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Dietary Reference Intakes for Calcium and Vitamin D (2011)

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

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Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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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 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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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  1. Is there a level of sunlight exposure that is sufficient to maintain adequate vitamin D levels but does not increase the risk of non-melanoma or melanoma skin cancer?

  2. Does intake of vitamin D above current reference intakes lead to toxicities (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 review 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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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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:

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

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

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

  1. Does dietary intake (fortified foods and/or vitamin D supplementation) or sun exposure affect circulating concentrations of 25(OH)D?

    1. Does this vary with different age groups, ethnicity, use of sunscreen, geography and/or body mass index (BMI)?

    2. What are the effects of fortified foods on circulating 25(OH)D concentrations?

    3. What is the effect of sun exposure and vitamin D supplementation on levels of serum 25(OH)D?

  1. What is the evidence regarding the effect of supplemental doses of vitamin D on bone mineral density, fractures and fall risk in:

    1. Women of reproductive age and postmenopausal women?

    2. Elderly men?

    3. Is there variation with baseline levels of 25(OH)D?

  1. 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?

  2. 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)?

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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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.

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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
  1. 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.

  2. 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.

  3. 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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

(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 casecontrols), 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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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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

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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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.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Figure 2. Modified QUOROM Flow Chart

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Note: 74 of the included studies were reported in more than one question. Therefore, the total number of citations across all questions (n=234) exceeds the number of unique included studies (167).

Note: 74 of the included studies were reported in more than one question. Therefore, the total number of citations across all questions (n=234) exceeds the number of unique included studies (167).

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Question 1. Are There Specific Concentrations of Serum 25(OH)D That Are Associated With Bone Health Outcomes in Infants, Children, Women of Reproductive Age, Postmenopausal Women and Elderly Men?
1A. Infants and Children

Question 1A (Part 1). Are There Specific Concentrations of Serum 25(OH)D That Are Associated With Established Vitamin D Deficiency Rickets in Infants and Young Children?

Overview of Relevant Studies

For the purposes of this review, infancy is defined as term birth to 12 months, and young children from one to five years of age. Studies that enrolled older children were included if the majority of children were in the above age groups. For studies on established rickets in infants and young children, 13 studies met our inclusion criteria and assessed the association between serum 25(OH)D and rickets.77-89 Of the 13 studies, there was one RCT,77 four before-after studies78-81 and eight case-control studies.82-89 For the RCT, bone health outcomes included improvement in the signs and symptoms of rickets, and serum PTH levels.77 The twelve observational studies included rickets as the bone health outcome,78-84,84-89 and seven of the 12 studies included assessment of serum PTH,78,79,82,84,87,88 as summarized in Table 1. In all studies, children were diagnosed with rickets using clinical and radiological criteria. No studies included BMD, BMC, or fractures as outcomes.


Study characteristics including country and type of vitamin D assay are summarized in the Table 1. All studies except for one case-control study with nine participants82 were conducted outside of North America. The North American study was conducted at a northern latitude (Canada, U.S. Midwest). Each study examined serum 25(OH)D concentrations at diagnosis and some included followup measurements during treatment.78-81,86,87 Six studies used an RIA assay for serum 25(OH)D assays,77,83-86,89 six studies used a CPBA method,78-82,87 and one study used an HPLC technique.88 We report, in this section, baseline measurements at diagnosis or pre-treatment.


Population characteristics. Children with rickets ranged in age from as young as two months up to 14 years, with most children between 24 and 36 months. In the studies that reported ethnicity, virtually all children were non-white except for two subjects in the one North American study.82 The sample sizes ranged from nine82 to 123 participants,84 with an average of 41. In 12 of the 13 studies, gender was mixed.


Outcome characteristics. For all studies, the diagnosis of rickets was ascertained by radiographic and clinical evidence.77-87,89 Serum PTH was measured in seven studies using either RIA or chemiluminescent immunoassays.78,79,82,84,87-89 No study evaluated BMC, BMD or fractures.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Study quality. The study quality of the RCT,77 four before-after and eight case-control studies ranged from poor to fair with the RCT scoring 1/5 on the Jadad scale (in relation to randomization for treatment).


Qualitative synthesis of individual study results. Six studies reported a mean77,78,80,85 or median79,88 serum 25(OH)D concentration < 27.5 nmol/L associated with rickets. These studies included measurements by RIA,77,85 CPBA78-80 or HPLC.88 Five studies reported that children with rickets had a mean 25(OH)D concentration above 27.5 nmol/L (range of means 36 – 50 nmol/L),82,84,86,87,89 and the other two studies reported at least some children with serum levels above this value.81,83 While 25(OH)D assays differed across the studies, these results suggest that the serum 25(OH)D concentration associated with rickets may be much higher than previously thought. In one study, deficient dietary calcium was the etiology for rickets83 whereas in another study, a mean dietary calcium intake of < 300 mg/d did not alter the Odds Ratio (OR) for rickets.84 Given the uncertainty of the dietary calcium measurement, it remains unclear whether the specific concentration of serum 25(OH)D consistent with rickets is confounded by dietary calcium.


In the studies that reported serum PTH, values in children with rickets were elevated above the normal range.78,79,82,84,87,89 One study confirmed a negative relation of PTH with 25(OH)D concentrations (r = −0.70),82 when cases and controls were analyzed together.


The majority of studies included in this review were from developing countries where dietary calcium intake is low. Low dietary calcium can confound 25(OH)D status and is a major limitation of the studies since some cases of rickets may be attributable to a calcium deficiency. Another limitation is the paucity of studies in children with rickets in North America. The specific concentrations of serum 25(OH)D associated with rickets in North America is uncertain, given the lack of studies in populations with dietary calcium intake similar to North American diets, as well as the different methods used to determine 25(OH)D concentrations. A better understanding of the inter-relationship between 25(OH)D concentrations, calcium and rickets would improve the specific values of 25(OH)D to be used as a biomarker in the diagnosis and treatment of rickets. Only studies of established rickets were included, and other RCTs have evaluated specific 25(OH)D concentrations in relation to the development of rickets. In a rickets prevention study in China, Specker et al. found that 25(OH)D concentrations above 30 nmol/L appeared to prevent rickets in infants with or without vitamin D deficiency at birth.90

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Summary. Circulating 25(OH)D levels associated with established rickets in infants and young children


Quantity: Six studies (one RCT, three before-after and two case-control studies) reported mean or median 25(OH)D concentrations < 30 nmol/L in children with rickets whereas the other studies reported mean or median values above 30 nmol/L and up to 50 nmol/L. In seven of eight case-control studies, serum 25(OH)D values were lower in the children with rickets compared with controls.


Quality: The study quality of the RCT, four before-after and eight case-control studies ranged from poor to fair (with the RCT scoring 1/5 on the Jadad scale).


Consistency: There is fair evidence for an association between low serum 25(OH)D and established rickets, regardless of assay type (RIA, CPBA, HPLC). There is inconsistent evidence to determine if there is a threshold concentration of serum 25(OH)D above which rickets does not occur.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 1. Serum 25(OH)D Levels in Established Rickets in Infants and Young Children

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Intervention

Duration

25(OH)D isoform Measured

Assay

Bone Health Outcomes

Results at baseline or diagnosis

Serum 25(OH)D (nmol/L)

Serum PTH (pmol/L)

Serum Ca (mmol/L)

RCTs

Cesur (2003)776}

56 Infants with nutritional rickets

IG1: vit D 150,000 IU

IG2: vit D 300,000 IU

IG3: vit D 600,000 IU (single dose )

25(OH)D3

Rickets

PTH

25(OH)D3 mean (SD) :

Stage* 1: 15.8 (6.4)

Stage II: 15.4 (4.8)

Stage III: 14.7 (3.9)

 

 

RIA

 

Turkey

36% female

 

 

NR

10.7 (6.1) mo (range 3- 36)

2 mo

 

 

PTH mean (SD):

Stage I: 30 (84)

Stage II: 34.1 (20)

Stage III: 44.3 (25.8)

 

NR

 

 

 

 

 

 

 

 

Ca mean (SD)

all patients

1.9 (0.33)

Before-After Studies

Bhimma (1993)80

23 Children with rickets:

9 vit D def rickets [25(OH)D < 25 nmol/L]

14 Ca def rickets

10 Phosphopenic rickets

4 Healing/healed rickets

5,000-10,000 IU/d vit D3 (plus 500-1,000 mg Ca)

25(OH)D^

Rickets

25(OH)D mean (SD):

vit D deficient rickets: 9.3 (8.8)

Ca deficient rickets: 45.5 (10)

 

 

CPBA

 

 

12 mo

 

 

South Africa

 

 

 

PTH: ND

NR

 

 

 

Ca mean (SD)

Vit D def rickets: 2.09 (0.27)

Ca def rickets: 2.16 (0.28)

Vit D def rickets: 56% female

 

 

 

NR (range 1-12 y)

vit D def rickets (N = 9): 6.1 (4.2) y

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Intervention

Duration

25(OH)D isoform measured

Assay

Bone Health Outcomes

Results at baseline or diagnosis

Serum 25(OH)D (nmol/L)

Serum PTH (pmol/L)

Serum Ca (mmol/L)

Elzouki (1989)81

22 Children < 2 y admitted for treatment of rickets

1-3 h/d of sunshine followed by single IM injection of 600,000 IU vit D2

25(OH)D^

Rickets

25(OH)D:

At diagnosis, 50% of patients had 25(OH)D > 20 nmol/L.

Range 4-65 (graph)

 

 

CPBA

 

Libya

37.5% female

 

 

Public/Private

15 mo (range 3-24 mo) reported only for 16 Libyan children

 

 

PTH: ND

 

 

 

 

Ca: ND

 

African black

followup median 17 d

 

 

 

Garabedian (1983)78

20 Infants and children with rickets 60 Controls

IG1: 2,000 IU/d vit D2

IG2: 400 IU/kg vit D3 (single dose)

25(OH)D^

Rickets PTH (RIA)

25(OH)D mean (SD):

all patients: 11.5 (8)

 

 

CPBA

 

PTH: 2-4 × ULN (N=8); values NR

France/Belgium

65% female

 

 

 

 

Mean age NR

Infants and young children (N = 15): range 4-26 mo;

Older children (N = 5): range 4-12 y

 

 

 

Ca mean (SD)

All patients: 1.8 (0.27)

NR

6 mo

 

 

 

 

80% Immigrants from North Africa, Black Africa, Turkey, Portugal, Pakistan

 

 

 

 

Markestad (1984)79

17 Children with rickets

1,700-4,000 IU vitamin D2/d (reduced to 500-1000 IU in 3 children at 2-4 wks)

25(OH)D^

Rickets

25(OH)D median (range):

N =9 diagnosed in summer: 21 (4.1-30.6)

N = 8 diagnosed in winter: 12.1 (3.8-19.4)

 

NR

CPBA

 

Norway

 

 

 

 

NR

 

 

Public

 

 

 

 

11 (64.7%) Immigrants from Pakistan, Cape Verde Islands, Turkey, Morocco, Sri Lanka, and West Africa; 6 (35.3%) Norwegians

 

 

At baseline, evidence of stimulated PTH in 11/12 (serum PTH or urinary cAMP, values NR)

 

10 wks

 

 

 

 

 

 

Ca: ND

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age

Ethnicity

Matching Variables

Duration

25(OH)D Isoform Measured

Assay

Bone Health Outcomes

Results at baseline or diagnosis

Serum 25(OH)D (nmol/L)

Serum PTH (pmol/L)

Serum Ca (mmol/L)

Case-control studies

Arnaud (1976)82

9 Children with mild (n=3), moderate (n=5) and severe (n=1) rickets 9 Controls

Age

Vit D 5,000 IU/d

25(OH)D^

Rickets

PTH

25(OH)D mean (SD) (range):

Mild rickets: 45 (7.5) (range 40-52.5)

Moderate: 30 (5)

Severe: 20 (NR)

Controls: 90 (30)

 

 

CPBA

Canada/Midwest U.S.

 

4 wks

 

Rickets: 22% female

Controls: NR

 

 

 

Public

 

 

 

 

Negative association between 25(OH)D and PTH (r=−0.70).

