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Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health

The purpose of this systematic evidence-based review, referred to as AHRQ-Ottawa,1 requested by the Office of Dietary Supplements, National Institutes of Health and conducted by the University of Ottawa Evidence-based Practice Center (UO-EPC) was to review and synthesize the published literature on five key questions.

  1. Are specific circulating concentrations of 25 hydroxyvitamin D (25[OH]D) associated with bone health outcomes in:

    1. Children: rickets, bone mineral density (BMD), bone mineral content (BMC), fractures, or parathyroid hormone (PTH)?

    2. Women of reproductive age (including pregnant and lactating women): BMD, calcaneal ultrasound, fractures, PTH?

    3. Elderly men and postmenopausal women: BMD, fractures, falls?

  1. Do food fortification, sun exposure, and/or vitamin D supplementation affect circulating concentrations of 25(OH)D?

  2. What is the evidence regarding the effect of supplemental doses of vitamin D on bone mineral density and fracture or fall risk and does this vary with age groups, ethnicity, body mass index, or geography?

1

Cranney, A., T. Horsley, S. O’Donnell, H. A. Weiler, L. Puil, D. S. Ooi, S. A. Atkinson, L. M. Ward, D. Moher, D. A. Hanley, M. Fang, F. Yazdi, C. Garritty, M. Sampson, N. Barrowman, A. Tsertsvadze and V. Mamaladze. 2007. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No. 158. (Prepared by the University of Ottawa Evidence-based Practice Center (UO-EPC) under Contract No. 290-02-0021.) AHRQ Publication No. 07-E013. Rockville, MD: Agency for Healthcare Research and Quality.



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C Methods and Results from the AHRQ- Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health The purpose of this systematic evidence-based review, referred to as AHRQ-Ottawa,1 requested by the Office of Dietary Supplements, National Institutes of Health and conducted by the University of Ottawa Evidence- based Practice Center (UO-EPC) was to review and synthesize the pub- lished literature on five key questions. 1. Are specific circulating concentrations of 25 hydroxyvitamin D (25[OH]D) associated with bone health outcomes in: A. Children: rickets, bone mineral density (BMD), bone mineral con- tent (BMC), fractures, or parathyroid hormone (PTH)? B. Women of reproductive age (including pregnant and lactating women): BMD, calcaneal ultrasound, fractures, PTH? C. Elderly men and postmenopausal women: BMD, fractures, falls? 2. Do food fortification, sun exposure, and/or vitamin D supplementa- tion affect circulating concentrations of 25(OH)D? 3. What is the evidence regarding the effect of supplemental doses of vitamin D on bone mineral density and fracture or fall risk and does this vary with age groups, ethnicity, body mass index, or geography? 1 Cranney, A., T. Horsley, S. O’Donnell, H. A. Weiler, L. Puil, D. S. Ooi, S. A. Atkinson, L. M. Ward, D. Moher, D. A. Hanley, M. Fang, F. Yazdi, C. Garritty, M. Sampson, N. Barrowman, A. Tsertsvadze and V. Mamaladze. 2007. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No. 158. (Prepared by the Univer- sity of Ottawa Evidence-based Practice Center (UO-EPC) under Contract No. 290-02-0021.) AHRQ Publication No. 07-E013. Rockville, MD: Agency for Healthcare Research and Quality. 539

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540 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D 4. Is there a level of sunlight exposure that is sufficient to maintain ad- equate vitamin D levels but does not increase the risk of non-melanoma or melanoma skin cancer? 5. Does intake of vitamin D above current reference intakes lead to toxici- ties (e.g., hypercalcemia, hypercalciuria, and calcification of soft tissue or major organs)? The review focused on electronic searches of the medical literature to identify publications addressing the aforementioned questions. Out of 9,150 citations, 112 RCTs, 19 prospective cohorts, 30 case–control studies, and 6 before-after studies 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-Ottawa 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/vitadtp.htm#Report.

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541 APPENDIX C Chapter 2. Methods Key Questions Addressed in This Report The University of Ottawa EPC's evidence report on Vitamin D is based on a systematic review of the scientific literature. A technical expert panel was recruited to help refine key questions and provide expertise to the review team during the review process. The finalized questions were: 1. Are specific circulating concentrations of 25(OH)D associated with the following health outcomes in: A. Children: rickets, bone mineral density (BMD) or bone mineral content (BMC), fractures, parathyroid hormone (PTH)? B. Women of reproductive age (includes pregnant and lactating women): BMD, calcaneal ultrasound, fractures, calcium absorption, PTH? C. Elderly men and postmenopausal women: BMD, fractures, falls? 2. Does dietary intake (fortified foods and/or vitamin D supplementation) or sun exposure affect circulating concentrations of 25(OH)D? A. Does this vary with different age groups, ethnicity, use of sunscreen, geography and/or body mass index (BMI)? B. What are the effects of fortified foods on circulating 25(OH)D concentrations? C. What is the effect of sun exposure and vitamin D supplementation on levels of serum 25(OH)D? 3. What is the evidence regarding the effect of supplemental doses of vitamin D on bone mineral density, fractures and fall risk in: A. Women of reproductive age and postmenopausal women? B. Elderly men? C. Is there variation with baseline levels of 25(OH)D? 4. Is there a level of sunlight exposure (time of year, latitude, BMI, amount of skin exposed) that is sufficient to maintain adequate vitamin D levels, but does not increase the risk of melanoma or non-melanoma skin cancer? 5. Does intake of vitamin D above current reference intakes lead to toxicities (e.g., hypercalcemia, hypercalciuria, calcification of soft tissue or major organs, kidney stones)? 21

