsibilities of sponsoring federal agencies, AHRQ, the TEP and the EPC is included to clarify the relationships that support the process and ensure transparency and that the approach adhered to the highest standards of scientific integrity. Because of the large number of abbreviations for unfamiliar terms are used, their explanations have been repeated whenever deemed necessary. A table of Abbreviations can be found after the references in page 316. We also provide a table with the latitudes of several major cities in Central and North America, right after the Abbreviations table, on page 320. Sponsoring federal agencies The sponsoring agencies were responsible for specifying the topic-specific task order requirements. They participated in a Kick-Off meeting with the EPC and the Task Order Officer (TOO) to facilitate a common understanding of the topic-specific work requirements, and responded to inquiries from the TOO if modifications to the work order were requested by the EPC. Any communication between the sponsoring agencies and the EPC occurred with oversight from the TOO. Review by Federal sponsors was limited to comments on factual errors, requests for clarification, and consistency with the original contract task order. Comments on the scientific content of the report were not provided. In all cases, reviewer comments are advisory only and are not binding on the scientific authors of the final report. AHRQ Task Order Officer (TOO) The TOO was responsible for overseeing all aspects of this Task Order. The TOO served as the point person for all communication required between the sponsoring agencies, the EPC, and other AHRQ officials. The purpose of this communication was to facilitate a common understanding of the task order requirements among the sponsors, the TOO, and the EPC, resolve ambiguities and to allow the EPC to focus on the scientific issues and activities. Technical Expert Panel (TEP) The TEP is comprised of qualified experts including, but not limited to, individuals with knowledge of DRI decision making processes, vitamin D and calcium nutrition and biology across the life cycle, health outcomes of interest, and the methodology of conducting systematic reviews. The EPC worked closely with the TEP in the formative stages of the project on question 9

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728 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D refinement and throughout the evidence review process to address questions that occurred. The EPC conducted the actual systematic review of the questions independent of the TEP and other stakeholders. It was specified, a priori, that external peer reviewers of the final report could not also serve as a member of the IOM’s calcium and vitamin D DRI Committee. Those serving on the TEP provided input on such factors as reviewing search terms to ensure they were adequately inclusive, assessing search strategies to ensure they comprehensively covered the questions of interest, and answering questions about technical details (e.g., nuances of laboratory methods of performing an assay). Members of the TEP did not participate in EPC research meetings or in reviewing and synthesizing evidence. Their function was limited to providing domain-specific knowledge and advising the proper context that is relevant to the process of evaluating DRI. They did not have any decision making role and did not participate in writing any part of the evidence report. EPC methodologists This evidence report was carried out under the AHRQ EPC program, which has a 12-year history of producing over 175 evidence reports and numerous technology assessments for various users including many federal agencies. EPCs are staffed by experienced methodologists who continually refine approaches to conducting evidence reviews and develop new methods on the basis of accumulated experience encompassing a wide range of topics. The Tufts EPC has produced many evidence reports on nutrition topics19-24 (http://www.ahrq.gov/clinic/epcix.htm). We have also conducted methodological research to identify the issues and challenges of including evidence-based methods as a component of the process used to develop nutrient reference values, such as the DRI, using vitamin A as an example.3 Development of the analytic framework and refinement of key questions The focus of this report is on the relationship of vitamin D only, calcium only, and combinations of vitamin D and calcium with specific health outcomes. Key questions and analytic frameworks were developed by defining each box in the generic analytic framework described in Chapter 1 with specific reference to vitamin D and calcium. A one-day meeting of the federal sponsors, TEP and Tufts EPC staff was held in Boston on September 20, 2008. At this meeting, the analytic framework was discussed, the key questions refined, and study eligibility criteria established. Two analytic frameworks were developed: one for intakes of vitamin D and/or calcium related to their beneficial effects and one for intakes associated with adverse effects (Figures 3 & 4). We used the PI(E)CO method to establish study eligibility criteria. This method defines the Population, Intervention (or Exposure in the case of observational studies), Comparator, and Outcomes of interest. Details are described in the sections that follow. 10