 

Moderate rickets (N = 5)

Mean age 1.69 (1.03) y

Controls: 2.71 (1.7) y

All rickets: age range 2 mo – 3.5 y

 

 

 

 

 

 

 

Ca mean (SD):

ND for mild, moderate, severe subgroups Stage II rickets: 2.4 (0.15)

Age matched controls: 2.53 (0.1)

 

7 Canadian (5 First Nations, 1 West Indian black, 1 Portuguese) and 2 American (mid NW U.S.)

 

 

 

Balasubraman (2003)86

40 Children (N = 24) and adolescents (N = 19) with rickets/osteolmalacia 53 controls (34 children and 19 adolescents)

NR

Cases: 6,000 IU/d vit D or single dose of 600,000 IU

25(OH)D^

Rickets

25(OH)D mean (SD): Children

rickets: 50 (38.9)

controls: 61.3 (35.9), NS

India

 

RIA

NR

 

3 mo

 

Adolescents:

rickets: 12.6 (7.1) all but one < LLN

controls: 46.0 (45.4), p<0.001

 

Rickets: 54.1% female

Controls: 47.0% female

 

 

 

 

 

 

 

 

PTH: NR

 

Children:

Rickets: median age 33 mo (range 11 – 120) ; Control: median 27 mo (range 6 mo – 84 mo)

 

 

 

 

 

 

 

 

Ca mean (SD) Children

Rickets: 2.2 (0.3)

Controls: 2.4 (0.3) NS

 

Adolescents:

Rickets: median 198 mo (range 168-240)

Controls: median 156 (range 120-228)

 

 

 

 

 

 

 

Adolescents

Rickets: 2.1 (0.2)

Controls: 2.3 (0.2), p=0.008

 

Hindu/Muslim

 

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age

Ethnicity

Matching variables

Duration

25(OH)D isoform measured

Assay

Bone Health Outcomes

Results at baseline or diagnosis

Serum 25(OH)D (nmol/L)

Serum PTH (pmol/L)

Serum Ca (mmol/L)

Dawodu (2005)88

38 Children with rickets 50 Historical controls

Community

NA

25(OH)D^

iPTH (rickets group only)

25(OH)D median (IQR):

Rickets: 8.0 (3.8, 15.3)

Controls: 43.8 (25, 64.3), p = 0.001

United Arab Emirates Public

 

 

NA

HPLC

 

Rickets: 50% female,

Controls: 40% female

 

 

 

 

 

 

 

 

 

PTH showed a trend toward negative correlation with 25(OH)D (data NR)

 

Rickets: 13.5 mo

Controls 13.0 mo

 

 

 

 

 

Ca median (IQR)

Rickets: 2.22 (1.88, 2.35)

Controls: 2.4 (2.25, 2.5), p= 0.001

 

Arab

 

 

 

 

Graff (2004)87

15 Children with rickets

15 Controls (unrelated)

Age, sex

Cases: 1,000 mg/d Ca (no vit D supplement)

Treatment duration: 6 mo; Followup: 12 mo

25(OH)D^

Rickets

PTH

(chemiluminescent immunometric assay)

25(OH)D mean (SD):

significantly lower in children with rickets

Rickets: 37.5 (13.5)

Controls: 72.5 (11.5), p<0.001

Nigeria

 

 

CPBA (Nichols)

 

60% female

 

NR

 

 

 

 

 

 

Rickets: 46 (22) mo

Controls: 47 (22) mo

 

 

 

 

 

 

 

 

PTH mean (SD)

significantly higher in rickets group; rickets: 32 (33)

controls: 4.0 (3.1), p=0.003

 

Rickets: 7 Muslim and 8 Christian

Controls: 4 Muslim and 11 Christian

 

 

 

 

 

 

 

 

 

 

Ca mean (SD)

Rickets: 2.13 (0.2)

Controls: 2.4 (0.1), p <0.001

Molla (2000)85

103 Children with rickets

102 Controls

Age, sex Socio- ethnic characteristics

NA

25(OH)D^

Rickets

25(OH)D mean (SD): significantly lower in children with rickets:

Rickets: 26.5 (15.5)

Controls: 83.5 (74.75), p<0.0001

Kuwait

 

NA

RIA

 

 

NR

 

 

 

NR

 

 

 

 

 

 

Rickets: 14.5 (5.2) mo (range 9 mo - 8y)

Controls: 15.2 (6.3) mo

 

 

 

 

PTH: ND

 

 

 

 

 

Ca, mean (SD)

Rickets: 2.24 (0.28)

Controls: 2.45 (0.15) p <0.0001

 

96.1% from mothers with Hijab use

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age

Ethnicity

Matching variables

Duration

25(OH)D isoform measured

Assay

Bone Health Outcomes

Results at baseline or diagnosis

Serum 25(OH)D (nmol/L)

Serum PTH (pmol/L)

Serum Ca (mmol/L)

Oginni (1996)

26 Children with active rickets, 90 healthy controls

Age, community

NA

25(OH)D^

Rickets PTH (radioimmunometric assay)

25(OH)D mean (SD) (range): significantly lower in rickets group

Rickets: 36 (28), range 7-147

Controls: 69 (22), range 32-140, p<0.0002

Nigeria

 

 

NA

RIA

 

Rickets: 50% female, Controls: 61% female

 

 

 

Public

 

 

 

 

Mean age NR

Children with rickets age range: 1-5 y

 

 

 

 

PTH mean (SD): higher in rickets group; Rickets: 5.9 (6.9), range 0-33.6

Controls: 1.0 (1.2), range 0-4.1, p<0.001

 

Nigerian

 

 

 

 

 

 

 

 

 

 

Ca (albumin corrected) mean (SD)

Rickets: 2.06 (0.23)

Controls: 2.35 (0.14), p<0.001

Thacher (2000)84

123 Active rickets

123 Controls

Age, sex if < 5 y, weight

NA

25(OH)D^

Rickets

25(OH)D median (25th and 75th percentile):

Rickets: 32 (22, 40);

< 30 nmol/L: 37%

Controls: 50 (42, 62), p<0.0001

 

 

NA

 

PTH (RIA)

Nigeria

49.6% female

 

 

RIA

 

Public

Mean age NR

Rickets: median (25th and 75th percentile) age: 46 (34,63) mo

Controls: 42 (25-70) mo

 

 

 

 

 

 

 

 

 

 

PTH median (25th and 75th percentile):

Rickets: 20 (13, 31)

Controls: 12 (11,16), p =0.0066

 

Christian/Islam:

Rickets: 82/41

Controls: 57/66

 

 

 

 

Ca mean (SD)

Rickets: 1.93 (0.22)

Controls: 2.24 (0.15), p<0.0001

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

mean Age (SD)

Ethnicity

Matching variables

Intervention Duration

25(OH)D isoform measured

Assay

Bone Health Outcomes

Results at baseline or diagnosis

Serum 25(OH)D (nmol/L)

Serum PTH (pmol/L)

Serum Ca (mmol/L)

Thacher (1997)83

37 Healthy controls with normal weight

37 Children with active rickets (median duration of 14 mo)

Age, sex

NA

25(OH)D^

Rickets

25(OH)D

Rickets: levels > LLN in 16/28 (57%); 2/28 (7%) had values < 12.5 nmol/L

Controls: ND

 

 

NA

 

 

Nigeria

 

 

RIA

 

NR

47% female

 

 

 

 

PTH: ND

 

Rickets: 3.16 (1.53) y

Controls 3.14 (1.51) y

 

 

 

 

Ca mean (SD)

Rickets: 2.09 (0.30)

Controls: 2.08 (0.31), NS

55% of rickets and 51% of controls were hypocalcemic (< 2.1)

 

All Nigerian

 

 

 

 

^ Vitamin D refers to both or one unspecified isoform; if the isoform was disclosed, it is specified as vitamin D2 or D3;

* stage I rickets: early phase (serum calcium is low but serum phosphorus is normal); stage II: serum calcium normal due to compensatory hyperparathyroidism; stage III: both serum calcium and phosphorus are low ;

Ca, calcium; CPBA, competitive protein binding assay; HPLC, high performance liquid chromatography; IQR, interquartile range; IU, international units; LLN, lower limit of normal reference range; mo, month(s); NA, not applicable: ND, not done; NR, not reported; PTH, parathyroid hormone; RIA, radioimmunoassay; ULN , upper limit of normal reference range; vit, vitamin; y, year

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Question 1A (Part 2). Are Specific Circulating Concentrations of 25 Hydroxyvitamin D [25(OH)D] Associated With Bone Health Outcomes in Infants?

Overview of Relevant Study Characteristics and Results

Infancy is defined by the Institute of Medicine as including two subcategories: birth to 6 months and 6 to 12 months.4 Seven studies included infants 12 months or younger and assessed the association between serum 25(OH)D and bone health outcomes.91-97 Of the studies, there were three RCTs, two in breast-fed infants92,93 and one in formula-fed infants,91 and four case-control studies.94-97


For the three RCTs, bone health outcomes included BMC92,93 and serum PTH levels91-93 (Table 2). No RCTs reported results of BMD or evaluated fracture incidence. Four observational studies reported BMC,95-97 BMD,96,97 fractures94 or PTH (Table 2).94-96


Study characteristics. Of the three RCTs, two were conducted in the U.S.92,93 Both of these trials randomized human milk-fed infants to receive vitamin D2 supplementation (400 IU/d) or placebo. One U.S. RCT was six months in duration,92 and the other was 26 weeks long at which time the placebo group were started on supplementation, and both groups were followed until 52 weeks.93 The RCT by Zeghoud et al. was three months in duration, and randomized infants to receive either 500 or 1000 IU/d D2.91 The 25(OH)D assays varied, with two studies using a CPBA method91,93 and one using HPLC.92


None of the four case-control studies were conducted in North America (Table 2). Outcomes were assessed at birth in three studies94,95,97 and at two to five months of age in the other.96 One study measured circulating 25(OH)D by CPBA,94 two studies used HPLC,95,96 and the fourth study97 did not report the method.


Population characteristics. For the three RCTs, the age at enrolment was within a few days of birth.91-93 The sample sizes ranged from 18 to 80 infants, without a predominance of male or female gender. In all three studies,91-93 participants had to be healthy and free of conditions known to affect calcium metabolism. Mean vitamin D and calcium intake were not reported in any of the studies, although maternal behavior related to breast feeding was reported in all studies. Baseline 25(OH)D concentrations are summarized in Table 2.


For the case-control studies, three studies evaluated infants at birth or within the first few days of birth,94,95,97 and one study evaluated infants at two to five months of age.96 The sample sizes ranged from 21 to 82 infants with sub-categorization as to ethnicity,94 term born,97 season of birth,95 or feeding type.96 In all case-control studies, participants had to be healthy and free of conditions known to affect calcium and bone metabolism. Data on dietary vitamin D or calcium intake plus exposure to sunshine were only relevant for the study that evaluated two to five month old infants,96 and these data were not reported.


Covariate/confounders. No relevant covariates or effect modifiers were controlled for in the RCTs. In one RCT, baseline 25(OH)D concentrations were used to divide the study cohort into three subcategories91 (Table 2). Seasonal effects were examined in one study.92 For case-control studies, matching on gestational age at birth and gender was not reported. Only one

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

study adjusted for weight when evaluating the relation between 25(OH)D and whole body BMC.95

Outcome characteristics. For the RCTs, BMC of the distal radius was measured by single photon absorptiometry,92,93 and PTH was measured using RIA.91-93

For the case-control studies, BMC (whole body or spine) and BMD were measured using dual-energy x-ray absorptiometry (DXA).95-97 PTH was measured using RIA techniques.94-96 Although all studies used RIA techniques to measure PTH, these may have varied in antibody specificity and measurement of PTH fragments.98

One case-control study reported fracture incidence94 although the methodology was not reported.


Study quality. For the RCTs, one trial each scored 1/5,91 3/593 and 4/592 on the Jadad scale. The four case-control studies were of fair quality.


Qualitative synthesis of individual study results. Of the two RCTs measuring BMC of the distal radius, one study showed transient elevation in BMC at 12 weeks of age in the supplemented group (with serum 25(OH)D concentrations of 95 nmol/L) compared to the placebo group (with 25(OH)D concentrations of 50 nmol/L).93 However, by 26 weeks there was no significant difference in BMC between the placebo and vitamin D2 supplemented infants who continued to have higher serum 25(OH)D levels. In a second trial by Greer,92 no difference in BMC was observed at 3 months in vitamin D2 supplemented or unsupplemented human milk-fed infants despite 25(OH)D concentrations of 97 nmol/L in the intervention group compared to 39 nmol/L in the control group. At six months, the control group had higher absolute BMC and was also noted to have higher levels of the (unsupplemented) D3 isoform. However, the change in BMC from 1.5 to 6 months was not significantly different in the two groups.

Two case-control studies measured BMC and BMD of the lumbar spine (L1-4).96,97 One study observed a negative correlation between 25(OH)D (levels ranging from 10 to 292 nmol/L) and spine BMC and BMD at birth but no relation was observed in regression analyses that included postnatal age and serum calcium.97 The other study96 did not find a difference in spine BMC at two to five months of age when a group of human milk-fed infants with an average 25(OH)D serum level of 40 nmol/L were compared with a group of formula-fed infants with an average 25(OH)D of 73 nmol/L. 8/18 infants in the human milk-fed group and 1/17 in the formula-fed group had a serum 25(OH)D level < 28 nmol/L; there was no correlation of BMC with serum 25(OH)D concentration. The one study that measured whole body BMC reported a positive relation between 25(OH)D and BMC.95 The values for 25(OH)D in this study were on average 27 nmol/L for winter born and 75 nmol/L for summer born who had eight percent higher whole body BMC at birth.

Overall, for BMC measurements reflecting mainly cortical bone, including whole body and radial assessments, two of three studies showed a positive association between 25(OH)D concentrations with BMC, one measuring whole body BMC and one showing a transient increase in distal radial BMC at 12 but not 26 weeks.93,95 Of the two studies examining predominantly trabecular bone (lumbar spine),96,97 one showed a negative correlation between 25(OH)D and BMC and BMD at birth that was not evident after using multiple regression;97 the other did not demonstrate any association.


Of the two RCTs reporting PTH levels, one study did not observe differences in PTH between vitamin D2 supplemented and non supplemented infants at 1.5 to six months of age.92 Both groups were characterized by mean serum 25(OH)D levels above 30 nmol/L (measured by

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

HPLC). At all timepoints, 25(OH)D values were higher in the supplemented group (range of means from 75.6 to 97.2 nmol/L compared to means of 39.4 to 58.8 nmol/L in the unsupplemented group). In the other RCT, PTH declined in all groups from birth to three months of age while 25(OH)D concentrations increased to at least 46 nmol/L (measured by CPBA).91 In that study, all neonates who had abnormally high PTH had serum 25(OH)D < 30 nmol/L. In a case-control study, serum PTH was not different among winter and summer born infants with mean serum 25(OH)D of 27 and 75 nmol/L respectively (measured by HPLC).95 Similarly, human milk-fed infants with a mean 25(OH)D concentration of 40 nmol/L did not have different serum PTH values than formula-fed infants with a mean 25(OH)D concentration of 73 nmol/L (measured by HPLC).96 Lastly, Asian infants had significantly higher PTH concentrations and lower 25(OH)D concentrations of 5 to 20 nmol/L (mean 6, SD 4) when compared to Caucasian infants characterized by serum 25(OH)D concentrations of 9 to 39 nmol/L (mean 15, SD 5) (measured by CPBA).94 Overall, these five studies suggest that PTH is inversely associated with serum 25(OH)D concentrations at lower 25(OH)D concentrations but there was inconsistent evidence for a threshold that may exist somewhere above 27 nmol/L (measured by CPBA). Variable evidence for a threshold may be in part due to the different assays used, both to measure serum PTH and serum 25(OH)D.