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542 Conceptual Framework SOURCES OF VITAMIN D Skin Cancer Sunlight Optimal Bone Health Adequate Infants Cutaneous synthesis Children/ (D3) Adolescents Dietary Intake Women of Active Serum (natural sources or Reproductive Age Vitamin D [25(OH)D] fortified foods) (1,25(OH)D) Abnormal Bone Postmenopausal Health: Women Clinical Outcomes: Vitamin D Elderly Men rickets, osteomalacia, Supplements osteoporosis, fractures, falls Inadequate excess Surrogate Outcomes: Toxicity BMD, BMC, and biochemical parameters: PTH Figure 1. Conceptual Framework for Evaluation of the Effectiveness and Safety of Vitamin D in Relation to Bone Health. Serum 25(OH)D levels reflect cutaneous synthesis and dietary intake of vitamin D including fortified foods and supplements. For the purposes of this review, only outcomes related to bone health are considered although it is recognized that vitamin D has pleiotropic effects in the body. Outcomes assessed include fractures (related to osteoporosis or impaired mineralization), falls, and surrogate outcomes such as bone mineral density (e.g., areal or volumetric BMD), bone mineral content (BMC) and biochemical parameters such as parathyroid hormone (PTH). For women of reproductive age, calcaneal ultrasound and calcium absorption were also identified as outcomes. Note that serum 25(OH)D measurements vary depending on the particular assay used as well as the laboratory and/or operator, suggesting the need for standardization or method/laboratory-specific decision limits for vitamin D deficiency or insufficiency. 22

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543 APPENDIX C Study Identification Search Strategy An initial search for systematic reviews related to vitamin D was conducted, and the review team and Technical Expert Panel (TEP) identified reviews relevant to each of the five research questions. These aided in the development of the search strategy for primary studies. Conceptual analysis was undertaken by one information specialist, and translation of the concepts and the Boolean logic of their combinations were confirmed by a second information specialist. No language restrictions were applied. Using the Ovid interface, the following databases were searched: MEDLINE ® (1966 to June Week 3 2006); Embase (2002 to 2006 Week 25); CINAHL (1982 to June Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990 to February 2005); and The Cochrane Central Register of Controlled Trials (CENTRAL; 2nd Quarter 2006). The MEDLINE ® search strategy is in Appendix A . Adjustments were made to the search when run in other databases to account for differences in indexing. All records were downloaded and imported into the Reference Manager software, and duplicate records were removed. This review underwent a formal update process following completion of a first draft report and prior to final submission with initial searches run in 2005. The dates of the initial search were as follows: MEDLINE ® (1966 to July Week 4 2005); Embase (2002 to 2005 Week 32); CINAHL (1982 to March Week 4, 2005); AMED (1985 to April 2005); Biological Abstracts (1990 to February 2005); and The Cochrane Central Register of Controlled Trials (CENTRAL; 1st Quarter 2005). Eligibility Criteria Published English-language studies, examining the safety and/or efficacy of vitamin D in humans, were eligible for inclusion, as follows: 1. The association between serum 25(OH)D concentrations and bone health outcomes was examined in the following populations: 1) children (0 to 18 years); 2) women of reproductive age (19 to 49 years) and; 3) elderly men (>65 years) and postmenopausal women (50+ years). Bone health outcomes included: BMD, BMC, fractures, falls, performance measures related to falls (e.g., muscle strength or balance) (age group 3 only), calcium absorption (age group 2), calcaneal ultrasound (age group 2), PTH (age groups 1 and 2), rickets (age group 1). Study designs: RCTs, prospective cohorts, before- after and case-control studies. 2. The effect of vitamin D from dietary sources (including fortified foods and/or vitamin D2 or D3 supplementation) and sun exposure, on serum 25(OH)D concentrations was examined in the age groups listed above. Vitamin D2 and D3 were evaluated separately. Study designs: RCTs of dietary intake/supplementation/sun exposure interventions. Appendixes cited in this report are available at http://www.ahrq.gov/clinic/tp/vitadtp.htm. 23

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544 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D 3. The effect of supplemental vitamin D2 or D3 alone or in combination with calcium on bone mineral density, fractures, and/or falls was examined in: 1) women of reproductive age (19 to 49 years); 2) postmenopausal women ( 50 years) and; 3) elderly men ( 65 years). Study designs: RCTs. 4. The relation between sun exposure, serum 25(OH)D concentrations and the risk of non- melanoma and/or melanoma skin cancer was evaluated. Study designs: existing systematic reviews. 5. The potential toxicity of supplemental vitamin D in doses above the adequate reference intakes (e.g., hypercalcemia, nephrolithiasis, soft tissue calcification) was examined in different age groups. Study designs: RCTs. Systematic and narrative reviews were excluded for all questions except for question 4. However, recent reviews were hand searched for additional potential primary studies that may be pertinent to all questions. Randomized trials of other osteoporosis therapies that included calcium and vitamin D as a control arm were not included unless they also included a placebo or lower dose vitamin D arm that would allow a comparison. Studies evaluating the efficacy of vitamin D for the treatment of secondary causes of osteoporosis (e.g., glucocorticoid-induced osteoporosis, renal and liver disease) or for treatment of vitamin D- dependent rickets were also not considered, in an effort to minimize clinical heterogeneity and since non-dietary sources of treatment are often used as the primary tereatment for some of these conditions. We restricted our inclusion criteria to studies of vitamin D2 (ergocalciferol) or D3 (cholecalciferol). Studies that evaluated the efficacy of the vitamin D preparations calcitriol or alphacalcidol were not included since they are not considered nutritional supplements and have a different safety profile than native vitamin D. Study Selection Process The results of the literature search were uploaded to the software program Trialstat SRS version 4.0 along with screening questions developed by the review team and any supplemental instructions (Appendix B ). Prior to the formal screening process, a calibration exercise was undertaken to pilot and refine the screening process. The results of the literature search were assessed using a three-step process. First, bibliographic records (i.e., title, authors, key words, abstract) were screened, using broad screening criteria, by one reviewer (Appendix B). All potentially relevant records, and those records that did not contain enough information to determine eligibility (e.g., no available abstract) were retained. The reasons for exclusion were noted using a modified QUOROM format (Figure 2). Full text relevance screening was performed independently by two reviewers and discrepancies resolved by consensus or third party (Appendix B). Records were not masked given the equivocal evidence regarding the benefits of this practice.65 Reasons for exclusion were noted. Relevant studies were then evaluated to determine study design and categorized accordingly for inclusion by question. The level of evidence reviewed was limited to RCTs where feasible since systematic bias is minimized in RCTs compared with all other study designs Appendixes cited in this report are available at http://www.ahrq.gov/clinic/tp/vitadtp.htm. 24