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729 APPENDIX D Figure 3. Analytic framework for vitamin D and/or calcium generic health outcomes Arrow 1 UV exposure Arrow 2 Hypertension Bone health Arrow 6 BMD, BMC Vitamin 25(OH)D; CVD D2,D3, 1,25(OH)D Cancer Arrow 5 25(OH)D Arrow 4 Muscle Foods & Arrow 3 Calcium supplements Function balance Calcium Immune Arrow 5 Outcomes Cancer markers Pregnancy Arrow 6 Outcomes Arrow 2 Blood Pressure All cause Breast milk or infant mortality circulating levels Body weight, BMI; Growth Arrow 1: Association of exposure with clinical outcomes of interest. Arrow 2: Association of exposure with surrogate or intermediate outcomes (that have good or possible evidence for linkage with clinical outcomes, respectively). (Surrogate outcomes are depicted in boxes with a solid outline, and intermediate outcomes are depicted in boxes with dashed outline.) Arrow 3: Association of indicators of exposure to clinical outcomes. Arrow 4: Association between exposure and indicators of exposure. Arrow 5: Association of indicators of exposure to surrogate or intermediate outcomes. Arrow 6: Association between surrogate or intermediate outcomes and clinical outcomes. 11

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730 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D Figure 4. Analytic framework for vitamin D and/or calcium safety-related (adverse) outcomes Arrow 1: Association of exposure with clinical outcomes of interest. Arrow 3: Association of indicators of exposure to clinical outcomes. Arrow 4: Association between exposure and indicators of exposure. Definitions Vitamin D and calcium exposures Vitamin D exposure included intake of vitamin D2 or vitamin D3 from foods and supplements, including human milk and commercial infant formulas. Because the primary source of vitamin D in the human body is produced in skin exposed to sunlight, background information on ultraviolet B (UVB) exposure was captured to the extent possible. However, we did not include studies that evaluated the effect of or association between exposure to sunlight (or UVB) and clinical outcomes or serum 25(OH)D concentrations. In other words, we did not investigate sunlight exposure as a proxy for or a source of vitamin D intake. Sunlight exposure was considered only as a potential confounder or effect modifier of associations between vitamin D or calcium and clinical outcomes. Calcium exposure included intake of calcium from foods and supplements, including calcium-containing antacids, mineral-supplemented water, human milk and commercial infant formulas. Combined vitamin D and calcium exposure included any relevant combinations of the above. Clinical outcomes Clinical outcomes are measures of how a person (e.g., a study participant) feels, functions or survives, or a clinical measurement of the incidence or severity of a disease (e.g., diagnosis of disease or change from one disease state to another). Examples of clinical outcomes used in this report are incidence of cancer, cardiovascular events, and preeclampsia. The clinical outcomes of interest in this report are described in the “Specific Outcomes of Interest” section. 12

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731 APPENDIX D Indicators of exposure (nutrient intake) Indicators of exposure are measures that correlate with dietary intake of a nutrient, such as nutrient biomarkers, nutritional status, or markers of nutritional status. Indicators of vitamin D exposure (i.e., vitamin D intake and sun exposure) included serum 25(OH)D and 1,25(OH)2D concentrations. Indicators of dietary calcium intakes included calcium balance (i.e., calcium accretion, retention, and loss). Surrogate outcomes Surrogate outcomes are biomarkers or physical measures that are generally accepted as substitutes for or predictors of specific clinical outcomes.18 Changes induced by the exposure or intervention on a surrogate outcome marker are expected to reflect changes in a clinical outcome. Examples of surrogate outcomes used in this report are bone mineral density (as a surrogate marker of fracture risk) and breast mammographic density (as a surrogate marker of breast cancer risk). The surrogate outcomes of interest in this report are described in “Specific Outcomes of Interest” section. Intermediate outcomes Intermediate outcomes are possible predictors of clinical outcomes that are not generally accepted to fulfill the criteria for a surrogate outcome. However, in the absence of data for surrogate outcomes, intermediate markers are often used. Examples of intermediate markers used in this report are prostate cancer antigen (as a marker of prostate cancer risk) and blood pressure (as a marker of stroke risk). All intermediate markers of interest in this report are described in “Specific Outcomes of Interest” section. Life stages In consultation with the TEP, the 22 life stages defined by the FNB/IOM for the development of DRI were consolidated to 9 categories to facilitate the reporting of results. Within each life stages, men and women (or boys and girls) were considered separately when possible. There are also some inevitable overlaps between these categories. For example, most women in 51-70 years life stage are postmenopausal women. The 9 categories created for this report are: o 0 – 6 months o 7 months – 2 years o 3 – 8 years o 9 – 18 years o 19 – 50 years o 51 – 70 years o ≥71 years o Pregnant and lactating women o Postmenopausal women In summarizing studies for each given outcome, we used our best judgment to describe the study results for each applicable life stage. 13