Of the studies examining a relation between 25(OH)D and bone health outcomes, most had small sample sizes and the baseline 25(OH)D was variable ranging from deficient values around the limitation of detection to values above 27 nmol/L. In studies with repeated measurements, the baseline 25(OH)D was not considered as an effect modifier in evaluating the relation between 25(OH)D and bone health outcomes. The three included RCTs used vitamin D2 supplementations and therefore conclusions cannot be drawn regarding supplementation with the D3 isoform. Lastly, a definitive conclusion as to whether a specific concentration of 25(OH)D is associated with an elevated PTH (secondary hyperparathyroidism) is not possible given the evidence put forth to date. Additional studies are required to define a threshold concentration of 25(OH)D below which serum PTH levels rise. This will require not only standardization of 25(OH)D assays but also PTH assays.98

Summary. Serum 25(OH)D levels and bone health outcomes in infants

Quantity: Of the two RCTs examining BMC, one demonstrated no benefit of higher serum 25(OH)D on radial bone mass while the other showed a transient increase of BMC compared to the unsupplemented group at 12 weeks but not 26 weeks. Of the three case-control studies, whole body BMC was positively related to and lumbar spine negatively related to serum 25(OH)D concentrations. Based on two RCTs and three case-control studies, a rise in PTH was either not observed with 25(OH)D concentrations above 27-30 nmol/L or occurred at a lesser rate than at lower values, suggesting a threshold value may exist somewhere above 27 nmol/L.


Quality: The three RCTs were of fair to high quality (two of the three RCTs had a Jadad score of ≥ 3/5) and the four case-control studies were of fair quality.


Consistency: There is inconsistent evidence for an association between a specific concentration of serum 25(OH)D and the bone health outcome BMC in infants. Overall, there is fair evidence that PTH is inversely associated with serum 25(OH)D concentrations at lower 25(OH)D concentrations, but there was inconsistent evidence for a threshold that may exist somewhere above 27 nmol/L (measured by CPBA).

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 2. Serum 25(OH)D and Bone Health Outcomes in Infants

Author (year)

Country

Funding

Population, N

Gender

Mean Age (SD)

Ethnicity

Intervention

Duration

Serum 25(OH)D

Assay

Time points

Bone Health Outcomes

Results

Jadad Score

RCTs

Greer (1982)93

18 Healthy term infants exclusively breast-fed IG1 9; CG 9

IG1: vit D2

400 IU/d

CG: placebo

25(OH)D^

PTH (RIA)

Serum 25(OH)D mean nmol/L

Baseline: no significant difference between groups

3

 

 

CPBA

distal L radius BMC (SPA)

 

 

U.S.

 

 

12 wks:

IG1:95* (graph)

CG: 50

 

 

 

12 wks (double blind); (unblinded to investigator at 3 mo); supplements continued until weaned

Measured at baseline, 12 and 26 wks

 

Public

At 9 mo, 6/13 and at 12 mo, 3/13 enrolled infants were still breastfeeding

 

 

 

 

 

Measured at 3, 6, 12, 26, 40 and 52 wks

 

 

 

 

 

26 wks:

IG1: 81.8

CG: 32.3

 

 

66% female

 

 

 

 

 

 

 

 

PTH: no significant difference between groups (data NR)

 

 

0 d (recruited at birth)

 

 

 

 

 

 

At 6 mo, unblinded to mother, and placebo group began to received daily vit D2 400 IU/d

 

 

 

 

 

17 Caucasian

1 Asian-Indian

 

 

BMC mean (SEM) mg/cm

12 wks: IG1 79 (3); CG 64 (3), p < 0.003

26 wks: IG1 70 (6); CG 75 (5), NS

52 wks: IG1 108 (20); CG 120 (19) (CG receiving vit D for 6 mo)

 

 

 

followed to 1 y

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean Age (SD)

Ethnicity

Intervention

Duration

Serum 25(OH)D

Assay

Time points

Bone Health Outcomes

Results

Jadad Score

Greer (1989)92

46 Healthy term born infants born to mothers willing to breast-feed for 6 mo, 12 additional controls (formula fed infants)

IG1: 400 IU/d D2

CG: placebo

25(OH)D^ and each isoform measured

PTH (RIA)

Total serum 25(OH)D mean (SD)

At birth:

IG1: 59.7 (11.8)

CG: 58.8 (19.1)

4

 

 

distal L radius BMC (SPA)

 

 

 

HPLC

 

 

USA

6 mo, starting at birth

 

 

 

 

 

 

Measured at birth, 1.5, 3 and 6 mo

 

6 mo:

IG1: 92.4 (29.7)

CG: 58.8 (24.9), p < 0.01

 

Public

 

 

 

Measured at 1.5, 3 and 6 mo

 

 

46% female

 

 

 

 

NR (range 37 to 40 wk gestation)

 

 

 

PTH: no significant difference between groups

 

 

 

 

 

 

BMC mean (SD) mg/cm:

No significant difference between groups at 1.5 and 3 mo. At 6 mo, CG was significantly greater than IG1: IG1 89.5 (12.5) vs. CG 101.0 (17.9), p<0.05 However, change in mean BMC from 1.5 to 6 mo was not different between groups.

 

 

All infants: Caucasian mothers;

fathers: 1 black, 1 American Indian, others Caucasian

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean Age (SD)

Ethnicity

Intervention

Duration

Serum 25(OH)D

Assay

Time points

Bone Health Outcomes

Results

Jadad Score

Zeghoud (1997)91

80 Healthy neonates, and their mothers; after initial measurements, infants were divided into 3 groups based on serum 25(OH)D (≤ or > 30 nmol/L) and PTH ≤ or > 60 ng/L)

IG1: 500 IU IU/d D2

IG2: 1000 IU/d D2

Starting at 3-6 d after birth

25(OH)D^

iPTH (RIA)

Serum 25(OH)D mean (SD)

Baseline total sample: 29.5 (13.8); (range 10-80)

51/80 (63.7%) 30 nmol/L

1

 

CPBA

Measured at 3-6 d, 1 mo, 3 mo

 

France

 

 

Measured at 3-6 d, 1 mo, 3 mo.

NR

 

 

 

Serum iPTH was negatively correlated wtih 25(OH)D (r = 0.45, p < 0.001)

 

 

All infants fed formula with mean (SD) 426 (46) IU vitamin D3/L

 

 

 

 

 

 

 

In neonates with 25(OH)D < 16 nmol/L, iPTH was significantly higher: mean (SD) 70 (30) pmol/L than those born with 25(OH)D > 30 nmol/L

 

 

NR

 

 

 

 

NR (range: 3 to 6 d)

 

 

 

 

 

 

 

 

 

Infants with high iPTH (> 60 ng/L) were born to mothers with 25(OH)D <30 nmol/L.

 

 

From birth to 3 mo, 28 (35%) excluded, some (< 10) due to digestive problems

 

 

 

 

 

 

 

 

Mean baseline 25(OH)D by group**:

Group 1 (N = 14): 25(OH)D ≤ 30 nmol/L and iPTH > 60 ng/L: 17.9 (7.8)

Group 2 (N = 36): 25(OH)D ≤ 30 nmol/L and iPTH < 60 ng/L: 22.7 (6.5)

Group 3 (N = 29) 25(OH)D > 30 nmol/L and iPTH < 60 ng/mL: 43.7 (10.6)

 

 

European

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean Age (SD)

Ethnicity

Intervention

Duration

Serum 25(OH)D

Assay

Time points

Bone Health Outcomes

Results

Jadad Score

Zeghoud (1997)91

 

 

 

 

At 1 mo, all 3 groups (pooled vit D doses): mean serum 25(OH)D was significantly increased and there was no significant difference between groups.

Group 1: 53.1 (12)

Group 2: 59.8 (17.7)

Group 3: 59.2 (11.4)

At 1 mo, iPTH decreased and there was no significant difference between groups (pooled doses).

At 3 mo, mean 25(OH)D for total sample (pooled doses) was 69 nmol/L; highest value 92.5 nmol/L.

 

 

 

 

 

 

IG1 (500 IU D2)

For group 1, at 1mo (45.5 nmol/L) and 3 mo (56.1 nmol/L), serum 25(OH)D values were significantly lower than the other 2 groups receiving same dose, and lower than all groups receiving 1,000 IU/d.

 

 

 

 

 

 

Serum iPTH remained elevated in 14.3% of infants in group 1 after 1 mo, and mean PTH was significantly higher than those of other grps at 1 and 3 mo.

 

 

 

 

 

 

IG2 (1,000 IU D2)

Serum iPTH was similar among the 3 groups receiving 1000 IU/d at 1 mo. PTH declined in all grps and did not change between 1 and 3 mo.

Change in serum 25(OH)D (3 mo) was not significantly different between the 3 groups.

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding Source

Population, N

Gender

Mean age (SD)

Ethnicity

Serum 25(OH)D

Assay

Time points

Bone Health Outcomes

Assay

Results

Case-control studies

Okonofua (1986)94

21 Healthy term born infants

25(OH)D^

PTH (RIA-midportion)

Serum 25(OH)D mean (SD) (nmol/L): Lower in Asian vs. white term born infants

(p<0.01) White: 15 (5) (range 9-39)

Asian: 6 (4) (range < 5 - 20)

 

NR

Cord and maternal sampling

fractures during birth

UK

 

 

 

NR

 

 

NR

 

 

 

Mean (SD) serum PTH (pmo/L): Higher in Asian vs. white infants (p < 0.05)

White: 55 (6)

Asian: 44 (7)

 

10 Caucasian (47.6%),

11 Asian (52.4%)

CPBA

 

 

 

Measured at baseline

 

 

 

 

 

Maternal 25(OH)D in white mothers was 30 (11) nmol/L and in Asian mothers was 15 (10) nmol/L serum PTH was higher in Asian mothers.

25(OH)D levels in mothers were significantly higher than neonatal levels; the two were correlated (r=0.60).

 

 

 

 

fractures during birth: 0

Bougle (1998)97

82 Healthy term born infants (also 44 preterm)

25(OH)D^

LS BMD and BMC (DXA)

Full term infants:

Serum 25(OH)D mean (SD) nmol/L (range) 75 (52.5) (10-292.5)

France

 

Assay NR

 

 

NR

 

 

 

NR

 

At or following hospital discharge

 

Full term infants:

25(OH)D negatively related to BMD (r =−1.7, p=0.02) and to BMC in full term (r =−0.04, p=0.02), in a simple regression analysis but not related to BMC or BMD in a multiple regression analysis.

 

Term 40 wks (range 37-42)

 

 

Asian

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding Source

Population, N

Gender

Mean age (SD)

Ethnicity

Serum 25(OH)D

Assay

Time points

Bone Health Outcomes

Assay

Results

Namgung (1998)95

71 Healthy term infants, 37 born in summer, 34 born in winter

25(OH)D^

iPTH (Allegro RIA)

Serum 25(OH)D mean (SD) (nmol/L):

Winter born infants had lower 25(OH)D than summer born (p<0.001).

Winter born: 26.8 (19.0)

Summer born: 75.0 (24.0)

 

Measured in cord samples

Whole body BMC (DXA) measured before 3 d of age

Korea

 

 

Winter 38% female

Summer 59% female

 

 

Public

HPLC

 

 

 

 

 

 

% of infants with levels < 27.5 nmo/L

Winter born: 97%

Summer born: 47%

 

Mean (SD) gestational age:

Winter: 38.3 (0.7) wks

Summer: 38.3 (0.8) wks, range 37 - 41 wka

Winter 26.8 (19.0)

Summer 75.0 (24.0)

 

 

 

No differences were observed for PTH.

Serum PTH geometric mean range):

Winter born: 5.8 (2.8 - 11.9)

Summer born: 5.1 (1.8 - 14.6), NS

 

Korean

 

 

 

 

 

 

Winter born had 8% lower whole body BMC than summer born (p = 0.0002).

BMC LSM (SD) (g/cm):

Winter born: 86.7 (7.7)

Summer born: 93.9 (7.8)

 

 

 

 

Whole body BMC correlated positively with serum 25 (OH)D (r=0.243, p=0.047).

 

 

 

 

Maternal 25(OH)D was lower in winter than summer: 24 (13) vs. 43 (18), p < 0.001.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding Source

Population, N

Gender

Mean age (SD)

Ethnicity

Serum 25(OH)D

Assay

Time points

Bone Health Outcomes

Assay

Results

Park (1998)96

Korea

NR

35 Healthy term born infants born in winter, 18 exclusively breast-fed, 17 formula-fed with 400 IU vitamin D enrolled at ages 2 - 5 mo

25(OH)D^

iPTH (Allegro RIA)

LS BMC and BMD (DXA)

Serum 25(OH)D mean (SD) nmol/L:

Mean was lower in breast-fed vs. formula-fed infants, p = 0.001

Breast-fed: 39.9 (28.2)

Formula-fed: 72.5 (22.2)

HPLC

 

 

Measured at recruitment (ages 2 - 5 mo)

 

 

 

% with 25(OH)D < 28 nmol/L

Breast-fed: 8/18 (44%)

Formula-fed: 1/17 (6%), p=0.01

 

Breast-fed: 28% female;

Formula-fed: 47% female

 

 

Breast-fed: 3.3 (1.2) mo;

Formula-fed: 3.6 (1.1) mo

 

 

Serum PTH mean (SD) (ng/L)

Breast-fed: 14.8 (6.93)

Formula-fed: 11 (5.47), NS

 

Korean

 

 

 

 

 

 

LS BMD no difference between breast-fed (N = 14.18) and formula-fed infants (N = 14/17) (data NR)

 

 

 

 

LS BMC mean (g/cm) (SD)

No difference between groups

Breast-fed: 0.62 (0.2)

Formula-fed: 0.65 (0.2)

 

 

 

 

25(OH)D did not correlate with BMC (r=0.173, p=0.39, N=28).

^ refers to both or either isoform of 25(OH)D (isoform not specified); if reported, the isoform is specified.

+ Jadad score out of 5; for all RCTs in the table, allocation concealment was assessed as "unclear".

*SEM provided in graph but not estimable

** 1/80 infants did not clearly fit into any category and had findings suggestive of transient congenital hypoparathyroidism

AC, allocation concealment: BMC, bone mineral content; BMD, bone mineral density; DXA, dual X-ray absorptiometry; iPTH, intact PTH; IU, international units; LS, lumbar spine; LSM, least squares mean; mo, months; NR, not reported; NS, not significant; PTH, parathyroid hormone; RIA, radioimmunoassay; SD, standard deviation; SPA, single photon absorptiometry; y, year(s)

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Question 1A (Part 3). Are Specific Circulating Concentrations of Serum 25 Hydroxyvitamin D [25(OH)D] Associated With Bone Health Outcomes in Older Children and Adolescents?