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545 APPENDIX C (e.g., cross-sectional, retrospective cohort). However, because of the paucity of RCT evidence addressing the association between circulating 25(OH)D concentrations and bone health outcomes, particularly in infants and young children, inclusion criteria were broadened to include single prospective cohorts, case-control, and before-after study designs for question one. Question four was restricted to existing systematic reviews to limit scope. Data Abstraction Following a calibration exercise, two reviewers independently abstracted relevant information from each included study using a data abstraction form developed a priori for this review (Appendix B ). One reviewer completed primary extraction, which was then verified by a second reviewer. Conflicts were discussed and resolved by consensus. Abstracted data included study characteristics, population characteristics, the type of 25(OH)D assay, source of vitamin (i.e., vitamin D2 or D3 supplements, including dosing regimen and route of administration; sun or UV exposure; dietary intake), use of supplemental calcium, and relevant outcomes such as fractures, BMD, falls and toxicity. Data Assessment Quality Assessment As part of RCT quality assessment, the Jadad scale was used (Appendix B) and scored by an experienced reviewer (Appendixes D and E). This validated scale assesses the methods used to generate random assignments and double blinding, and also scores whether there is a description of dropouts and withdrawals by intervention group.66 The scoring ranges from 1 to 5, with higher scores indicating higher quality. An a priori threshold scheme was used for sensitivity analysis: a Jadad total score of > 3 was used to indicate studies of higher quality. In addition, allocation concealment was assessed as adequate (=1), inadequate (=2) or unclear (=3) (Appendix B).67 To assess the quality of the observational studies (prospective cohorts and case-controls), we used a grading system adapted from Harris et al.68 Quality assessment of observational studies included variables such as representativeness of the study population, whether bias and confounding were controlled for in the study design and reported, and description of losses to followup. An aggregate level of evidence (good, fair, inconsistent) was rated based on quantity, quality and consistency of results. As an example, for assessment of an association of circulating 25(OH)D concentrations with a bone health outcome, good evidence was defined as evidence for or against an association that was consistent across studies with at least one study graded as a higher quality study. Fair was defined by evidence sufficient to determine an association, but limited by consistency, quantity, or quality of studies (i.e., no studies graded as good). Appendixes cited in this report are available at http://www.ahrq.gov/clinic/tp/vitadtp.htm. 25

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546 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D Inconsistent evidence was defined by an inability to make a conclusion for or against an association in that studies had conflicting results.69 Qualitative Data Synthesis Outcomes were summarized using a qualitative data synthesis for each study. A description of each study that included information pertaining to sample size and demographics, setting, funding source, 25(OH)D concentrations and assay used, intervention (form of vitamin D) and comparator characteristics, study quality, details of matching or methods of adjustment, and confounders (where applicable) were recorded and summarized in the text, and/or summary tables throughout the report. These methods were used to help generate hypotheses and to identify any heterogeneity of study populations or in the reporting of data within the published reports. For the purpose of this review, we defined vitamin D deficiency as a serum 25(OH)D measurement below 30 nmol/L, recognizing that variable definitions have been used in the literature including values of 50 nmol/L to > 80 nmol/L (32 ng/dL), and that there is potentially large error or variability in measurement depending on the particular assay used. Similarly, vitamin D insufficiency may be defined using different values. A cutpoint of 30 nmol/L for vitamin D deficiency was used in this report to assist in classifying trials to report the results, and also when conducting subgroup analyses of trials that included vitamin D-deficient populations. In reporting individual study results, the investigator-defined definitions of vitamin D deficiency or insufficiency were noted and reported. We did not attempt to calibrate different 25(OH)D assays. As outlined in the introduction, variability may exist even when laboratories are using the same technique. Quantitative Synthesis For outcomes where meta-analysis was deemed appropriate, we extracted quantitative data (e.g., number of subjects in each group, mean, standard deviation) from trials, using a standardized data extraction form that included intervention characteristics (coded for vitamin D source, type of vitamin D and unit of dosing) vitamin D intake and baseline and outcome variables for all followup intervals including unit of measurement and assay used for serum 25(OH)D measurement. Where data were only available in graph form, we attempted to extract data for the report. If relevant data (e.g., standard deviation) were not reported adequately, we contacted authors to obtain the missing data. A list of additional data received by authors is in Appendix F . We calculated standard deviation from standard errors or 95 percent confidence intervals, and the absolute and percent change for continuous outcomes (e.g., serum 25(OH)D) from baseline and end of study data using standard formulae. To avoid differences in the reporting of units for serum 25(OH)D concentrations (i.e., nmol/L, ng/mL, μg/dL, μg/L and ng/dL) all values were converted to nmol/L, the unit that was Appendixes cited in this report are available at http://www.ahrq.gov/clinic/tp/vitadtp.htm. 26