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732 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D Key questions In agreement with the TEP, the following key questions were addressed in this evidence report. It was decided that arrow 6 in the analytic framework (What is the relationships between intermediate or surrogate outcomes and clinical outcomes?) is outside the scope of the DRI literature review in this report. All outcomes of interest in this report are described in “Eligibility Criteria” section. Key Question 1. What is the effect of vitamin D, calcium, or combined vitamin D and calcium intakes on clinical outcomes, including growth, cardiovascular diseases, weight outcomes, cancer, immune function, pregnancy or birth outcomes, mortality, fracture, renal outcomes, and soft tissue calcification? (Arrow 1) Key Question 2. What is the effect of vitamin D, calcium or combined vitamin D and calcium intakes on surrogate or intermediate outcomes, such as hypertension, blood pressure, and bone mineral density? (Arrow 2) Key Question 3. What is the association between serum 25(OH)D concentrations or calcium balance and clinical outcomes? (Arrow 3) Key Question 4. What is the effect of vitamin D or combined vitamin D and calcium intakes on serum 25(OH)D concentrations? (Arrow 4) Key Question 5. What is the association between serum 25(OH)D concentrations and surrogate or intermediate outcomes? (Arrow 5) Literature search strategy We conducted a comprehensive literature search to address the key questions. For primary studies, the EPC used the Ovid search engine to conduct searches in the MEDLINE® and Cochrane Central database. A wide variety of search terms were used to capture the many potential sources of information related to the various outcomes (see Appendix A). Search terms that were used to identify outcomes of interest, for both EARs and ULs, can be categorized into the following groups: 1) body weight or body mass index; 2) growth (height and weight); 3) fracture or bone mineral density; 4) falls or muscle strength; 5) cardiovascular diseases; 6) hypertension or blood pressure; 7) cancer or neoplasms, including adenomas, colon polyps, and mammography; 8) autoimmune diseases (e.g., type 1 diabetes, psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease); 9) preeclampsia, eclampsia and pregnancy-related hypertension; 10) preterm or low birth weight; 11) breast milk or lactation; 12) death; 13) infectious diseases; 14) soft tissue calcification (for ULs only); and 15) kidney disease or hypercalcemia (for ULs only). The different outcomes were crossed with terms to identify vitamin D and calcium exposure: “vitamin D”, “plasma vitamin D”, “25-hydroxyvitamin D” and its abbreviations, “25-hydroxycholecalciferol”, “25- hydroxyergocalciferol”, “calcidiol”, “calcifediol”, “ergocalciferol”, “cholecalciferol”, “calciferol”, “calcium”, “calcium carbonate”, “calcium citrate”, “calcium phosphates” and 14

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733 APPENDIX D “calcium malate”. Literature searches of the outcomes alone without references to vitamin D or calcium were not conducted. The searches were limited to human studies, English language publications, and citations from 1969 to September 2008 for all but bone outcomes. For outcomes related to bone health (i.e., bone mineral density, fracture, fall or muscle strength), we relied on a recent comprehensive systematic review performed by the Ottawa EPC.6 The Ottawa EPC report was updated from January 2006 to September 2008. The electronic search was supplemented by bibliographies of relevant review articles. Unpublished data, including abstracts and conference proceedings, were not included. An updated literature search was performed in April 2009 for all the topics to include relevant primary studies published since September 2008 for the final report. For potentially relevant systematic reviews, we also searched MEDLINE®, the Cochrane Database of Systemic Reviews, and the Health Technology Assessments database up to December 2008. We searched for systematic reviews of the relationships between vitamin D or calcium and the prespecified outcomes. In this search, terms for identifying vitamin D or calcium exposures were crossed with terms for identifying systematic reviews, such as “systematic,” “evidence,” “evidence-based,” “meta-analysis,” or “pooled analysis”; specific terms for the outcomes were not included (Appendix B). Study selection Abstract screening All abstracts identified through the literature search were screened. Eligible studies included all English language primary interventional or observational studies that reported any outcome of interest in human subjects in relation to vitamin D and/or calcium. Full text article eligibility criteria Articles that potentially met eligibility criteria at the abstract screening stage were retrieved and the full text articles were reviewed for eligibility. Rejected full text articles were examined only once, unless the articles were equivocal for inclusion or exclusion. In that event, the article in question was examined again by a different reviewer and a consensus was reached after discussion with the first reviewer. We recorded the reason for rejection of all full text articles. Primary studies Because the outcomes of interest ranged from very broad topics with common occurrences (e.g., cardiovascular disease) to narrowly focused topics with relatively few occurrences (e.g., preeclampsia), the number and types of studies available for each outcome varied widely in the distribution of study designs and sample sizes. It was neither possible nor desirable to use a uniform, strict set of inclusion and exclusion criteria applicable to all outcomes. Therefore, additional eligibility criteria germane to the specific outcome were applied to all accepted full text articles. Details are described in the “Eligibility criteria” section. General eligibility criteria for the full text articles were: Population of interest: • Primary population of interest is generally healthy people with no known disorders 15