Definition of study populations. The Institute of Medicine defines early childhood as ages 4 though 8 years, and puberty/adolescence as ages 9 through 13 years, and 14 through 18 years.4 Grouping by age for the purpose of this report were based on the study populations. In this section, children six years of age or older who had not yet entered puberty were included, and adolescence (marked by the onset of puberty) was defined by the presence of at least Tanner Stage 2 for sexual development.99 The age groups in the included studies for this section were: 6-10 years,100 age 9 years,101 8 – 10 years,102 9-15 years,103 15-16 years,104 10 – 17 years,105 and 10 – 18 years.106

Study characteristics. Three studies that included older children (one RCT,102 one prospective cohort101 and one before-after study100) assessed the association between serum 25(OH)D concentrations and bone health outcomes.


Four studies in adolescents assessed the association between 25(OH)D levels and bone health outcomes.103-106 There were two cohort studies,103,104 one case-control study106 and one RCT.105 The first cohort evaluated the association between serum 25(OH)D levels and lumbar spine and femoral neck BMD/bone mineral apparent density (BMAD) at baseline and 3 years.103 The second cohort study evaluated the seasonal variation in serum 25(OH)D concentrations and its relation to intact (i) PTH levels over an 18 month period.104 El Hajj Fuleihan105 evaluated the effect of low (1,400 IU/week) and high (14,000 IU/week) dose vitamin D3 on areal BMD and BMC of the lumbar spine, hip, forearm, and total body and body composition. Marwaha 106 evaluated 25(OH)D concentrations in 5,137 children and adolescents (aged 10-18 years) from Northern India and the association with serum PTH, ionized calcium and BMD of the forearm and calcaneus, with stratification by upper and lower socioeconomic status.


Bone health outcomes – ascertainment. For the studies on older children, PTH was measured by an immunoradiometric assay that detects the mid-region of the molecule, 102 and distal radial BMC was measured by single-photon absorptiometry (SPA).102 Javaid101 measured whole body and lumbar spine BMC and areal BMD by DXA , and calculated an apparent volumetric BMD at nine years of age in relation to maternal third trimester 25(OH)D status. Rajakumar100 evaluated the association between serum 25(OH)D concentrations, serum PTH and markers of bone turnover.

For adolescents, lumbar spine BMD, femoral BMD, and lumbar spine bone mineral apparent density (BMAD) was measured by DXA103 and iPTH by immunoradiometric assay.104 Fuleihan measured areal BMD and BMC at the lumbar spine, hip and forearm, and total body and lean body mass by DXA.105 Marwaha106 evaluated forearm and calcaneal BMD using peripheral DXA and PTH with an immunoradiometric assay.

There were no studies that assessed the association between serum 25(OH)D concentrations and fractures in older children or adolescents.

For assessment of 25(OH)D levels, different methods were used depending on the study. These included radioimmunoassay or radioimmunometric methods in three studies,101,103,106 and CPBA in three studies.100,104,105

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Population characteristics. For older children, ages ranged from eight to ten years in two studies with mixed gender.101,102 Included subjects were aged 6 – 10 years in the Rajakamar study who exhibited a combination of pre- and early pubertal status (33/42 pre-pubertal Tanner stage I).100 Eligibility criteria for two studies required that participants be healthy, without comorbidities.100,102 The prospective cohort study by Javaid did not state whether children with comorbidities were excluded. The mean dietary intake of calcium/vitamin D was reported in two studies.100,101


For adolescents, subjects ranged in age from nine to 16 years.103-106 All patients were at least Tanner Stage 2 for pubertal development with the exception of the Marwaha study which did not report pubertal status. However, the patients in the latter study were 10-18 years of age and it is anticipated that the majority were at least Tanner Stage 2 puberty. The studies involved either female,103,105 male,104 or mixed genders.106 Participants were reported as healthy, without known comorbidities, in two of four studies.103,104 The mean dietary intake of calcium/vitamin D was reported in three studies.100,103,104 Additional characteristics are summarized in Table 3.


Confounders/effect modifiers. In the studies on older children, Javaid adjusted for the age of the child at the time of the BMC measurement due to the strong association between age and whole body BMC.101 Since bone size can affect the BMD results, volumetric BMD at the lumbar spine was calculated. For adolescents in the 25(OH)DBMC/BMD cohort study,103 adjustments were made for the time to followup, and regression analyses were performed to determine covariates for BMD and BMC. El-Hajj Fuleihan105 made adjustments for lean mass and bone area, and did exploratory subgroup analyses on pre and post menarcheal girls in their analysis of vitamin D status in relation to BMD and BMC. Marwaha106 adjusted BMD for both height and weight.


Study quality. On the Jadad scale, one RCT scored 3/5102 and one scored 4/5105 indicating both were of high quality. The overall study quality for the observational studies was fair. Limitations included failure to adjust for relevant confounders or other sources of bias, and higher numbers of participants lost to followup.


Qualitative synthesis of individual study results. In a study of pre-pubertal Finnish girls, 400 IU vitamin D2, increased serum 25(OH)D levels (measured by RIA) compared with placebo but did not impact mid-region PTH or distal radial BMC (SPA) after 13 months.102 Radial BMC was not adjusted for bone size in this study.


In the before-after study by Rajakumar,100 baseline vitamin D status (measured by CPBA with deficiency defined as a serum 25(OH)D < 25 nmol/L (10 ng/ml) and insufficiency defined as < 50 nmol/L) was negatively correlated with PTH (but not associated with baseline serum calcium, phosphorus, albumin, or 1,25-(OH)2D). Serum PTH remained stable at levels of 25(OH)D around 75 nmol/L. There were no significant differences between the vitamin D insufficient and sufficient groups with regard to gender, weight, height, BMI and skin pigmentation. The mean (SD) daily dietary vitamin D intake was 277 (146) IU (mean intakes of 233 in the insufficiency group and 318 IU in the sufficient group were not significantly different). Dietary calcium intake was significantly higher in the sufficient group.


Javaid101 reported that low serum 25(OH)D concentrations (measured by RIA) in mothers during late pregnancy were weakly but significantly associated with reduced whole body (r =

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

0.21, p<0.01) and lumbar spine (r = 0.017, p = 0.03) age-adjusted BMC (DXA-Lunar DPX-L). Bone mass in children of mothers who were vitamin D deficient (25(OH)D < 28 nmol/L) during pregnancy was significantly lower compared to children born to vitamin D sufficient mothers. Reduced umbilical venous calcium also predicted reduced childhood bone mass (p = 0.0286). Whether this observation is mediated, totally or in part, through an effect on bone size and/or muscle mass is not clear. Maternal vitamin D status was positively associated with whole body and spine BMC in the offspring, and neither childhood height nor lean mass was associated with maternal 25(OH)D levels. Adjustment for childhood height did not significantly weaken the relation between maternal vitamin D status and whole body BMC. In contrast, volumetric BMD of the lumbar spine (which corrects for bone size) was not associated with maternal vitamin D status. Milk intake and physical activity at age nine were not significant determinants of bone mass although these findings do not rule out the possibility that factors such as UV exposure, diet and other lifestyle characteristics may have affected bone mass. When socioeconomic status was adjusted for, it did not change the association substantially. The type of postnatal feeding in the first three months also did not affect bone mass.

For girls age 9 – 15 years, the three year cohort study (N = 171) by Lehtonen-Veromaa evaluated the relation between baseline 25(OH)D levels (measured by RIA) and the change in lumbar spine (r = 0.35, p < 0.001) and femoral neck BMD (r = 0.32, p < 0.001). Baseline 25(OH)D also correlated with the change in LS BMAD (size-corrected form of BMD) (r = 0.35, p < 0.001) and FN BMAD (r = 0.24, p < 0.002). The difference in the percent increase from baseline in lumbar spine BMD (adjusted for the followup period) between those with low 25(OH)D levels (<20 nmol/L) and those with higher 25(OH)D levels was four percent. The difference in lumbar spine BMD was 12.7, 13.1 and 16.7 percent for the lowest, middle and highest 25(OH)D tertiles, respectively.103


In another cohort (N = 175) of French teenage boys, there was a significant negative correlation between serum iPTH and 25(OH)D levels (measured by CPBA), with a plateau in PTH demonstrated at 25(OH)D levels of 83 nmol/L and above.104 At this level of 25(OH)D, the iPTH reached a plateau at 2.48 pmol/L.


El-Hajj Fuleihan105 found a significant association between baseline serum 25(OH)D levels (measured by CPBA) and baseline BMD at the lumbar spine (r=0.16, p=0.033), femoral neck (r = 0.17, p = 0.028), and radius (r = 0.24, p = 0.002) (DXA-Hologic 4500). There was also a significant association between baseline serum 25(OH)D levels and baseline radius BMC (r = 0.16, p = 0.033). The mean baseline serum 25(OH)D was 35 nmol/L (14 ng/ml). In post hoc analyses, there were negative correlations between baseline serum 25(OH)D levels and percent change in lumbar spine BMD (r = −0.16, p = 0.044) or subtotal body BMD (r = −0.20, p = 0.009) over one year. Significant negative associations were found between baseline serum 25(OH)D levels and percent change in spine, femoral neck and radius BMC.


After vitamin D supplementation for one year, total hip BMC increased in the high dose (14,000 IU/wk) group (pre- and post-menarcheal girls combined) but there were no significant changes in BMC or BMD at other skeletal sites. In an exploratory subgroup analysis in pre-menarcheal girls alone (N = 34), total body lean tissue mass increased in both supplementation groups. Lumbar spine areal BMD was significantly increased in the low dose (1,400 IU/wk) group, and trochanter BMC was increased in both the high and low dose groups. The magnitude of the treatment effect was not significant after adjusting for both bone area and lean tissue mass. The authors acknowledge a limitation of DXA in evaluating areal BMD and BMC is the lack of

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

consensus on how best to adjust for bone size. In postmenarcheal girls, there were no differences in changes in lean mass, BMD or BMC amongst the three groups. In boys (data not shown), the authors reported there was no consistent positive effect of vitamin D supplementation on lean mass, BMD or BMC.


Marwaha106 showed that children with a lower socioeconomic status had significantly lower 25(OH)D concentrations (measured by RIA) and mean BMD (unadjusted for bone size) for the forearm and calcaneus (DXA-PIXI-1.34) was higher in the upper socioeconomic group. There was a significant negative correlation between serum immunoreactive PTH and 25(OH)D concentrations (r = −0.202, p < 0.001). PTH concentrations only increased at 25(OH)D concentrations below 12.5 nmol/L. There was no significant correlation between the mean serum concentration of 25(OH)D and BMD in both groups.

Summary. Serum 25(OH)D and bone health outcomes in older children and adolescents


Quantity: There were seven studies in older children and adolescents (two RCTs, three cohorts, one case-control and one before-after study) that evaluated the relation between circulating 25(OH)D and bone health outcomes. In older children, there was one RCT, one prospective cohort and one before-after study. One RCT did not find an association between 25(OH)D and distal radial BMC. Both the RCT and before-after study found no evidence of an association between 25(OH)D levels and PTH in older children.


Three studies in older children or adolescents evaluated serum 25(OH)D and PTH levels, and found an inverse non-linear relation with a plateau of PTH at 25(OH)D levels above 75-83 nmol/L in two studies (both measured by CPBA) and above 30 nmol/L in another (measured by RIA). Two of three studies found a positive association between baseline 25(OH)D status and BMC/BMD. The effect of bone size and muscle mass on these outcomes in relation to baseline 25(OH)D status was not reported. One RCT demonstrated a significant relation between baseline 25(OH)D and baseline BMD of the lumbar spine, femoral neck and radius. However, only high dose supplementation with 14,000 IU/wk of vitamin D3 increased BMC of the total hip.


Quality: The two RCTs each scored ≥ 3/5 on the Jadad scale and therefore were of higher quality. Most observational studies were of fair quality.


Consistency: Overall, there was fair evidence of an inverse association between 25(OH)D and PTH in adolescents. There was also fair evidence of an association between serum 25(OH)D levels and baseline BMD and change in BMD/BMC indices from the studies in older children and adolescents. However, the results from two randomized trials of vitamin D supplementation have not confirmed a consistent benefit on BMD/BMC across sites and age groups.


One cohort showed that maternal vitamin D status was weakly associated with whole body and spine BMC in nine year olds. Adjustment for childhood height did not significantly weaken the relation between maternal vitamin D status and whole body BMC, in contrast to the lumbar spine data, where apparent volumetric BMD (adjusts for bone size) was not associated with maternal vitamin D status.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 3. Serum 25(OH)D Levels and Bone Health Outcomes in Older Children and Adolescents

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age

Ethnicity

Intervention

Duration

25(OH)D

Assay

Bone Health Outcomes

Results

Jadad AC

RCTs

Ala-Houhala (1988)102

60 Children, 8 - 10 y old

IG1: 30; CG: 30

IG1:Vit D2400 IU 5-7×/wk

CG: placebo

25(OH)D^

Measured at baseline (1st winter) mid-study (autumn), and end of study 2nd winter)

PTH (midregion 44-68, RIA)

Serum 25(OH)D mean (SD) nmol/L Baseline (winter):

IG1: 49.3(19.0) vs. CG: 46 (15.5)

Mid-study (autumn):

IG1: 78 (24.3) vs. CG 59 (17.8)

End-of-study (winter):

IG1: 71.3 (23.4) vs. CG 43.3 (19.5), p < 0.01

1

 

Unclear

 

distal radius BMC (SPA)

 

Finland

Excluded:

IG1 6; CG 3

 

 

 

 

 

13 mo

 

 

Public

 

 

 

 

 

 

 

% female:

IG1 62%;

CG 48%

 

CPBA

 

 

 

 

 

 

 

Baseline serum PTH mean (SD) pmol/L:

IG1: 40 (20); CG 39 (19) (NS)

No difference between groups in PTH at 13 mo

 

 

NR; range 8-10 y

 

 

 

 

 

 

 

 

No difference between groups in distal radius BMC at 13 mo

 

 

Caucasion

 

 

 

 

 

Fuleihan (2006)105

179 children and adolescent girls (34 pre-menarcheal and 134 post-menarcheal)

IG1: 62

IG2: 59

CG: 58

IG1: 1,400 IU D/wk

IG2:14,000 IU D/wk

CG: Placebo

25(OH)D^

Measured at baseline, 6 mo, 1y

BMD and BMC LS, forearm, total body DXA (Hologic 4500A)

25(OH)D mean (SD) nmol/L baseline:

IG1: 35 (22.5)

IG2: 35 (20.0)

CG: 35(17.5)

4

 

Unclear

Lebanon

 

 

 

CPBA (Incstar, DiaSorin)

 

 

Private

 

 

 

 

 

1 y

 

 

1y:

IG1: 42.5 (15)

IG2: 95 (77.5)

CG: 40 (20.0)

 

 

Lost to follow up or discontinued: 11

 

 

 

Covariates: percent change in bone area, percent change in lean mass

Significant association between baseline serum 25(OH)D and:

LS BMD (r=0.16, p=0.033),

Femoral neck (r=0.17, p=0.028), and

Radius BMD levels (r=0.24, p=0.002)

Radius BMC levels (r=0.16, p=0.033).