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547 APPENDIX C used for data synthesis. The conversion formula is 1 ng/mL = 2.5 nmol/L. To limit the variable reporting in vitamin D dosing (e.g., nmol, IU, ug and mg), IU was chosen as the standard unit used for meta-analysis and all other units were converted using a standard formula. The conversion formula for micrograms is 1 ug = 40 IU. Serum 25(OH)D outcomes included absolute change values (nmol/L). Fracture outcomes were classified as vertebral, non-vertebral, hip or total fractures. BMD outcomes included absolute values (e.g., areal BMD, g/cm2), mean percent change from baseline or the difference in the mean percent change from baseline for the treatment versus comparator groups. Followup intervals were recorded for each trial. It is common for variation to exist between trials with regard to length of followup intervals. For the purpose of meta-analyses, the most distal followup and the change between the last followup and the baseline were applied. Statistical Analyses For the effect measures for continuous outcomes (e.g., serum 25(OH)D concentrations) the difference in means between different treatment groups was used for the meta-analyses. The ‘difference in means’ is a standard statistic that measures the absolute difference between the mean values in the two groups in a clinical trial. Absolute change in 25(OH)D concentrations was used for quantitative pooling of 25(OH)D. For the pooling of BMD results, the percent change in BMD from baseline in the treatment versus control or placebo was used as the unit of analysis since this is clinically relevant. For continuous outcomes, the difference in means and standard deviations were calculated for each individual study. To avoid multiple comparison issues in studies with more than one treatment arm, a weighted average (e.g., 25(OH)D) of similar groups was calculated within the study. A weighted average method was used to calculate the 25(OH)D values for the combined treatment group and combined placebo group. The difference in means was then calculated using the weighted averages for the two combined groups. This estimate, with its standard deviation was then used for the meta-analyses. The number in each group was based on intention-to-treat data; however, when these data were not available, we used what was provided in the published report. For dichotomous outcomes (e.g., fractures, falls), studies were grouped by method of administration and type of vitamin D as we anticipated different treatment effects with (1) oral versus injectable vitamin D, (2) type of vitamin D (D2 versus D3) and (3) if calcium was given as a co-intervention. We used these groupings to generate pooled estimates to minimize clinical heterogeneity. The intent-to-treat group or number enrolled at the time of study was used for analyses and when unavailable, we used the number provided in the report. Combined odds ratios were generated using the number of individuals who had an event (e.g., fall or fracture) and not the absolute number of events. This was determined to be a more conservative approach to quantify the effects. For the meta-analysis of fracture and fall outcomes, we pooled studies with different treatment durations and doses. In all cases, meta-analyses were conducted using a weighted mean method. The fixed effect model was used initially to obtain combined estimates of weighted mean differences and their standard errors. When heterogeneity (p<0.10) was present between studies, the Dersimonian and Laird random-effects method was used to obtain combined estimates across the studies.70 The degree of statistical heterogeneity was evaluated for all analyses using the I2 statistic.71-73 An I2 27

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548 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D of less than 25 percent is consistent with low heterogeneity, 25 to 50 percent moderate heterogeneity, and over 50 percent high heterogeneity.73 When significant heterogeneity was identified, then heterogeneity was explored through subgroup, sensitivity analyses and meta- regression analyses if appropriate. Sources of heterogeneity include methodologic as well as clinical heterogeneity. The interpretation of heterogeneity estimates requires caution especially when small numbers of trials were included. Publication bias was explored through funnel plots by plotting the relative measures of effect (odds ratio) versus a measure of precision of the estimate such as a standard error or precision (1/standard error).72 Funnel plots are scatter plots in which the treatment effects estimated from individual studies, are plotted on the horizontal axis against a measure of study precision on the vertical axis. Asymmetry suggests the possibility of publication bias, although other potential causes of asymmetry exist. The degree of funnel plot asymmetry was measured by the intercept from regression of standard normal deviates against precision, with evidence of asymmetry based on p < 0.1.74-76 Throughout the report, vitamin D or 25(OH)D without a subscript represents either D2 or D3 or both isoforms. Wherever possible i.e., when reported in the particular study, the isoform is specified. All interventions are oral, unless it is specifically stated that injected vitamin D was used. 28