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734 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D Studies that include a broad population that might have included some people with • diseases. For example, some hypertensive and diabetic patients were included. People with prior cancers (or cancer survivors), prior fractures, and precancer conditions • (e.g., colon polyps) were included Studies that enrolled more than 20% subjects with any diseases at baseline were • excluded. An exception was made for older adults (mean age ≥65 years old) due to high prevalence of diseases in this population. For studies of older adults, only studies that exclusively enrolled subjects with particular disease (e.g., 100% type 2 diabetes) were excluded. In addition, for studies of blood pressure, studies of people exclusively with hypertension were included. For adverse or safety outcomes, we included any adverse effects of high intake in any • population. Intervention/exposure of interest • For observational studies: o Serum 25(OH)D or 1,25(OH)2D concentration o Dietary intake level of vitamin D were not included due to inadequacy of nutrient composition tables for vitamin D.25 o Dietary intake level of calcium from food and/or supplements o Calcium balance (i.e., calcium accretion, retention, and loss) • For interventional studies: o Vitamin D supplements (but not analogues) with known doses o Calcium supplements with known doses o The only combination of dietary supplements of interest was the combination of vitamin D and calcium. Any other combinations of supplements and/or drug treatments were excluded unless the independent effects of vitamin D and/or calcium can be separated. Thus studies of multivitamins were excluded. o Trials in which participants in both study groups took the same calcium (or vitamin D) supplement were evaluated as vitamin D (or calcium) versus control trials. In other words, the intervention common to both study groups was ignored (though it was noted). o Food based interventions were included if the doses of vitamin D and/or calcium were quantified and there were differences in the doses between the comparison groups. For example, a trial of dairy supplementation (with 500 mg/d calcium) versus no supplementation was qualified to be included. However, a trial of calcium fortified orange juice (with 1200 mg/d calcium) versus milk (with 1200 mg/d calcium) was not qualified to be included because there are no differences in the calcium doses. o Nonoral routes of nutrient delivery were excluded Specific Outcomes of interest • Growth outcomes o In infants and premenarchal girls and boys of corresponding age: weight and height gain • Cardiovascular disease clinical outcomes o Cardiac events or symptoms (e.g., myocardial infarction, angina) 16

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735 APPENDIX D o Cerebrovascular events (stroke, transient ischemic attacks) o Peripheral vascular events or symptoms (diagnosis, claudication) o Cardiovascular death o Study-specific combinations of cardiovascular events CVD intermediate outcomes • o Diagnosis of hypertension o Blood pressure Weight outcomes • o In adults only: incident overweight or obesity, body mass index, or weight (kg) Cancer (incident or mortality) • o Cancer from all cause (or total cancer) o Prostate o Colorectal cancer o Breast cancer o Pancreatic cancer o Cancer-specific mortality Cancer intermediate outcomes • o Colorectal adenoma o Aberrant cryptic o Breast mammographic density (quantitative whole breast density) Immune function clinical outcomes • o Infectious diseases o Autoimmune diseases o Infectious disease-specific mortality Pregnancy-related outcomes • o Preeclampsia o High blood pressure with or without proteinuria o Preterm birth or low birth weight o Infant mortality Mortality, all cause • Bone health clinical outcomes • o Rickets o Fracture o Fall or muscle strength Bone health intermediate outcomes • o Bone mineral density or bone mineral content Dose-response relationship between intake levels and indicators of exposure (arrow 4 of • Figures 2 and 3) o Serum 25(OH)D concentration o Breast milk or circulating concentrations of 25(OH)D in infants Outcomes of tolerable upper intake levels (ULs) • o All-cause mortality o Cancer and cancer-specific mortality o Renal outcomes o Soft tissue calcification o Adverse events from vitamin D and/or calcium supplements 17