Largest increases in bone mass in IG2 (high dose) subjects with lowest 25(OH)D levels at baseline

 

 

100% female

 

 

 

 

 

10-17 y

 

 

 

 

 

Middle Eastern

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age

Ethnicity

Intervention

Duration

25(OH)D

Assay

Bone Health Outcomes

Results

Prospective Cohort Studies

Guillemant (1999)104

175 Healthy adolescent boys from a jockey training center

NA

25(OH)D^

Measured after summer (Sept–Oct) and after winter (March-April)

iPTH (immunoradiometric assay, Nichols)

25(OH)D mean (SD)

Post-summer 58.5 (10)

Post-winter 20.6 (6.0), P=0.0001

France

 

 

 

 

 

 

 

iPTH negatively correlated with 25(OH)D, non-linear, (p <0.001, r=−0.504)

NR

100% male

 

 

 

 

 

 

CPBA

 

 

 

Range 13 y 5 mo to 16 y 1 mo

 

 

 

At > serum 25(OH)D > 83 nmol/L, iPTH plateau occurred at 2.48 pmol/L

 

Caucasion

 

 

 

seasonal variation in mean (SD) iPTH: summer 2.76 (0.97) vs. winter 4.20 (1.21) pmol/L

Javaid (2006)101

198 Children with known maternal 25(OH)D status in third trimester (original cohort: children born to 596 white women in a study of maternal nutrition and fetal growth 1991- 1992)

NA

25(OH)D^

Measured in mothers in third trimester

Total body and lumbar spine BMC and areal BMD

calculated volumetric BMD

(DXA Lunar DPX-L)

Maternal serum 25(OH)D in late pregnancey: 18% had serum 25(OH)D levels < 27.5 nmol/L and 31% had levels 27.5-50 nmol/L

U.K.

 

 

 

 

RIA (IDS)

Mothers with lower 25(OH)D during pregnancy had children with reduced total body (r=0.21, p=0.0088) and lumbar spine BMC (r=0.17, p=0.03). Adjustment for height did not weaken the relationship between total body BMC and 25(OH)D; Volumetric LS BMD was not associated with maternal 25(OH)D.

Public

 

 

 

9 y old

 

 

 

adjusted for age of child

 

Caucasion

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age

Ethnicity

Intervention

Duration

25(OH)D

Assay

Bone Health Outcomes

Results

Lehtone-Veromaa (2002)103

191 Healthy adolescent girls

NA

25(OH)D^

baseline, 1 and 3 y

LS BMD and BMAD

FN BMD and BMAD

DXA

(QDR 4500C Hologic)

25(OH)D mean (SD) nmol/L

baseline: 34.0 (13.2) (winter)

1 y: 33.2 (11.1)

3 y: 40.6 (15.8)

15 (7.9%) dropped out during the 3 y (final N=171)

 

RIA (DiaSorin)

Finland

 

 

 

 

 

 

 

 

Baseline 25(OH) D correlated with ∆ LS BMD (r=0.35, p < 0.001) and ∆ FN BMD (r=0.32, p < 0.001)

Public

 

 

 

 

 

100% female

 

 

 

 

 

 

 

 

 

Baseline 25(OH)D correlated with ∆ LS BMAD (0.35, p < 0.001) and ∆ FN BMAD (0.24, p < 0.002)

 

12.9 (1.7) y, range 9-15 y

 

 

 

 

 

 

 

Adjusted for: baseline reproductive y, bone mineral values, increases in height and weight, mean intake of calcium and mean amount of physical activity Significant correlation between baseline 25(OH)D and ∆ 3-y adjusted LS or FN BMD and BMAD.

 

Caucasian

 

 

 

 

 

 

 

 

Difference in mean 3-y ∆ LS BMD between group with baseline 25(OH)D<20 nmol/L and group with baseline 25(OH)D ≥37.5 was 4%.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age

Ethnicity

Intervention

Duration

25(OH)D (isoform measured)

Assay

Bone Health Outcomes

Results

Case-Control Studies

Marwaha (2005)106

5137 Healthy school children 3089 from Lower Social Economic Status (LSES), 2048 from Upper Social Economic Status (USES)

NA

25(OH)D^

BMD (distal forearm and calcaneum) using DXA (Lunar PIXI-1.34)) measured in subset N = 555

Serum 25(OH)D mean (SD): 29.5 (18)

LSES: 26 (1); USES: 34 (1)

25(OH)D < 22.5 nmol/L: 35.7%; LSES 42.3% vs. USES 27%, p < 0.01

 

 

RIA

Measured in subset N = 740

India

 

NR

 

 

Prevalence of clinical vitamin D deficiency (defined by genu varum or genu valgum): LSES 11.6% vs. USES 9.7%, p=0.07

 

 

 

 

iPTH (immunoradiometric assay, DiaSorin) N = 740

 

 

% female:

LSES: 65.1%

USES: 52.7%

 

 

Forearm mean BMD significantly higher (p<0.01) in USES group compared to LSES

BMD adjusted for height and weight

 

Mean age NR Range 10 – 18 y

 

 

 

Serum Ca no significant difference between groups but dietary calcium intake lower in LSES group

 

Indian

 

 

 

No significant correlation between BMD and serum 25(OH)D in either group

 

 

 

 

 

Significant negative correlation between PTH and 25 (OH)D, r=0.020, p<0.01

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age

Ethnicity

Intervention

Duration

25(OH)D (Isoform Measured)

Assay

Bone Health Outcomes

Results

Before-After Studies

Rajakumar (2005)100

42 Healthy 6 - 10 y olds

Tanner stage I/II (81% I)

Skin type III/IV (81% IV)

Vit D dietary intake:

mean (SD) 277 (146) IU/d

16/41 (39%) dietary intake < 200 IU/d

Vit D 400 IU/d (isoform not specified)

25(OH)D^

Measured at baseline and 1 mo

iPTH (Immulite iPTH chemiluminescent assay)

Serum 25(OH)D mean (SD) nmol/L

baseline: 60.0 (26.3)

49% < 50

71% < 75

U.S.

 

 

 

1 mo

CPBA (Nichols Advantage chemiluminescence)

 

 

Public

 

 

 

Group 1 = 25(OH)D < 50 nmol/L at baseline: 38.5 (8.0)

Group 2 = 25(OH)D > 50 nmol/L at baseline: 80.3 (20.5)

 

 

 

 

1 mo (total group): 68.8 (18.8)

Group 1: 57.5 (16)

Group 2: 79.5 (14.5)

Increase in serum 25(OH)D was observed only in group 1

7/39 (18%) of group 1 continued to have a level < 50 nmol/L after 1 mo of supplementation

 

2 withdrew for personal reasons

 

 

 

 

34% female

 

 

 

 

 

 

 

 

Negative correlation between 25(OH)D and PTH at baseline (r = -0.325, p = 0.038)

Inflection point for PTH started at 25(OH)D ~ 75 nmol/L

 

8.9 (1.2) y (range 6 -10 y)

 

 

 

 

African American

 

 

 

iPTH mean (SD) pmol/L

Baseline: 4.62 (1.9)

1 mo: 4.24 (2.1)

 

 

 

 

 

Negative correlation of 25(OH)D with body weight (r = −0.378, p = 0.015) at baseline

 

 

 

 

 

No significant differences at baseline or 1 mo in markers of bone turnover, 1,25-(OH)2D or PTH between groups with 25(OH)D < 50 nmol/L or > 50 nmol/L at baseline

BMC, bone mineral content; BMD, bone mineral density; BMAD, bone mineral apparent density; CG, control group; CPBA, competitive protein binding assay; d, day; DXA, dual X-ray absorptiometry; IG, intervention group; iPTH, intact p; arathyroid hormone; LSES, lower socioeconomic status; mo, month(s); FN, femoral neck; LS, lumbar spine; RIA, radioimmunoassay; SD, standard deviation; SPA, single photon absorptiometry USES, upper socioeconomic status; y, year

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Question 1B. Are Specific Circulating Concentrations of 25-Hydroxvitamin D [25(OH)D] Associated with Bone Health Outcomes in Pregnant and Lactating Women?

Vitamin D is essential for calcium homeostasis in the body including transport of calcium across the placenta in order to provide the fetus with mineral, especially during the last trimester of pregnancy. The rate of fetal accretion of calcium increases from approximately 50 mg/day at 20 weeks gestation to 330 mg/day at 35 weeks.107 To provide for such fetal calcium needs, physiological changes occur naturally during pregnancy so that intestinal absorption of calcium is doubled; this occurs via an up-regulation of the active hormone of vitamin D, 1,25-(OH)2D. The mechanism mediating the increase in vitamin D activity is not fully understood; it may involve pregnancy-associated hormones, placental synthesis of vitamin D, or a change in the balance between production of 1,25-(OH)2D and 24,25-(OH)2D. During lactation, the typical daily loss of calcium has been estimated to range from 280 to 400 mg. To meet these demands, skeletal calcium is released by temporary bone demineralization. This section presents the results of studies that investigated the association between vitamin D status in pregnant or lactating women and their bone health outcomes.

Overview of Relevant Study Characteristics and Results

Five observational studies evaluated the association between vitamin D status and bone health outcomes in mothers, or their offspring. One prospective study101 involved the analysis of the bone status by DXA at nine years of age in 198/596 previously studied offspring and the results of this study are summarized in the section on children (Section 1A part 3). The remaining four studies provided data on changes in vitamin D status during pregnancy, and the effect of maternal vitamin D status during pregnancy on outcomes of birth gestation or size. All studies included serum 25(OH)D measurements and other markers of calcium homeostasis. Study characteristics and 25(OH)D assays are outlined in Table 4.


The time of assessment of vitamin D status, the assay method for 25(OH)D and bone health outcomes varied across studies which precluded quantitative synthesis of results.

Vitamin D Status in Pregnant and Lactating Women

Study characteristics. Three prospective cohort studies reported on vitamin D status during pregnancy,108-110 one included assessment six weeks postpartum109 and one also measured 25(OH)D concentrations postpartum and during lactation.108 A prospective cohort study110 measured vitamin D status in early pregnancy (11 weeks) and at the beginning of the third trimester and then assessed the relationship between vitamin D status with infant size at birth.


In the before-after study, serum 25(OH)D and PTH were measured.111 The study duration was from first “booking” into the maternity clinic (presumably in the first trimester) to delivery

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

with measurement of vitamin D status at 36 weeks of gestation for those mothers identified as vitamin D deficient at baseline.


Bone health outcomes. Only one of the prospective cohort studies in lactating women included change in bone mineral density as an outcome.108 None of the included studies evaluated bone mineral content (BMC), fractures or ultrasound parameters as an outcome. Three studies evaluated serum PTH concentrations as an outcome.108,109,111 One study evaluated maternal vitamin D status during pregnancy and the association with infant body size at birth.110


Population characteristics. Sample sizes ranged from 40 to 160 women who were recruited during pregnancy. Mean vitamin D intake and calcium intake were not reported for any of the studies which is important given that calcium intake modulates serum PTH. All studies involved pregnant women but ethnicity and geographical location varied widely. One study enrolled non-European ethnic minority women,111 another study enrolled only Asian women,109 and two studies enrolled mainly Caucasian women.108,110


Confounders/covariates. Intake of vitamin D supplements111 was identified as covariate in one study. Sowers108 used multiple linear regression and linear mixed models (paired comparisons between early and late pregnancy) to examine the predictability of calciotrophic hormones on the rate of change in BMD of the spine and femoral neck, after adjusting for concentrations of other hormones and the time since parturition. Morley adjusted for maternal BMI, smoking during pregnancy, and maternal PTH levels in the evaluation of the association of serum 25(OH)D levels at less than 16 weeks and 28 weeks gestation with offspring birth size.110 One study did not adjust for any confounders in the analysis.111


Outcome characteristics. One cohort study measured BMD with dual energy x-ray absorptiometry (DXA) at the femoral neck and lumbar spine over 4 to 6 time points ranging from just after delivery to 18 months postpartum during lactation.108 Midmolecule or Intact PTH was measured using radioimmunoassay,108 immunoradiometric assay,109 or chemiluminescent methodology.110,111

Qualitative Synthesis of Individual Study Results

Maternal vitamin D status. In the study of non-European minority women from South Wales,111 50 percent of the women were vitamin D deficient at the first antenatal visit, using a criterion of serum 25(OH)D < 20 nmol/L. Vitamin D supplementation (800-1600 IU) D during pregnancy normalized vitamin D status in 60 percent of the deficient group. In the study in Saudi Arabia of 40 Asian women,109 serum 25(OH)D declined significantly from baseline (about 11 weeks gestation) to the third trimester (mean of 31.4 wk of gestation) and remained low through to 6 weeks post-delivery. However, at all timepoints, mean serum 25(OH)D concentrations were within the normal range of a reference group of non-pregnant women (N = 280) who were healthy and non-lactating, suggesting that although serum levels decline during the end of the third trimester, they do not differ extensively from those of the non-pregnant state. None of the pregnant women were classified as having subclinical vitamin D deficiency (25(OH)D < 20 nmol/L). In the study110 in primarily Caucasian women in Australia, serum 25(OH)D was similar at recruitment (11 weeks of gestation) and at the beginning of the third trimester of pregnancy (28-32 weeks of gestation) but there were significant differences between

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

mean values in winter versus summer months. The percent who were vitamin D deficient (9-10 percent as defined by 25(OH)D < 28 nmol/L) was significantly greater in winter than summer.