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549 APPENDIX C Chapter 3. Results Results of the Literature Search The results of the literature search for the original review and for the update are presented in Figure 2. For the updated review that incorporated the original search data, literature searching identified a total of 9150 potentially relevant bibliographic records. The reviewers nominated an additional 59 potentially relevant studies that were subjected to the same screening process as the other records; the majority of these (55) was nominated after the original search and were likely not detected by the original search due to their publication date. After 2,643 duplicate and review articles (systematic and narrative) were removed, 6,566 unique records remained eligible for broad relevance assessment. These reports were evaluated against the eligibility criteria and after the initial screening for relevance, 5,119 records were excluded. The remaining 1,447 reports were then retrieved and subjected to a more detailed relevance assessment using the full text; 765 of the 1,447 reports failed to meet the inclusion criteria as determined by consensus. (Appendix I ) Given the magnitude of the potentially relevant evidence, an additional eligibility criterion of level of evidence was then applied to the 682 remaining studies. The evidence base was limited to RCTs where possible. In total, 515 bibliographic records were excluded from the evidence synthesis as they were deemed to provide an inadequate level of evidence for their respective question.(Appendix J) Question one (the association of 25(OH) D and bone health outcomes) required that study designs other than RCTs be included (e.g., prospective cohort, case-control, and before-after studies). The reasons for exclusion for all other records are listed in the QUOROM flow chart in Figure 2. In total, 167 studies were deemed relevant and provided sufficient level of evidence for the systematic review. Our search strategy did not reveal pertinent reviews for question four. Since our search strategy may not have identified studies in the dermatology or photobiology literature that evaluated the effect of solar UV-B exposure in terms of a minimal erythemal dose and the risk of skin cancer, this was discussed with the Technical Expert Panel. It was decided that a separate search was not feasible for this report. In total 167 studies (112 RCTs (106 unique trials, 6 companion reports), 19 prospective cohorts (18 unique studies, 1 companion report), 30 case-controls and 6 before-after studies) were included for evidence synthesis. Study characteristics, interventions and results are presented in tables throughout the report. Where applicable, the order of discussion is the following order of study design: RCTs; clinical controlled trials; prospective cohorts; case-control studies; and before-after studies. Appendixes cited in this report are available at http://www.ahrq.gov/clinic/tp/vitadtp.htm. 29

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) 714 Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Bischoff 50% Baseline serum 25(OH)D < IG1: 62 median (IQR) hypercalcemia: IG1: 800 IU vit D3 + (2003)114 30 nmol/L CG: 60 1,200 mg Ca/d IG1: 65.5 (49.8-82.8) IG1: 0 90% < 77.5 nmol/L CG: 1,200 mg Ca/d CG: 28.5 (24.5-41.5) CG: 0 12 wks Residents of long-stay geriatric 89 completers hypercalciuria: urinary Ca excretion facility both genders; mean age ND (SD): IG1: 84.9 (7.7); CG: 85.4 (6.9) RIA GI: (3 mo) Excluded if: IG1: 2 (constipation) hyperparathyroidism, compliance NR CG: 0 hypocalcemia, hypercalcemia, or renal insufficiency; prior HRT or bisphosphonates in last 2 y NR (Switzerland) Brazier 100% Baseline serum 25(OH)D IG1: 23 median (IQR) hypercalcemia: IG1: 800 IU vit D3 + 178 (2002) < 30 nmol/L CG: 25 1,000 mg Ca + IG1: 65 (52.5-72.5) IG1: 0 alendronate 10 mg (p<0.001) CG: 0 3 mo Osteopenic or osteoporotic withdrawals by CG: 1,000 mg Ca + CG: 35 (22.5-47.5) postmenopausal community 3 mo: IG1: 3 alendronate 10 mg (p<0.01) hypercalciuria: dwelling women; mean age and CG: 4 46 IG1: 0; urine Ca/Cr ratio increased (SD): 70 (6) y had at least CPBA significantly from baseline (0.5, 1 and 3 one evaluation compliance NR CG: 0 mo) Excluded if: concomitant post baseline disease; drugs that alter bone urine Ca/Cr ratio (mmol/mmol) by d metabolism 30 increased significantly from baseline in IG1 NR (France) IG1: 0.676 (0.372, 0.963) CG: 0.434 (0.233, 0.623) 24h urinary Ca (mmol/24h) IG1: 5.11 (3.30, 6.99) CG: 3.25 (2.00, 4.64) 194

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Brazier 100% with baseline serum IG1: 95 median (IQR -Q1, Hypercalcemia: IG1: 800 IU vit D3 (2005)191 25(OH)D < 30 nmol/L CG: 96 + 1,000 mg Ca/d Q3): IG1: 7 (7.4%) (2 withdrawn from study) CG: Placebo IG1: 71.8 (58.1, vs. CG: 11 (11.5%) (0 withdrawn) 1 year Ambulatory community dwelling 89.4) women > 65 years of age who CG : 26.8 (20, 35) Hypercalciuria (24 h Ca/Cr ratio >6.25 have vitamin D insufficiency; total mmol/L): mean age 70 (6) y withdrawals: compliance 92.0- IG1: ~20% (3, 6, 9 and 12 IG1: 22.2% 92.5% (pill count) CG: NR mo) Excluded if: hypercalcemia, CG: 30.2% CPBA 24 h urinary Ca/Cr ratio significantly primary hyperparathyroidism, higher in IG1 renal or hepatic insufficiency; IG1: 3.97 vs. CG: 2.35, p < 0.001 medications affecting bone metabolism in last 6 mo CrCl: no significant difference NR (France) Proportion of subjects with serum uric acid above normal threshold significantly increased in IG1 (53% vs. 37.2%, p = 0.046) but no difference in uric acid clearance Individuals with > 1 AE: IG1: 72.6% vs. CG: 72.9%, NS WDAE: IG1: 15.8% vs. CG: 17.7%, NS SAE: IG1 14 (14.7%) vs. CG: 11 (11.5%), NS Osteomuscular: IG1 32 (33.7%) vs. CG 24 GI: IG1: 22 (23.2%) vs. CG: 21 (21.9%), NS Mortality: IG1: 3 (3.2%) CG; 1 (1.0%) 715 195