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1002 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D source of fortified food. It is important to note that there is potential for study contamination through altered intake of other nutrients such as calcium, phosphate and acid load that can affect the study outcomes. RCTs on Vitamin D supplementation and serum 25(OH)D concentrations Synopsis Because the availability of serum 25(OH)D concentration is unlikely to be adequately indexed in the Medline citation, it would be difficult to comprehensively search the literature for this question. We believe that studies summarized here is a small but representative random sample of all available data. We plot the net changes in serum 25(OH)D concentration against the doses of vitamin D supplementation using data from 26 RCTs with 28 comparisons in adults. Only RCTs of daily vitamin D3 supplementation (doses ranged from 200 to 5000 IU/d) alone or in combination with calcium supplementation (doses ranged from 500 to 1550 mg/d) that provided sufficient data for the calculations were included in the plot. It is important to note that the studies had varied compliance rates in the vitamin D intake; limited or no adjustment for skin pigmentations, calcium intake, or background sun exposure; different vitamin D assay methodologies and measurement (both intra- and interassay) variability. All these factors increase the heterogeneity and limit the usefulness of an overall summary estimate for an intake dose response in serum 25(OH)D concentration. Nonetheless, the relationship between increasing doses of vitamin D3 with increasing net change in 25(OH)D concentration was evident in both adults and children (Figure 23). It was also apparent that the dose-response relationships differ depending on study participants’ serum 25(OH)D status (≤40 vs. >40 nmol/L) at baseline (Figure 24), and depending on duration of supplementation (≤3 vs. >3 months) (Figure 25). Vitamin D2 supplementation was more commonly used in RCTs of infants and pregnant or lactating women, than vitamin D3 supplementation. Results showed that supplementation of vitamin D2 significantly increased 25(OH)D concentrations in infants, lactating mothers and in cord blood. Detailed presentation (Table 106; Figures 23, 24 & 25) The results from 26 RCTs with 28 comparisons in adults and two RCTs with three comparisons in children evaluating the effect of vitamin D3 supplementation alone or in combination with calcium supplementation on serum 25(OH)D concentrations were shown in Table 106. Most of the data were extracted directly from the Ottawa EPC report. In adults, the doses of vitamin D3 ranged from 200 to 5000 IU/d, and the doses of calcium supplementation ranged from 500 to 1550 mg/d across the 25 comparisons. In children, the doses of vitamin D3 ranged from 200 to 2000 IU/d across the three comparisons. Duration of supplementation ranged from 0.5 to 60 months. Study populations and baseline vitamin D concentrations varied across these comparisons. Ottawa EPC report - Infants Seven RCTs included infants and few trials used vitamin D3 supplementation. One RCT concluded that 200 IU of vitamin D2 may not be enough to prevent vitamin D deficiency in those infants residing at northern latitudes. A dose-response relationship 284

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1003 APPENDIX D was noted in this trial (100, 200, 400 IU/day). Consistent responses to vitamin D supplementation were noted across the seven trials, and some trials suggested that infants who are vitamin D deficient may respond differently and require higher doses of vitamin D to achieve serum 25(OH)D concentrations within the normal range. Ottawa EPC report - Pregnant or lactating women There were six small RCTs of vitamin D supplementation in pregnant or lactating women. No randomized trials studied the effect of 400 IU vitamin D3/d. Three trials used 1000 IU vitamin D2/d and one trial used 1000 IU/d of vitamin D3. Supplementation of vitamin D2 1000-3600 IU/d and vitamin D3 1000 IU/d resulted in significant increases in serum 25(OH)D concentrations in lactating mothers and in cord blood. One trial found that supplementation of lactating mothers with 1000 IU vitamin D2/d during winter months did not significantly increase serum 25(OH)D concentrations in the infants. Ottawa EPC report - Children and adolescents There were four trials that examined the effect of vitamin D on serum 25(OH)D concentrations in children or adolescents with doses ranging from 200 to 2000 IU of vitamin D3 per day and 400 IU of vitamin D2. There were consistent increases in serum 25(OH)D concentrations ranging from 8 nmol/L (200 IU/d), 16.5 (with 600 IU D3/d) to 60 nmol/L (2000 IU of vitamin D3/d). Ottawa EPC report - Premenopausal women and younger men Ten small trials included premenopausal women and younger males. Three trials compared vitamin D2 to vitamin D3 in healthy young adults. Two of the three trials used RIA, and one used HPLC to measure serum 25(OH)D concentrations The doses of vitamin D3 ranged from 600 to 10,000 IU/day and vitamin D2 (4000 IU/d or 50,000 to 100,000 for single dose). Three trials found that supplementation with vitamin D2 and D3 in healthy adults may have different effects on serum 25(OH)D concentrations. One trial compared 100,000 IU vitamin D2 given orally versus injection and found a greater variability in response with the intramuscular preparation. There appeared to be dose-response effect in those trials that used multiple doses of vitamin D3, although there were insufficient data to perform a meta-analysis. Ottawa EPC report - Postmenopausal women and older Men Forty-four trials were conducted exclusively in postmenopausal women and older men, with 14 of these in elderly populations living in long-term care or nursing homes. One trial enrolled only women in early menopause (n=129). Doses of vitamin D3 ranged from 100 to 4000 IU/day and vitamin D2 was 9000 IU/day. One trial was conducted in African American women. One trial found that wintertime declines in serum 25(OH)D concentrations were prevented with 500 IU vitamin D3 per day. A dose response with increasing doses of vitamin D3 was noted for serum 25(OH)D concentrations. There was variability in response to similar doses across trials that may have been due to differences in serum 25(OH)D assays or baseline 25(OH)D concentrations. Similarly, although some trials reported a greater response to vitamin D in populations that were vitamin D deficient at baseline compared to those who were not, there were insufficient data on which to base a definitive conclusion on this point. 285