One cohort study assessed vitamin D status postpartum and in relation to breast-feeding.108 There was a non-significant trend to a decline in vitamin D status in the initial 2 -4 months and the pattern was not influenced by the season of birth. Vitamin D status was not influenced by the duration of breast-feeding. The percent of women who were vitamin D deficient was not provided but based on the mean values, some of the women would have had 25(OH)D values less than 20 nmol/L. Data on vitamin D intake or sun exposure were not provided.


Vitamin D status and bone health outcomes. In the cohort study by Sowers, bone mineral density of lumbar spine and femoral neck was measured in 115 mothers with different breast-feeding practices during the postpartum period and vitamin D status was not associated with changes in BMD of the femur or spine.108 Women were recruited during the third trimester, lumbar spine BMD was measured at two weeks, 6, 12 and 18 months postpartum and femoral neck at two weeks, two, four, six, 12 and 18 months. Serum PTH and the other calciotrophic hormones were not associated with changes in femoral or lumbar spine BMD, suggesting that 25(OH)D, PTH and 1,25-(OH)2D do not explain the calcium mobilization and bone turnover that occurs during lactation.108


In the before-after study in pregnancy,111 serum 25(OH)D did not appear to correlate with serum PTH concentrations, with 65/80 women with low 25(OH)D having PTH in the normal range.


In a prospective cohort study on 40 Asian women (280 non-pregnant controls),109 serum 25(OH)D levels negatively correlated with intact PTH (r = −0.62, 0<0.001). In this study, serum osteocalcin, a bone formation marker was below the reference range observed in non-pregnant women, and declined in the second trimester compared to the first, but then rose to within or above the reference range at term and 6 weeks postpartum. This suggests changes in bone turnover do occur during early pregnancy, irrespective of normal vitamin D status.


In the prospective cohort study by Morley there was no association between baseline maternal 25(OH)D concentrations and measures of infant size at birth.111 There was an inverse association between maternal log2 25(OH)D and log2 PTH. Using the maternal 25(OH)D concentrations at 28-32 weeks, the mean gestational length was significantly shorter (0.7 weeks, 95% CI -1.3,-0.1 weeks) in the vitamin D-deficient mothers compared to mothers with 25(OH)D concentrations over 28 nmol/L. This association was not altered by inclusion of log2 PTH, serum calcium and albumin concentrations. Infants born to mothers who were vitamin D deficient at 28-32 weeks gestation, had lower mean knee-heel length (−2.7 mm) compared to infants born to mothers who were not vitamin D deficient, after adjusting for gestation length.110 Further nonparametric smooth regression analysis and adjustment of confounders suggested the possibility of a linear association when 25(OH)D levels were below 30-40 nmol/L, but there was no association at higher 25(OH)D levels. Low maternal 25(OH)D levels were associated with a negative impact on long bone growth and the authors postulated that maternal PTH may affect fetal growth via an affect on 1,25-(OH)2D production.110

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Study quality. There were no RCTs identified that evaluated the association between serum 25(OH)D concentrations and bone health outcomes in pregnant and lactating women. The before-after study111 was poorly designed, lacked detail regarding the duration and compliance with the vitamin D supplements, and the analyses were incomplete. A limitation of the included studies was failure to adjust for all relevant covariates. Only one six-week cohort study was considered to be of good quality, since it included an age-matched non-pregnant cohort with control values for all biochemical measurements (N = 280) and provided six serial measures with no attrition during followup.109 The cohort study conducted during lactation,108 was of good quality as it included six serial biochemical measures, four measures of spinal BMD and six of femoral neck BMD throughout lactation, and adjusted for a number of covariates. The one study in which the primary outcome was size of offspring at birth was judged to be of fair quality due to loss of followup of over 20 percent.110

Summary. Serum 25(OH)D levels and bone health outcomes in pregnancy and lactation


Quantity: Four studies (no RCTs, three cohorts, one before-after study) assessed vitamin D status at various time points in pregnancy with vitamin D deficiency being observed in 0 to 50 percent of subjects. Only one cohort study (N=115) included maternal BMD as an outcome and there was no relation between vitamin D status and postpartum changes in BMD.


Quality: Quality scores ranged from poor to good. Skin color, vitamin D supplementation, calcium intake and sun exposure were not controlled for or assessed in all studies.


Consistency: Two studies observed no change in vitamin D status during pregnancy, whereas another observed a decline in serum 25(OH)D from the 1st to 3rd trimester. There was insufficient evidence on the association between 25(OH)D and change in bone density during pregnancy. One good prospective cohort did not find an association between serum 25(OH)D and the changes in BMD that occur during lactation. There was fair evidence that serum 25(OH)D correlated negatively with PTH levels in pregnancy. Limitations in the study design and sources of bias highlight the need for additional research on vitamin D status in pregnancy and lactation, and the association with bone health outcomes.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 4. Serum 25(OH)D Levels and Bone Health Outcomes in Pregnant or Lactating Women

Author (year)

Country,

Funding

Population, N

Attrition

Mean age

Ethnicity

Duration

Serum 25(OH)D

mean (SD) (nmol/L)

Assay

Bone Health Outcomes

Results

Prospective Cohorts

Ardawi (1997)109

40 Pregnant women

280 Non-pregnant women

6 wks

25(OH)D^

Pregnant women:

1st trimester: 54 (10)

2nd trimester: NR

3rd trimester: 33 (8)

term: 35 (11)

6 wks postpartum: 33 (8)

iPTH (IRMA)

Serum 25(OH)D declined significantly from 1st to 3rd trimester and remained low through 6 wks postpartum. No values were < 20 nmol/L.

Saudia Arabia

 

 

 

 

NR

 

 

 

Public

 

 

 

PTH (pregnant women):

Serum 25(OH)D levels correlated negatively with serum iPTH (r=-0.62, p <0.001);

1st trimester: 1.31 (0.25)

2nd trimester: 2.26 (0.39)

term: 1.86 (0.87);

6 wks postpartum: significant increase compared to pregnancy values (~ 3.5, graph only, exact value NR)

 

NR

 

 

 

Pregnant women 26.8 (5.8) y;

non-pregnant women 27.8 (5.3) y

 

 

 

 

 

CPBA

 

 

Arab

 

 

 

 

 

 

 

 

Serum 25(OH)D in pregnancy correlated positively with 1,25-(OH)2D (r=0.52, p < 0.001), serum PTH-related peptide (r =0.51, p < 0.001), serum Ca (r=0.23, p < 0.001), serum Mg (r=0.62, p < 0.01)

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country,

Funding

Population, N

Attrition

Mean age

Ethnicity

Duration

Serum 25(OH)D

mean (SD) (nmol/L)

Assay

Bone Health Outcomes

Results

Morley (2006)110

475 Pregnant women recruited at < 16 wks gestation from antenatal clinic Unclear if recruitment was consecutive

NA

25(OH)D^ geometric mean at recruitment:

In summer: 62.6

In winter: 49.2, p < 0.001

PTH (chemiluminescent enzyme-labelled immunometric assay)

After adjustment for seasonal variation, increase in 25(OH)D concentrations between early and late pregnancy: gemometric mean ratio 1.06, 95% CI 1.02, 1.10, p = 0.004

Australia

 

 

 

 

 

Infant linear growth (head, mid-arm, calf circumference)

Knee-heel length

 

Public

 

% < 28 nmol/L:

In summer: 0.8%

In winter: 9.4%, p < 0.001

 

 

 

 

 

No association between maternal 25(OH)D and PTH levels at recruitment (11 wks gestation)

 

21% attrition

 

 

 

29.3 (6.4) y

 

At 28 – 32 wks gestation:

In summer: 48.3

In winter: 68.9, p < 0.001

 

 

 

 

 

 

Positive association between maternal PTH and measures of infant size (to knee-heel length, birth weight) independent of 25(OH)D status.

 

98.6% Caucasian (excluded those thought to be at high risk for deficiency including dark skinned individuals)

105 White, 7 Asian American, 3 African American

 

 

 

 

% < 28 nmol/L

In summer: 3.7%

In winter: 10.0%, p = 0.02

 

 

 

 

Mothers with serum 25(OH)D < 28 nmol/L, at 28-32 wk gestation, had babies with: shorter (−0.7 wk) gestation length, and knee heel length (−2.7mm) after adjustment for gestation length, and lower birth weight (−157 g) than those with 25(OH)D ≥28 nmol/L

 

 

RIA

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Mean age

Ethnicity

Duration

Serum 25(OH)D

mean (SD) (nmol/L)

Assay

Bone Health Outcomes

Results

Sowers (1998)108

115 Women in third trimester, with a parity of 0 – 1, recruited on basis of intent to breastfeed or formula-feed exclusively.

18 mo

25(OH)D^

postpartum stages:

2 wks 40.3 (11.3)

2 mo 30.1 (7.5)

4 mo 37.4(10.5)

6 mo 33.6 (10.4)

12 mo 29.5 (8.4)

18 mo 27.0 (7.3)

BMD: FN and LS (DXA-Lunar)

25(OH)D concentration was not predictive of changes in FN or LS BMD or bone turnover markers.

U.S.

 

PTH (midmolecule, RIA)

 

 

 

 

Pattern of decline in 25 (OH)D concentration over 18 mo period was independent of lactation status

Public

 

 

 

2 wks: N = 115;

18 mos: N = 71

 

 

 

PTH, 25(OH)D and 1,25-(OH)2D had no association with prolactin or PTH-related peptide and did not differ by lactation practice.

 

 

 

RIA

 

 

Mean age: 29.3 (20-40) y

 

 

 

 

91% Caucasian; 6% Asian American; 3% African American

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country,

Funding

Population, N

Attrition

Mean age

Ethnicity

Duration

25(OH)D nmol/L

Assay

Bone Health Outcomes

Results

Before-After Studies

Datta (2002)111

160 Consecutive ethnic minority pregnant women in the U.K. recruited at first antenatal visit; those identified as vit D def (serum 25(OH)D < 20 nmol/L) were treated with vit D 800 IU/d and followed to delivery

Early pregnancy to delivery

25(OH)D^

80/160 (50%) had 25(OH)D < 20 nmol/L

PTH levels provided for vit D def women only

At baseline, 65 of 80 (81%) women with serum 25(OH)D < 20 nmol/L had normal PTH (< 5.6 pmol/L)

Wales

 

Funding NR

 

Reported for vit D def women only:

Recruitment: 14.5 (2.3)

End of study (with treatment): 28.1(15.9)

 

35/58 (60%) re-tested at delivery had 25(OH)D within normal range

 

 

 

At delivery, mean serum 25(OH)D increased from 15 to 27.5 nmol/L, but mean PTH level remained the same

 

 

Vit D status at delivery in those treated with supplements reported for 58/80

 

 

 

 

serum PTH mean (SD) pmol/L:

at recruitment: 3.69 (2.78) pmol/L

end of study (post treatment): 4.06 (3.17), NS

 

Attrition: 58/80 (73%) vit D def women had post treatment (post delivery) assessment

 

 

 

 

RIA

 

Compliance with vit D not measured

 

Mean age NR

 

 

 

 

 

African (N = 36), Afro-Caribbean (N = 4), Indian (N = 100), Middle Eastern (N = 9), Far Eastern (N = 11)

 

 

 

 

^ total 25(OH)D or either isoform of 25(OH)D (isoform not specified);

def, deficient or deficiency; IRMA, immunoradiometric assay; IU, international units; Mg, magnesium; NR, not reported; PTH, parathyroid hormone; RIA, radioimmunoassay; SD, standard deviation; vit, vitamin; wk. weeks; y, year;

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Question 1C. Are Specific Circulating Concentrations of 25 Hydroxyvitamin D [25(OH)D] Associated With Bone Health Outcomes in Postmenopausal Women and Elderly Men?

Overview of Relevant Studies

This section summarizes the evidence from the studies that investigated the association between serum 25(OH)D concentrations and bone health outcomes in postmenopausal women and/or elderly men. The discussion focuses on observational studies and only the few (vitamin D supplementation) RCTs that specifically investigated the association of serum 25(OH)D with one or more bone health outcomes are discussed. The majority of RCT data are presented in Question 3. Tables 5-8 summarize the studies included in this section, including the vitamin D assays used.


For the prospective cohorts, assessment of study quality was based on a number of factors including how representative the cohort was, the method of ascertainment of the outcome, whether key confounders were adjusted for in the analysis, the adequacy of followup, size of the study and whether the main objective was to evaluate the association between serum 25(OH)D and bone health outcomes. For the case-control studies, study quality was evaluated based on whether methods were used to minimize sample bias: for example, similar sampling of cases and controls, matching on relevant variables and the use of population based controls or more than one control group.


Study characteristics. A total of 41 studies (42 records) evaluated the association between serum 25(OH)D concentrations and bone health outcomes in postmenopausal women and elderly men. Of these 41 studies, 10 were RCTs,112-121 14 were single prospective cohorts,122-135 and 17 were case-control studies (18 records).29,136-152 One publication was companion paper,146,147 and we refer to the primary record with the most relevant data in the results.146 Study characteristics such as population, sample size, duration of followup, country, and 25(OH)D assays are summarized in Tables 6-8.


Variability in the measurement and reporting of serum 25(OH)D and bone health outcomes, along with differences in populations precluded formal meta-analysis. The results are reported by bone health outcome: fractures, bone mineral density (BMD), falls and performance measures.