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) 716 Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Chapuy NR IG1: 1,634 mean (SD): Hypercalcemia: IG1: 1 (0.06%) (due to IG1: 800 IU vit D3 + (1992)181 healthy ambulatory female CG: 1,636 1,200 mg Ca/d IG1: 105 (22) primary hyperparathyroidism); CG: 0 residents of senior facilities CG: Placebo CG: 27.5 (17.5) 1.5 years mean age (SD): 84(6) y Subset for lab Hypercalciuria: NR tests: 142 excluded if taking drugs that alter IG1: 73; CG: GI (nausea, diarrhea, epigastric pain): (every 6 mo) bone metabolism, vitamin D 69 CPBA IG1:40; CG 28 (all WDAE), NS (within 6 months) Of total Renal stones: IG1: 0; CG: 0 NR (France) sample, 54% completers Mortality: IG1: 258/1634 (15.8%) CG: 274/1636 (16.5%) 196

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Chapuy 76.8% Serum 25(OH)D < 30 IG1: 199 mean: Hypercalcemia (12 mo): IG1: 800 IU vit D3 + (2002)180 nmol/L IG2: 194 1,200 mg Ca /d IG1 75 IG1 + IG2: 3 (1 related to myeloma, 2 2 years Ambulatory female residents of CG: 190 fixed combination IG2: 80 hyperparathyroidism) apartments for the elderly with CG 15 IG2: 800 IU vit D3 + low vitamin D and Ca intakes 1,200mg Ca Hypercalciuria (12 mo) defined as urinary (every 3 mo) 583/608 (separate) /d Ca > 350 mg/24 h: Excluded subjects with assessed at CG: Placebo IG1+IG2: 5 (3%) malabsorption, hypercalcemia, least once CPBA CG: 2 (1.3), NS chronic renal failure; or taking drugs that alter bone 69.2% Compliance Serum Cr: no change in either group metabolism, or vitamin D (> 100 completed 2 y (sachets, tablet IU/d) in last year count): > 95% 24h Ca/Cr ratio: significant increase in IG1 at 12 and 24 mo: NR (France) 24 mo IG1+IG2: 167.86 (123.10) CG: 113.15 (97.28), p<0.003 Renal stones: IG1 + IG2: 0 CG: 0 Mortality: IG1+ IG2: 18% CG: 23.9%, NS GI: IG1 + IG2: 24 (3 WDAE) CG: 16, NS 717 197

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) 718 Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Corless NR; mean baseline serum IG1: 41 IG1: 9,000 IU vit IG1: mean ranged Hypercalcemia: (1985)112 25(OH)D (sem): IG1: 17.63 CG: 41 from ~90 to ~160 IG1: 1/41 (2.4%) (hyperparathyroidism) D2/d up to 40 wks (2.05); CG: 16.60 (2.10); all CG: Placebo (30 wks) over CG: 0 subjects had baseline level < 40 Completed: course of study; nmo/L IG1: 32 Compliance NR CG: ~30 (estimated Mortality: CG: 33 from graph) IG1: 1 (2.4%) (every 6 wks) Elderly patients in long-stay CG: 4 (9.8%) geriatric hospital wards plus 18 day patients CPBA mean age (sem): IG1: 82.3(6.0); CG: 82.6 (6.9) Excluded if renal insufficiency; clinical osteomalacia; hypokalemia; plasma 25(OH)D >40 nmol/L. NR (U.K.) Dawson- NR IG1: 124 IG1: 100.1 (24.5) Hypercalcemia: IG1: 100 IU vit D3 Hughes IG2: 123 + 500 mg Ca IG2: 66.3 (25.5) IG1: 0 (1995)118 Healthy ambulatory IG2: 0 IG2: 700 IU vit D3 + postmenopausal women with Withdrawals: 500 mg Ca 2 years mean dietary intake of vit D 100 5% (IG1: 8; CPBA Hypercalciuria: IU and Ca intake < 1000 mg; IG2: 5) IG1: 2/124 (1.6%) (reversed by lowering (9, 12, 24 mo) mean age (SD) calcium from 500 to 250 mg/d) IG1: 64.0 (5.3) Compliance 98% IG2: 2/123 (1.6%) (reversed by lowering IG2 63.0 (5.1) y (pill count) calcium from 500 to 250 mg/d) Excluded if: malignancy, renal, hepatic, other disorders of bone metabolism; corticosteroids, estrogen, anticonvulsants; current use of vitamin D or calcium 100% White (U.S.) 198

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Dawson- NR IG1: 187 Absolute increase Hypercalcemia: IG1: 700 IU vit D3 + Hughes CG: 202 500 mg Ca (citrate in mean 25(OH)D IG1: 0; CG: 0 (1997)184 Healthy ambulatory community initial enrolled malate) IG1: men +29.5 Serum ionized Ca mean change (SD): dwelling women and men 65 445, 389 CG: placebo (29) (calc. mean IG1: men +0.1 (0.2); women 0.1 (0.1). 3 years years of age or older, mean age baseline 112) CG: men 0.0 (0.1) women 0.0 (0.2) 70-72 y characteristics women +40.3 Compliance: 92- (35.8) (calc. mean Hypercalciuria (WDAE): Subjects with cancer or Withdrawals: 93% (pill count) 112) IG1: 1/187 (every 6 mo) hyperparathyroidism; kidney 127 CG: 0/202 stones, renal or liver disease; Completers: anti-resorptive medications (prior 318 (IG1 170; CPBA 24-h urinary Ca/Cr ratio mean change 6 mo), fluoride (prior 2 y); Ca CG 148) (SD): men: IG1: +35 (51) vs. CG: -4 (44); intake of >1500 mg/d excluded. women: IG1: +67 (64) vs. CG: +9 (62), p < 0.005 for comparison between Caucasian 6%, African American treatment groups 2%, Asian 1% (U.S.) Withdrawals: total number 20 11 due to difficulty swallowing pills; WDAE: IG1: 3 constipation, 1 epigastric distress, 1 sweating, 1 hypercalciuria; CG: 3 (2 epigastric distress; 1 flank pain) Mortality: 4 (NR by group) 719 199