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1004 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D Figure 23. Relationship between doses of Vitamin D3 supplementation and net changes in serum 25(OH)D concentrations in RCTs 100 Adults Net change in 25(OH)D, mnol/L 80 60 40 20 0 0 1000 2000 3000 4000 5000 Vit D3 daily dose(IU) 100 Children 80 Net change in 25(OH)D, mnol/L 60 40 20 0 0 1000 2000 3000 4000 5000 Vit D3 daily dose(IU) Legends: Each empty circle represents one study. The area of the circle is proportional to the inverse of the within-study variances. Typically, the larger the bubble, the larger the sample size and the smaller the standard error of the changes in 25(OH)D. 286

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1005 APPENDIX D Figure 24. Relationship between doses of Vitamin D3 supplementation and net changes in serum 25(OH)D concentrations in RCTs by baseline vitamin D status among adults 100 Adults with low 25(OH)D concentrations 80 Net change in 25(OH)D, mnol/L 60 40 20 0 0 1000 2000 3000 4000 5000 Vit D3 daily dose(IU) 100 Adults with normal/high 25(OH)D concentrations Net change in 25(OH)D, mnol/L 80 60 40 20 0 0 1000 2000 3000 4000 5000 Vit D3 daily dose(IU) Legends: Each empty circle represents one study. The area of the circle is proportional to the inverse of the within-study variances. Typically, the larger the bubble, the larger the sample size and the smaller the standard error of the changes in 25(OH)D. 287

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1006 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D Figure 25. Relationship between doses of Vitamin D3 supplementation and net changes in serum 25(OH)D concentrations in RCTs by duration of supplementation among adults 100 Duration of supplementation <=3 mo 80 Net change in 25(OH)D, mnol/L 60 40 20 0 0 1000 2000 3000 4000 5000 Vit D3 daily dose(IU) 100 Duration of supplementation >3 mo Net change in 25(OH)D, mnol/L 80 60 40 20 0 0 1000 2000 3000 4000 5000 Vit D3 daily dose(IU) Legends: Each empty circle represents one study. The area of the circle is proportional to the inverse of the within-study variances. Typically, the larger the bubble, the larger the sample size and the smaller the standard error of the changes in 25(OH)D. 288

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Table 106. The relationship between vitamin D3 daily doses and changes in 25(OH)D concentrations in RCTs Vit D3 ± C a Group Placebo or Ca Group Base 25(OH)D, Vit D3 dose Ca dose Duration Mean Mean Author Year Life stage nmol/L (IU/d) (mg/d) (mo) change change n SD n SD from from baseline baseline 209 Bjorkman 2008 71+ 23 400 0 6 60 26.5 11.8 59 1.9 10.2 209 Bjorkman 2008 71+ 23 1200 0 6 63 49.1 19.5 59 1.9 10.2 216 A Blum 2008 71+ 73 700 500 12 132 48.5 35.3 125 9.3 21.5 80 A Bunout 2006 71+ 40 400 800 9 46 33.4 14.3 46 3.5 10.0 217 Chapuy 1992 71+ 36 800 1200 18 73 65.0 16.5 69 -4.5 13.5 218 Chel 71+ 23 600 0 4 46 46.9 15.4 45 0.3 12.2 2008 219 A Deroisy 2002 71+ 28 200 500 3 50 14.7 10.0 50 4.5 10.0 220 Himmelstein 1990 71+ 45 2000 0 1.5 15 39.7 15.7 15 -2.7 13.4 221 A Kenny 2003 71+ 62 1000 500 6 29 22.3 10.1 31 -2.5 11.4 222 Krieg 1999 71+ 29 880 500 24 34 36.5 14.0 38 -15.0 11.1 223 A Pfeifer 2000 71+ 25 880 1200 2 74 40.5 27.0 74 18.3 20.9 97 Pfeifer 2001 71+ 25 800 1200 2 73 39.2 22.4 72 19.7 23.8 224 Sorva 1991 71+ 11 1000 1000 10 5 44.6 28.9 10 -1.4 2.3 214 A Zhu 2008 71+ 68 1000 1200 60 29 36.2 27.5 34 -2.9 27.4 225 A Barnes 2006 adults 52 600 1500 2 12 38.6 15.1 15 -7.2 11.3 213 Bolton-Smith 2007 adults 60 400 100 24 50 12.0 15.1 56 -8.2 14.3 Dawson- 226 1997 adults 74 700 500 36 145 35.2 32.6 167 -2.1 22.7 Hughes 227 Harris 2002 adults 55 800 0 2 27 22.3 14.0 23 -4.6 6.3 228 Heaney 2003 adults 71 1000 0 5 16 12.0 16.0 16 -11.4 17.6 228 Heaney 2003 adults 71 5000 0 5 17 91.9 37.6 16 -11.4 17.6 229 A Heikkinen 1998 adults 26 300 500 12 18 9.4 10.9 18 -3.3 6.4 230 Honkanen 1990 adults 31 1800 1550 2.75 55 39.5 12.1 60 -13.1 9.2 231 Jensen 2002 adults 41 400 1450 36 33 34.6 23.2 33 16.5 28.2 232 Nelson 2009 adults 62 800 0 12 55 35.3 23.2 31 10.9 16.9 233 Orwoll 1988 adults 58 1000 1000 12 46 25.0 19.1 46 3.0 19.1 234 Patel 2001 adults 72 800 0 12 35 8.4 13.1 35 -9.2 12.8 235 Riis 1984 adults 41 2000 500 12 8 87.5 14.1 7 -5.0 23.8 1007 continued 289