Association with Fractures

Study characteristics. Fifteen studies reported on the relation between serum 25(OH)D and fractures. Of the 15 studies, three were single prospective cohort studies130,131,133 and 12 case-control studies (Table 6).29,137,139,141,142,144-146,148-151


Population characteristics. Two cohorts included females only131,133 and one cohort130 included both genders. Six case-control studies included females,29,137,139,142,145,148 one included males only,150 four included both genders,141,144,146,151 and one study did not specify the gender.149

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Fracture outcomes and ascertainment. Gerdem included low-trauma fractures (hip, wrist, humerus, vertebral) identified in followup interviews with participants and from a hospital x-ray database.131 Cummings included x-ray-confirmed hip and vertebral fractures133 and Woo included osteoporotic fractures (hip, wrist and vertebral) that were validated with hospital records or death certificates.130 All case-control studies involved hip fracture cases.


Cohorts. The study quality of the cohorts ranged from poor130 to good.133 Losses to followup ranged from 6 to 34 percent. Two studies reported adjusting for weight and one also adjusted for BMD, age and use of estrogen and self-rated health.133 Duration of followup ranged from 30 months to a maximum of 5.9 years.


Woo et al. (1990), followed 427 independently living elderly Chinese subjects (mean age 69 years for men and 70 years for women) for 2.5 years to determine which biochemical variables predicted fractures. A relative risk of fractures for subjects with lower serum 25(OH)D levels (<79 nmol/L in males and < 65.5 nmol/L in females) was reported but the confidence intervals were wide and the result was not significant (RR 3.42, 95% CI, 0.79-14.9). The study had a number of limitations, including a high loss to followup (34 percent), a low event rate (only nine subjects had fractures) and a lack of adjustment for confounders such as BMD and age (although adjustment was made for alcohol intake, smoking and BMI).130


Gerdhem et al. (2005) evaluated the association between 25(OH)D and fractures in a three year prospective cohort of 1044 ambulatory women in Sweden. The mean 25(OH)D level was 95 ± 30 nmol/L. Only 4.4 percent of subjects had a serum 25(OH)D level below 50 nmol/L. Of the cohort, 119/986 (12 percent) sustained a low-trauma fracture (159 fractures). Nine out of the 43 women (21 percent) who had 25(OH)D levels below 50 nmol/L had at least one fracture versus 110 of 943 (12 percent) women with levels above 50 nmol/L, representing a two fold increased risk of fracture (HR 2.04, 95% CI 1.04-4.04). Women with serum 25(OH)D levels below 75 nmol/L had a hazard ratio of 1.01, (95% CI 0.71-1.61). When women who took vitamin D supplements were excluded from the analysis, those with a 25(OH)D level < 50 nmol/L had a hazard ratio of 1.99 (95% CI 0.97-4.0). It was unclear if relevant confounders were adjusted for.131


Cummings et al. (1998) in a prospective cohort of 9,704 Caucasian community-dwelling women age 65 years and older evaluated risk factors for hip and vertebral fractures.133 Women were followed for a maximum of 5.9 years, and a random sample was selected from the subset of the original cohort who experienced fractures (N = 133 hip and 138 vertebral fracture cases). Controls were randomly selected from the same cohort (case-cohort) and logistic regression and proportional hazards analysis were used to evaluate predictors. Variables adjusted for included age, weight, BMD, season, and use of vitamin D supplements. Twenty-two percent of subjects had 25(OH)D levels below 47.5 nmol/L. The authors did not report a significant association (adjusted for age and weight) between serum 25(OH)D concentrations and risk of hip (RR 1.2, 95% CI 0.7-1.9) or vertebral fractures (RR 1.1, 95% CI 0.6-1.8) in those with serum 25(OH)D concentrations <47.5 nmol/L. They did report an association between lower serum 1,25-(OH)2D3 levels and risk of hip fractures but not vertebral fractures.


Case-controls. All 12 case-control studies reported cases of hip fractures (radiographically confirmed).29,137,139,141,142,144-146,148-151


Nine case-control studies matched cases and controls on age.29,137,139,141,142,145,147,148,150 Four studies matched cases and controls on gender and postmenopausal status.29,137,139,140 Two case

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

control studies did not provide details on matching.149,151 None of the studies matched cases and controls on BMD. A limitation of case-control studies in the evaluation of the association with fractures is that measurement of serum 25(OH)D concentrations are made after the hip fracture has occurred and can be affected by hospitalization, trauma or treatment. Two studies included both hospitalized and community controls.141,150


Ten of twelve case-control studies found significantly lower 25(OH)D levels in hip fracture patients compared to controls.29,139,141,142,144-146,148,150,151 Three case-control studies adjusted for relevant covariates in their analysis, but this did not alter the difference in serum 25(OH)D between cases and controls.29,142,146 Cooper, however, reported that there was no residual difference in serum 25(OH)D between cases and controls after adjusting for age and albumin (Table 6).145


Diamond et al. performed a multiple regression analysis to determine the predictors of hip fractures in men (e.g., age, weight, comorbidity, 25(OH)D levels, free testosterone) and found that a serum 25(OH)D concentration < 50 nmol/L was the strongest predictor of hip fracture (regression coefficient 0.34 +/− 0.19, p = 0.013).150


Two case-control studies did not find a significant difference in serum 25(OH)D concentrations between hip fracture cases and controls.137,149 In one of these studies, there was no mention if the controls and cases were matched by age.149

Summary. Serum 25(OH)D levels and fractures in postmenopausal women and older men


Quantity: Fifteen studies (three prospective cohorts and twelve case-controls) reported on the association between serum 25(OH)D and fractures.


Quality: The quality of the prospective cohorts and case-controls ranged from poor to good.


Consistency: One of three cohorts reported an inverse association between serum 25(OH)D and fractures, and nine of twelve case-control studies found lower 25(OH)D concentrations in cases versus controls. Differences in results may be attributed to whether or not all relevant confounders were controlled for and differences in baseline serum 25(OH)D status.


Based on the above studies, the level of evidence for an association between serum 25(OH)D and fractures is inconsistent.

Association with Falls

Study characteristics. The relation between serum 25(OH)D and falls was reported in one RCT,114 three prospective cohorts,122,123,134 and one case-control study.138


Population characteristics. The RCT included elderly women in long-term geriatric care facilities.114 Two prospective cohorts included institutionalized elderly men and women,122,123 and one included older community-dwelling women.134 The case-control study included both elderly men and women living in nursing homes or hostels (intermediate-care facilities).138

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Fall outcomes – definition and ascertainment. Falls were defined as “an event resulting in a person inadvertently coming to rest on the ground” in the RCT114 and in one cohort.123 Another cohort defined falls as “landing on the ground or falling and hitting an object like a table”134 and the third cohort did not provide a definition for falls or the method of ascertainment.122 Falls were ascertained by the staff completing regular fall diaries in two studies.123,134 In the case-control study, falls were retrospectively evaluated by nursing staff using a rating scale.138


RCTs. One RCT by Bischoff, with a Jadad quality score of 3/5, evaluated the effect of vitamin D3 on falls in elderly residents in long-term care.114 Fifty percent of the participants were vitamin D deficient (< 30nmol/L). Bischoff reported a significant inverse association between serum 25(OH)D and falls.


Prospective cohorts. All three cohorts were representative and adjusted for one or more relevant covariates (age, cognitive status, illness severity) in the analysis.122,123,134 Losses to followup were small in all cohorts and overall study quality of the cohorts was good. The proportion of participants who were vitamin D deficient (investigator-defined) varied from 2.6 percent (<25 nmol/L) in one,134 to 22-45 percent (< 25 nmol/L) in another,123 and 64-74 percent in the third cohort (<39 nmol/L).122


Sambrook et al. (2004) explored the relation between serum 25(OH)D, PTH and falls in 646 elderly ambulatory elderly institutionalized males and females (mean age 85-86.6 yrs). Serum 25(OH)D and PTH were significant predictors of time to first fall. However, after adjusting for age, incontinence and illness severity, serum 25(OH)D did not remain a predictor [adjusted HR, 0.99 (95% CI 0.98-1.00), p=0.06]. Participants were divided into four groups based on serum 25(OH)D and PTH concentrations: group 1, 25(OH)D < 39 nmol/L and PTH > 66 pg/ml; group 2, 25(OH)D < 39 nmol/L and PTH < 66 pg/ml; group 3, 25(OH)D > 39 nmol/L and PTH > 66 pg/ml and; group 4, 25(OH)D > 39 nmol/L and PTH < 66 pg/ml. Survival analysis found that subjects in group 1 were 1.65 times more likely to fall than those in group 4, after adjusting for age, incontinence and illness severity [HR 1.65 (95% CI 1.10-2.46), p=0.02].122


Flicker (2003), in a cohort of 1,619 older individuals in residential care (mean age 83.7 years), examined the association between serum 25(OH)D and fall risk (adjusted for weight, cognitive status, psychotropic drug use, prior wrist fracture and wandering behavior, but not functional status). The log serum 25(OH)D remained an independent predictor of time to first fall [HR 0.74 ( 95% CI 0.59-0.94), p=0.01] and was consistent with a 20 percent lower risk of falls with a doubling of serum 25(OH)D.123


Faulkner et al. (2006),134 in a secondary analysis of a sample of women (median age 70 years) with falls (N = 389) who were randomly selected from a cohort of 9,526 community-dwelling older women, evaluated the relation between serum concentrations of vitamin D metabolites and fall rates. Although there was a trend of higher 25(OH)D3 concentrations with weaker grip strength, in multivariate models after adjustments for age, height, BMI, season, activity, self-rated health and other variables, serum 25(OH)D3 concentrations were not associated with increased falls.


Stein et al. in a case-control study of 83 vitamin D deficient subjects (33 fallers and 50 non-fallers) who were residents of nursing homes or hostels, examined whether falls were associated with serum 25(OH)D and PTH concentrations. Cases and controls were matched on age, setting and level of independence. Falls were scored after serum 25(OH)D measurements. The study

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

quality was fair. Stein found that serum 25(OH)D was significantly lower in fallers versus non-fallers (p = 0.02). Multiple logistic regression analysis revealed that predictors of falls included: walking unaided, hostel residence and serum PTH. Neither serum 25(OH)D or 1,25-(OH) 2D were independent predictors for falls, after adjustment for PTH concentrations.138

Summary. Serum 25(OH)D levels and falls in postmenopausal women and older men


Quantity: Five studies (one RCT, three cohorts and one case-control) evaluated the association between serum 25(OH)D concentrations and falls. The one RCT, two of the three cohorts and one case-control study found an inverse association between serum 25(OH)D and a risk of falls. In one cohort with a low percentage of vitamin D deficient participants, the association did not persist after adjustment for age and illness severity. Another cohort did not observe an association between serum 25(OH)D and falls, and one case-control study did not find an association after adjusting for serum PTH.


Quality: The RCT and three prospective cohorts were of good quality and the case-control study was of fair quality.


Consistency: There is fair evidence of an association between lower serum 25(OH)D concentrations and an increased risk of falls in institutionalized elderly. PTH may be an important confounder. One study suggested a specific serum 25(OH)D concentration of 39 nmol/L, below which fall risk is increased.

Association with Performance Measures

Study characteristics. The relation between 25(OH)D and performance measures was examined in seven studies including three randomized trials,112,113,115 and four prospective cohort studies.124,125,131,134 Multiple performance measures were evaluated as outlined in Table 7.


RCTs. Three RCTs reported on the relation between 25(OH)D concentrations and performance measures including the Physical Activity Scale for the Elderly (PASE),113 postural sway and quadriceps strength,115 and muscle strength and activities of daily living.112 The study quality ranged from 3/5 to 5/5 on the Jadad scale and sample sizes ranged from 65 to 139. Corless did not find an association between the change in serum 25(OH)D concentrations and change in muscle strength or independence indices. However, two RCTs did find an association between baseline serum 25(OH)D and performance measures: PASE, single leg stance and aggregate functional performance.113,115


Prospective cohorts. The study quality of the cohort studies ranged from fair (three of the four) to good. Losses to followup were over 30 percent in two cohorts.124,125


Gender was 100 percent female in three cohorts and the remaining cohort included both males and females.124 Three cohorts adjusted for age, body mass index, chronic disease,124,125,134 serum creatinine,124 and two adjusted for the effect of seasonal variation, activity or baseline strength assessments.101,125

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Four cohorts124,125,131,134 examined the relation between serum 25(OH)D and various performance measures. Visser et al. (2003) assessed whether low serum 25(OH)D and high serum PTH concentrations were associated with a loss of muscle strength in a cohort of 1,509 older individuals. Followup data were available on 1,008 participants and 9.6 percent were vitamin D deficient and 3.8 percent had secondary hyperparathyroidism (> 7 pmol/L). Participants with low serum 25(OH)D levels (< 25 nmol/L) compared to those with levels (> 50 nmol/L were more likely to experience loss of grip strength and appendicular skeletal muscle mass (ASMM), even after adjusting for sex, age, BMI, physical activity level, chronic disease, creatinine, season and smoking, [adjusted OR 2.57 (95% CI 1.40-4.70); p<0.05 and OR 2.14 (95% CI 0.73-6.33); p = 0.09, respectively]. Participants in the highest tertile of PTH (> 4.0 pmol/L) were 1.71 times more likely to experience loss of grip strength and ASMM. The high loss to followup in this study (33 percent of the 501 participants) may have affected the association, as those lost to followup were more likely to have poorer health status.124


Gerdhem et al. (2005), in a prospective cohort of 1,044 ambulatory women, found that serum 25(OH)D concentrations correlated with gait speed (r = 0.17, p<0.001), Romberg’s balance test (r = 0.14, p<0.001), and activity level (r=0.15, p<0.001). In a multiple regression analysis, however, only 5 percent of the variability in serum 25(OH)D was explained by fall and anthropometric variables. The authors suggested a threshold level between serum 25(OH)D concentration and physical activity exists at 87.5 nmol/L.131


Verreault et al. (2002) in a three year cohort of 1,002 community-dwelling elderly (mean age 75 yrs) found the annual rate of decline in strength, walking speed and time to perform repeated chair stands was similar across baseline serum 25(OH)D tertiles: (deficient < 25 nmol/L, low normal: 25-52 nmol/L and high normal > 53 nmol/L), after adjusting for age, race, education, BMI, seasonal variation and presence of chronic conditions. Adjusted rates of decline in performance, except grip strength, were not associated with baseline PTH. This cohort included women who were moderately to severely disabled so participants may have been below a functional level where vitamin D deficiency might have had an additional impact. There was high loss to followup in this study (37 percent).125


Faulkner (2006), in the cohort of 389 women described above, reported that serum 25(OH)D3 concentrations were not associated with changes in neuromuscular function, including grip strength, balance and chair stand time in an age, BMD and height-adjusted multivariate models.134

Summary. Serum 25(OH)D levels and performance measures in postmenopausal women and older men


Quantity: Seven studies (three RCTs and four cohorts) assessed the relation between 25(OH)D and performance related measures.