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) 720 Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Grant b NR IG1: 1343 Baseline, mean Hypercalcemia: IG1: 800 IU vit D3/d (2005)248 IG2: 1306 (SD), 38 (16.25) in Total cases 21, no significant difference IG2: 800 vit D3 + Excluded those with daily intake IG3: 1311 1,000 mg Ca/d n=60; b/w groups 5 years >200 IU vitamin D, >500mg Ca, CG: 1332 IG3: 1,000 mg Increase after 1 y IG1; 6 (0.4%) use of vitamin D metabolites Ca/d (nmol/L): IG2: 7 (0.5%) (1 y, other within previous 5 years. CG: placebo IG1 24.5 (21.8) timepoints not IG2 24 (17.25) Renal stones: specified) 99% Caucasian IG3 3.5 (14.25) IG1: 2 (0.1) Compliance > 80% CG 7.8 (18) IG2: 0 in 78-80% at 1 y; IG3: 0 54.5% taking 25(OH)D CG: 2 (0.2) medication at 2 y IG2 (Vit D3+Ca) 62 nmol/L Total adverse events: IG1: 153 (11.4); HPLC IG2: 210 (16.1%) IG3: 218 (16.6) CG: 166 (12.5) GI symptoms: IG1: 62 (4.6) IG2: 115 (8.8) IG3: 118 (9.0) CG: 76 (5.7) Renal insufficiency (creatinine >250 mol/L): IG2: 2 (0.2) IG3: 4 (0.3) CG: 1 (0.1) Mortality: IG1: 217 (15.7%) IG2: 221 (16.1%) IG3: 243 (18.5%) CG: 217 (16.4%) b Includes unpublished data received from primary author 200

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Harwood % with 25(OH)D <30 nmol/L: IG1: 38 IG1: 300,000 IU vit baseline 25(OH)D Serum Ca (mmol/L): (2004)197 IG1: 31( 82%) IG2: 36 28 - 30 nmol/L IG1: 2.46 D2 (IM) IG2:26 (72%) IG3: 39 IG2: 300,000 IU IG1: 40 IG2: 2.45 1 year IG3: 26 (67%) CG: 37 IG2: 44 IG3: 2.42 (IM) vit D2 + 1g/d CG: 22 (60%) Ca (tablet/d) IG3: 50 CG: 2.40 (p=0.02) Completers CG: 27 IG3: 800 IU vit D2 + Excluded subjects using 84.4% 1 g/d Ca (tablet/d) Hypercalcemia: (3, 6 and 12 mo) medication affecting bone CG: no treatment Total group: 0 metabolism. RIA Renal stones: NR (U.K.) Total group: 0 Mortality: IG1 7/32 (22%) IG2: 11/25 (44%) (calc; reported in table as 31%) IG3: 6/31 (19%) CG: 536 (14%) Jackson NR IG1: 18,176 levels reported for for entire cohort IG1: 400 IU vit D3 + 243 (2006) CG: 18,106 1000 mg Ca /d a nested case renal stones: Subjects with hypercalcemia, CG: placebo control study of IG1:449 7 years renal calculi excluded as well as fractures only CG: 381 subjects using corticosteroids. hip fracture group: GI: Caucasian ~83% Withdrawn or 46.0 (22.6) IG1: 10.3% moderate-severe (annual clinic African American ~9% lost to followup controls: 48.4 constipation, 20.4% bloating, visits) Hispanic ~4%, American Indian 2.7% (23.5) CG: 8.9% moderate-severe constipation, or Native American ~0.4%, Asian 19.5% bloating, or Pacific Islander ~2%, and chemiluminescent unknown~1.2%) IA Mortality: IG1: 744 (4.1%) CG: 807 (4.5%), NS 721 201

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) 722 Author (year) % Vitamin D Deficient Followup Duration Intervention Population Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Honkanen Baseline mean 25(OH)D (SE): IG1: IG1: 1,800 IU vit mean (95% CI) Hypercalcemia: (1990)202 Home: IG1 42.8 (3.5); CG 36.2 Home 30, Home: maximum Ca values were 2.75, 2.75 and D3+ 1,558 mg Ca/d (2.7) Hospital 33 CG: No treatment IG1 80.7 (75-86) 2.82 in CG 11 weeks Hospital: IG1 24.0 (1.9); CG 23.9 CG: CG: 10.4 (8-13) largest individual increase in serum Ca (2.4) Home 30, Hospital: was 0.18 mmol/L for one subject in IG1 Hospital 33 IG1 64.4 (57-72) and 0.25 mmol/L in one subject in CG. (pre/post Old community dwelling (Home) CG: 23.3 (18-28) intervention) or institutionalized women Completed Serum Ca, mean (SE): (Hospital) , 62-72 year IG1: Home: Home 25; CPBA IG1: 2.40 (2.3-2.5) Excluded subjects with active Hospital 30 CG: 2. 41(2.3-2.6) malignant disease, renal Hospital dysfunction IG1: 2.58 (2.4-2.8) CG: 2.73 (2.5-2.9) NR (Finland) Hypercalciuria: urinary Ca ND Increased serum Cr observed in all groups (greater in CG); 2 CG post trial Cr > 115 micromol/L Renal stones: IG1: 0 CG: 0 GI: 9/25 Home IG1 group had "mild" GI symptoms. WDAE: IG1: Home 2 (‘unrelated symptoms’ not specified) 202