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Vit D3 ± C a Group Placebo or Ca Group 1008 Base 25(OH)D, Vit D3 dose Ca dose Duration Mean Mean Author Year Life stage nmol/L (IU/d) (mg/d) (mo) change change n SD n SD from from baseline baseline 236 Trang 1998 adults 42 4000 0 0.5 24 23.3 17.5 24 3.0 19.8 237 Chan 1982 children 43 400 0 6 30 22.5 6.6 30 -2.5 6.6 El-Hajj 35 (Fuleihan) 2006 children 35 200 0 12 58 7.5 19.8 55 5.0 18.8 El-Hajj 35 (Fuleihan) 2006 children 35 2000 0 12 55 59.9 67.1 55 5.0 18.8 A Calcium supplement was given to all patients The format of this table has been slightly modifies to fit each RCT in one line. 290

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1009 APPENDIX D Adverse or safety outcomes We included only clinical outcomes of tolerable upper intake levels, such as all-cause mortality, cancer (incidence and mortality), soft tissue calcification, renal outcomes, and adverse events reported in RCTs. Results of all-cause mortality and cancer have been described in previous sections. In brief, we did not find vitamin D and/or calcium associated with an increased risk of mortality. For cancer risk, there were some observational studies reporting high calcium intake may be associated with an increased risk of prostate cancer (see “Prostate cancer” in “Calcium and cancer” section). We did not identify any studies on soft tissue calcification and tolerable upper intake levels. Renal outcomes The WHI trial on women aged 50 to 79 years, examined the effect of vitamin D3 400 IU (the Recommended Dietary Allowance for women aged 50 to 70 years and below the 600 IU recommended intake for women > 70 years) in combination with 1000 mg calcium carbonate versus placebo and found an increase in the risk of renal stones (Hazard Ratio 1.17 95% CI 1.02, 1.34), corresponding to 5.7 events per 10,000 person years of exposure.71 It should be noted that women in both groups were allowed to take additional vitamin D supplements up to 600 IU and later 1000 IU per day and calcium supplements up to 1000 mg per day. The baseline total calcium intakes (from foods and supplements) were high: 34% consumed less than 800 mg/d, 26% consumed 800 to 1200 mg/d, and 40% consumed more than 1200 mg/d. A prior publication from WHI trial provided the same data on the risk of renal stones was also included in the Ottawa EPC report. No studies were identified that evaluated the effect of vitamin D, calcium, or combined vitamin D and calcium on other renal outcomes. Adverse events reported in RCTs The reporting of adverse events in RCTs was generally inadequate, and most trials were not adequately powered to detect adverse events. Among the 63 RCTs included in this report, 47 did not report information on adverse events. Five RCTs (in 6 publications) that enrolled a total of 444 subjects reported no adverse events during the trial periods.35,51,227,238,239 Of these, one RCT administered combination of vitamin D2 (1600 or 3600 IU/d) and vitamin D3 (400 IU/d) supplements for 3 months, two RCTs administered vitamin D supplements (type of vitamin D not reported) with doses ranging from 200 to 2000 IU/d for 3 weeks or 1 year, one RCT used high-dose intermittent vitamin D3 supplement (120,000 IU sachets given 3 times, every 2 weeks, for 6 weeks), and one RCT administered 1200 IU/d vitamin D2 supplement for 5 years. Eleven RCTs reported at least one adverse event (Table 107). Excessive gas, bloating, and gastrointestinal discomforts were reported to be associated with calcium supplementation (doses ranged from 600 to 1000 mg/d). Other RCTs of vitamin D (doses ranged from 400 to 5714 IU/d vitamin D3 or ranged from 5000 to 10,000 vitamin D2) 291