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Kenny (2003)113 NR IG1: 33 IG1: I,000 IU/d vit baseline mean Hypercalcemia: 0 hypercalciuria: 0 CG: 32 (SD) No AE identified D3 + 500 mg Ca/d 11 weeks men > age 65 years CG: Placebo + 500 IG1: 65 (17.5) 92% mg Ca/d CG: 60 (17.5) Urinary Ca (mg)/Cr (g) increased (baseline, 3 and excluded those with systemic completers 6 mo followup: similarly in both groups. 6 mo) disease or unresolved endocrine significant increase IG1: baseline 96 (65) and 6 mo 134 (89) disorder known to affect muscle in IG1 but not CG CG: baseline 95 (80) and 6 mo 129 metabolism; use of androgens, (graph) (101) estrogens, or dehydroepiandosterone 87.3 (13.8) WDAE: 0 (previous 12 months), use of cholecalciferol (previous 4 wks). CPBA NR (U.S.) 207 Krieg (1999) NR IG1: 124 mean (SEM): Mean serum Ca (SEM): IG1: 440 IU D3 + CG: 124 1,000 mg Ca baseline IG1: 2.31 (0.02) 2 years Elderly institutionalized women carbonate/d (Ca in IG1: 29.8 (3) CG: 2.23 (0.01) completers: 2 doses) CG: 29.3 (3) NR IG: 50 (40.3%) CG: No treatment 1y Hypercalcemia: CG: 53 IG1: 74.5 (2.3) IG1: 1 (withdrew) NR (Switzerland) (42.7%) compliance NR CG: 20.8 (2.8) CG: 0 2y IG1: 66.3 (4) GI: CG: 14.3 (2.5) IG1: 6 subjects (5%) with upper GI side effects withdrew CPBA CG: 0 withdrew due to upper GI symptoms Mortality: IG1: 21/124 (16.9%) CG: 26/126 (20.6%) 723 203

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Table 18. (continued) Reported Safety Outcomes by Intervention Group (RCTs) 724 Author (year) % Vitamin D Deficient Followup Duration Population Intervention Serum 25(OH)D Sample Size Safety Outcomes (Timepoints for (nmol/L) Compliance Exclusion Criteria Toxicity Assay Ethnicity (country) Assessment) Lips (1988)209 79 % (serum 25(OH)D 40 Hypercalcemia: nmol/L) IG2: 72 nmol/L in all IG1: 0 D3/d 1 year 35% < 20 nmol/L IG2: 800 IU vit subjects IG2: 1 (associated with thiazide use) (means (SD) D3/d (2, 3 and every Men and women living in two Completers: presented in graph Ca/Cr ratio: 3 mo thereafter) different levels of institutional nursing home: only) fasting urinary Ca excretion increased ~ 15% care; mean age (SD): 81 (9) y 50/72 (69%) unrelated to treatment in all groups, NS (nursing home); 84 (6) y (senior seniors home: Compliance NR serum Cr: increase of ~ 4% in all groups home) 59/70 (84%) (significant increase from baseline) Excluded subjects with CPBA Mortality: hypercalcemia, active IG1: 223/1291 (17.2%) urolithiasis, or chronic renal CG: 251/1287 (19.5%) failure NR (The Netherlands) Mastaglia NR median 36.25 (range 27.5- IG1 13 25(OH)D median Hypercalcemia: IG1: D2 5,000 IU/d 212 (2006) 48.12) IG2 13 + Ca 500 mg (25-75th IG1: 0; CG 12 percentile): IG2: 0 (increase in mean serum Ca at 2 mo but IG2: D2 10,000 3 mo Post menopausal IU/d + Ca 500 mg WNL) osteopenic/osteoporotic women CG: Ca 500 mg IG1 77.5 (66.2- CG: 0 (0, 1, 2 and 3 aged 50 - 70 y presenting for 156.2) mo) bone mass evaluation IG2 97.7 (79.3- Hypercalciuria: Compliance (pill 123.1) IG1: 1 (urinary Ca excretion increased from Excluded subjects treated with and drop counts): CG: 55.0 (72.5- 99.0 (69.5-147.5) to 152 (102-204) mg/24 h, vitamin D or drugs known to 89 (11)-92 (10)% 68.0) p<0.05, at 3 mo); affect bone or vitamin D IG2: 1 (urinary calcium excretion increased metabolism RIA (Diasorin) from 121 (88.7-140) mg/24h to 149 (120.7- 225.7) mg/24h, p<0.05, at 3 mo); NR (Argentina) CG: 1 (urinary Ca excretion not increased) no urinary Ca/Cr ratio >0.37mg/dL 2 3 oral route of administration unless otherwise specified; measured at 2 wks and 6 mo post dose; measured at 2 wks post 1st and 2nd dose, and 3 mo after each of the three doses Ca, calcium; CG, control group; CPBA, competitive protein binding assay; Cr, creatinine; d, day; D, vitamin D, isoform not specified in publication; dL, deciliter; GI, gastrointestinal; HRT, hormonal replacement therapy; IG, intervention group; IQR, interquartile range; IU, international units: mo, month(s); mg, milligram; mo, month(S); ND, not done: NR, not reported; RIA, radioimmunoassay; WNL, within normal limits; 204