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1010 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D and/or calcium supplementations (doses ranged from 200 to 1500 mg/d) reported few cases of gastrointestinal disruption such as constipation, diarrhea, upset stomach, musculoskeletal soreness, primary hyperparathyroidism, hypercalcemia, renal calculi and craniotabes. One RCT reported some adverse events that required hospital admission, including retrosternal pain, a non-ST elevation myocardial infarction and a transient ischemic attack (all 3 cases in vitamin D 400 IU/d plus exercise training group) and one case of acute cholecystitis (in calcium, vitamin D plus exercise training group).80 Another RCT reported that “there were no significant differences between the vitamin D and the control groups in the rate of incident cancer and vascular disease (ischemic heart disease and stroke)” (actual data not provided), and one participant died during the study.98 However, these adverse events may or may not be associated with vitamin D and/or calcium supplementation in this study. Also described earlier in the “Renal outcomes” section, the WHI trial examined the effect of vitamin D3 400 IU in combination with 1000 mg calcium carbonate versus placebo and found an increase in the risk of renal stones (Hazard Ratio 1.17 95% CI 1.02, 1.34), corresponding to 5.7 events per 10,000 person years of exposure.71 Ottawa EPC report: A total of 22 trials reported data on toxicity-related outcomes, 21 of which used doses above 400 IU/d. Toxicity results from trials with intakes of vitamin D above current reference intakes varied and this may have been related to different doses, baseline characteristics of populations or exposure times. Most trials excluded subjects with renal insufficiency or hypercalcemia, were of small sample sizes and had short durations of exposure to vitamin D. Event rates were low across trials in both the treatment and placebo arms. 292

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Table 107. Adverse events reported in RCTs Author Year N enrolled Vit D dose (IU/d) Ca dose (mg/d) Duration Adverse Event data (n=case#) 117 Yamamoto 1995 471 0 1000 6 mo Comparing calcium group to the placebo group, excessive gas and bloating were more frequently reported by white women at 3 months and by whites, in general, at 6 months, and white men reported more loose stools at 6 months. 215 Moschonis 2006 112 600 or 1200 12 mo Bloating, constipation and intestinal discomfort apparently related to the 300 D3 calcium supplement 80 Bunout 2006 96 400 800 9 mo Adverse events that required hospital admission: Vit D plus exercise training group (n=3): retrosternal pain, a non-ST elevation myocardial infarction and a transient ischemic attack. Calcium, Vit D plus exercise training group (n=1): acute cholecystitis Wactawski-Wende 36282 400 1000 7y The WHI trial found an increase in the risk of renal stones (Hazard Ratio 71 2006 1.17 95% CI 1.02, 1.34), corresponding to 5.7 events per 10,000 person years of exposure. 81 Burleigh 2007 205 1200 Median 1 Hypercalcemia (n=2) 800 D3 mo 208 Lappe 2008 5201 800 200 8 wks GI disruption such as constipation, diarrhea, upset stomach (4%), and musculoskeletal soreness (0.9%) 34 rd Brooke 1980 126 1000 0 3 Vit D group (craniotabes, n=2), placebo group (hypocalcemia, n=5; trimester craniotabes, n=6) only 52 Lappe 2007 1180 1400-1500 4y Renal calculi in placebo (n=1), renal calculi in calcium only (n=3), renal 1000 D3 calculi in calcium plus vit D (n=1) 240 Mastaglia 2006 65 500 3 mo Hypercalciuria (n=1) in control group 5000 or 10,000 D2 98 Zhu2008 256 1200 12 mo There were no significant differences between the vitamin D and the control 1000 D2 groups in the rate of incident cancer and vascular disease (ischemic heart disease and stroke). There were 8 and 5 adverse events in vitamin D and the control groups, respectively. One participant in the vitamin D group had mild asymptomatic hypercalcemia one occasion. No case of renal calculus was reported. 1 participant was deceased during the study. 50 Sneve 2008 445 Group 1: 2 capsules of 500 12 mo Primary hyperparathyroidism (n=2), increase in serum calcium to 2.62 mmol/L (n=1), transient increases in serum calcium > 2.59 mmol/L (n=4). vitamin D3 each 20,000 IU taken twice a week (Monday and 317 other adverse events were recorded, most of them related to GI Thursday): ~5714 IU/d discomfort. There were no significant differences between the treatment Group 2: 1 capsules of groups regarding adverse events. vitamin D3 each 20,000 IU taken twice a week (Monday and Thursday): ~2857 IU/d 1011 293

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