Quality: The overall quality of the evidence from RCTs and cohorts was fair to good.


Consistency: Two RCTs and two cohorts reported an association between 25(OH)D and performance measures. Two cohorts and one RCT did not find association between 25(OH)D and performance measures.


Overall, there is inconsistent evidence for an association of serum 25(OH)D concentrations with performance measures. In studies that did report an association, specific concentrations below which declines in performance measures were increased ranged from 50 to 87 nmol/L.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Association with Bone Mineral Density

Study characteristics. Nineteen studies evaluated the association between serum 25(OH)D and bone mineral density. Of these, six were RCTs,116-121 seven single prospective cohorts,126-129,131,132,135 and six case-control studies.136,139-141,143,152


Population characteristics. All RCTs included postmenopausal women.116-121 Four cohorts included females only128,129,131,135 and three included both genders.126,127,132 Three case-control studies included females only,139,140,143 two included both genders,136,153 and one included 100 percent males.152


Bone density measurement. The BMD sites assessed in each study are in Table 8. Types of bone densitometry included dual photon absorptiometry (DPA) or dual energy-x-ray absorptiometry) (DXA) (Hologic or Lunar manufacturer).


RCTs. The study quality of the six RCTs116-121 ranged from 2/5 to 5/5 on the Jadad score with five trials having a score of ≥ 3/5.116,117,119-121 Only one RCT reported an association between baseline 25(OH)D levels and change in BMD.119


Prospective Cohorts. Four of the seven cohorts adjusted for either BMI or weight, which is an important confounder of the association with BMD126,128,129,132 and three cohorts adjusted for age.128,129,132 Only two cohorts adjusted for physical activity, calcium use, smoking status or levels of other hormones.128,132 The study quality of the prospective cohorts ranged from fair to good.


Three cohorts evaluated the relation between serum 25(OH)D levels and BMD,127,131,132 and five examined the relation between 25(OH)D levels and changes in BMD.126-129,135


Of the seven cohorts, four reported an association between serum 25(OH)D and femoral neck BMD,126,128,129,132 and one found a positive association between change in 25(OH)D and lumbar spine, but not femoral neck, BMD.135


Stone et al. in a cohort of 231 older Caucasian women (mean age 65.5 years), found that women in the highest quartile of serum 25(OH)D (≥ 80 nmol/L) had a mean annual loss in total hip BMD of −0.1 percent (95% CI −0.5, 0.3) compared to −0.7 percent (95% CI −1.1, −0.4) in the lower quartile (< 52.5 nmol/L). The association remained significant after adjusting for age, weight, season, use of calcium, multivitamins, serum estradiol and other hormones. Serum PTH and 1,25-(OH)2 D were not significantly associated with hip bone loss. There was no association between serum 25(OH)D levels and calcaneal BMD after adjusting for age and weight.128


In a cohort of older men and women (mean age 74 years, 228/327 with complete data) from the Framingham study with knee osteoarthritis, Bischoff-Ferrari reported a positive association between 25(OH)D and BMD of the femoral neck that was independent of age, gender, BMI, disease severity and physical activity.132 Fifteen percent of the cohort were classified as vitamin D deficient (<40 nmol/L), and 51 percent had levels between 40-80 nmol/L. Individuals in the 40-80 nmol/L group had a 7.3 percent higher BMD than those in the deficient group and individuals in the > 80 nmol/L group had an 8.5 percent higher BMD than the deficient group. In a subgroup analysis, the relationship was similar in both genders but most pronounced in men.132


Two small cohorts found a positive association between serum 25(OH)D and BMD of the femoral neck..126,129 Del Puente et al. (2002) investigated the relation between serological

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

markers and change in BMD in 139 healthy premenopausal and postmenopausal women (mean age 58 years).129 They reported that serum 25(OH)D was an independent predictor of change in femoral neck BMD and lumbar spine. However, in stepwise analysis discrimination models, only the association with femoral neck remained significant (r2 = 0.26).129


Melin et al. (2001) examined the relation between serum 25(OH)D, PTH and femoral neck BMD in 64 community-dwelling older individuals (mean age 83.7 years) and found that femoral neck Z-score was associated with serum 25(OH)D after both summer (r = 0.38, p = 0.003) and winter (r = 0.37, p = 0.003). In a multiple regression analysis with Z-score as the dependent variable and 25(OH)D and BMI as independent variables, only 25(OH)D remained a significant predictor of BMD after winter (adjusted r2 = 0.14, p=0.005).126


A small cohort study of eighteen healthy older women (mean age 77 years) reported an association between serum 25(OH)D and lumbar spine bone mineral density.135 Rosen noted that differences in serum 25(OH)D between the first and second winter were associated with bone loss at the lumbar spine (r = 0.59, p = 0.04) but not at femoral neck, supporting the hypothesis that seasonal changes in serum 25(OH)D influence the rate of annual bone loss in postmenopausal women.135


Dennison et al. did not find an association between baseline serum 25(OH)D and BMD or bone loss at either proximal femur or lumbar spine in 316 healthy, active older individuals (mean age 66 years), after adjusting for adiposity. Limitations of this study included a change in densitometer model between the baseline and followup assessment and lack of adjustment for season of data collection or vitamin D intake.127


Case-control studies. Five out of six studies matched cases and controls on age136,139-141,143 and three studies matched on gender and postmenopausal status.139,140,143 None of the studies adjusted for weight or BMI in analyses.


Of the six case-control studies that evaluated the relation between 25(OH)D and BMD, one reported a weak association between 25(OH)D and BMC of the femoral neck (r = 0.054 p = 0.05).136 Two case-control studies reported significantly lower 25(OH)D levels in women with osteoporosis.140,143 Boonen reported that both serum 25(OH)D3 and PTH were highly predictive of femoral neck BMD (r2 = 32 percent, p<0.001).139 Thiebaud reported that femoral neck BMD was weakly correlated with 25(OH)D concentrations and the only significant association was with trochanteric BMD.141 Villareal reported that lumbar spine BMD correlated with serum 25(OH)D (r = 0.41, p < 0.01) in participants with low 25(OH)D levels (< 38 nmol/L). However, multivariate analysis revealed that iPTH was the main determinant of the decrease in spine BMD.143 Al-Oanzi conducted a study in men and did not find a significant difference in serum 25(OH)D between those with osteoporosis (T score ≤ 2.5) versus those without.152

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Summary. Serum 25(OH)D levels and bone mineral density


Quantity: Nineteen studies assessed the association between 25(OH)D and bone mineral density. Five RCTs, and three cohort studies did not find an association between serum 25(OH)D levels and BMD or bone loss. Four cohorts found a significant association between 25(OH)D and bone loss, which was most evident at the hip sites and evidence for an association between 25(OH)D and lumbar spine BMD was weak. Six case-control studies suggested an association between 25(OH)D and BMD and the association was most consistent at the femoral neck BMD. In some studies, it was unclear whether the effect of serum 25(OH)D on bone loss was mediated by serum PTH.


Quality: The overall quality of studies varied from fair to good.


Consistency: There was discordance between the results from RCTs and the majority of observational studies that may be due to the inability of observational studies to control for all relevant confounders. Based on results of the observational studies, there is fair evidence to support an association between serum 25(OH)D and BMD or changes in BMD at the femoral neck. Specific circulating concentrations of 25(OH)D below which bone loss at the hip was increased, ranged from 30-80 nmol/L.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 5. Studies Reporting Serum 25(OH)D Levels and Bone Health Outcomes in Postmenopausal Women and Older Men

Outcome

(N studies)

Study Design

Associations

Fractures

(N=15)

RCTs=0

Cohorts=3

Case-controls=12

Association:

1 cohort131

9 case-controls29,139,141,142,144,146,148,150,151

 

 

No Association:

2 cohorts130,133

3 case-controls137,145,149

Falls

(N=5)

RCTs=1

Cohorts=3

Case-controls=1

Association:

1 RCT114

1 cohort123

1 case-control138

 

 

No Association:

2 cohorts122,134

BMD/BMC

(N=19)

RCTs=6

Cohorts=7

Case-controls=6

Association:

1 RCT119

4 cohorts: FN BMD126,128,129,132; 1 cohort LS BMD135

6 case-controls: FN BMC136; FN, Tr and TH BMD139,141 LS BMD140,143,152

 

 

No Association:

5 RCTs116-118,120,121

3 cohorts: FN BMD135; proximal femur, LS BMD127; FN, LS BMD131

Performance measures

(N=7)

RCTs=3

Cohorts=4

Association:

2 cohorts124,131

2 RCTs113,115

 

 

No Association:

2 cohorts125,134

1 RCT112

BMC, bone mineral content; BMD, bone mineral density; FN, femoral neck; LS, lumbar spine; RCTs, randomized controlled trials; TH, total hip; Tr, trochanter

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 6. Serum 25(OH)D Levels and Fractures in Postmenopausal Women and Older Men

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Duration

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Prospective Cohorts

Cummings (2006)133

Subset of a cohort of 9704 ambulatory community-dwelling women ≥ 65 years of age (nested case-control study)

5.9 y

25(OH)D^

Hip fractures

Adjusted for age, weight and calcaneal BMD (SPA)

 

 

22% in the subset had serum 25(OH)D ≤47.5 nmol/L

vertebral fractures

 

US

 

There were no statistically significant unadjusted or adjusted (age, weight, season, use of vit D supplements) association between serum 25(OH)D or PTH and the risk of hip or vertebral fracture.

Public

Groups analyzed:

Of the 332 women in the cohort who had hip fractures, 133 were randomly selected; Of the 389 women who had new vertebral fractures in the cohort, 138 were randomly selected; 359 ctrls were randomly selected; of these, 343 served as ctrls for hip fracture cases and 264 served as ctrls for vertebral fractures (based on availability of XRs)

 

 

 

 

 

RIA

BMD calcaneus (SPA)

PTH (measured by IRMA)

 

 

 

 

For women in the lowest quintile of serum 25(OH)D levels, there was no increased risk for hip or vertebral fracture.

 

 

 

 

Women in the lowest quintile of serum 1,25-(OH)2D had a significant increase in hip fracture risk (RR 2.1, 95% CI 1.2-3.5) but not vertebral fracture risk.

 

100% female

 

 

 

 

 

72.6 y (subset)

 

 

 

 

 

White

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Duration

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Gerdhem (2005)131

1,044 Ambulatory independently living women

3 y

25(OH)D^

95 (30)

< 50 nmol/L: 4.4%

< 75 nmol/L: 26%

Fractures (low energy)

119/986 (12%) had a total of 159 low energy fractures (29 hip, 28 wrist, 12 proximal humerus, 43 vertebral and 47 other)

Sweden

58/1044 (6%) did not complete

 

 

Public

100% female

 

CPBA

 

9/43 (21%) with 25(OH)D < 50 nmol/L had one or more fractures vs. 110/943 (12%) with 25(OH)D > 50 nmol/L: HR 2.04 (95% CI, 1.04 - 4.04).

 

75 y (range 75-75.9 y)

 

 

 

 

NR

 

 

 

 

 

 

 

 

 

Fracture association was independent of season although a seasonal difference was noted in mean level of 25(OH)D (Sept 101 nmol/L vs. Feb 89.8 nmol/L).

Woo (1990)130

427 Elderly ≥ 60 y living independently in sheltered housing.

144/427 (34%)

30 mo

25(OH)D^

Fractures

Adjusted for age, gender, drinking, smoking and BMI.

 

 

fracture subset N=9) 63.3 (6.9) no fracture subset 74 (1.15), NS

 

 

Hong Kong

 

 

 

Subjects with lower serum 25(OH)D (males < 79 nmol/L and females < 66 nmol/L) had a nonsignificant increase in adjusted RR for fracture.

NR

60% females

 

 

 

 

Women: 70 y

Men: 69 y

 

CPBA

 

 

 

Asian (Chinese)

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Case-Control Studies

Bakhtiyarova (2006)151

64 Hip fracture cases (spontaneous or low trauma)

NR

25(OH)D^

Hip fractures

Median serum 25(OH)D levels significantly lower in hip fracture cases vs. ctrls (graph only).

 

 

Cases: 22.4 (11.4)

Ctrls: 28.1 (10.1)

 

Russia

97 ctrls admitted to opthamology dept

 

 

 

 

 

 

 

Hip fracture patients more likely to have serum 25(OH)D < 25 nmol/L than ctrls (65% vs. 47%, p=0.006).

NR

 

 

25(OH)D <25 nmol/L: Cases: 65%; Ctrls: 47%

25(OH)D<40 nmol/L: Cases 89%; Ctrls 89%;

25(OH)D <50 nmol/L: Cases 100%, Control 98%

 

 

Cases: 69% female Ctrls: 55% female

 

 

 

 

Cases: 68.8 (9.5) y Ctrls: 70.2 (8.3) y

 

 

 

 

White (Caucasion)

 

CPBA

 

 

Boonen (1997)142

117 Elderly women with hip fractures and 117 community-dwelling ctrls

Age, PM status, gender, ethnicity

25(OH)D^

Hip fractures

Serum 25(OH)D significantly lower in cases vs. ctrls (p=0.001).

 

Cases 25.25 (22)

Ctrls: 53.75 (33.25)

BMD (FN and Tr) (DXA)

 

Belgium

 

Hip BMD (FN and Tr) significantly lower in cases vs. ctrls (p < 0.001).

 

100% female

 

 

 

 

Public

 

 

CPBA

 

 

 

Cases: 79.2 y

Ctrls: 77.7 y

 

 

 

 

 

White (Caucasion)

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Boonen, (1999)139

100 Postmenopausal women

50 osteoporotic hip fracture patients and

50 independently living ctrls

Age, gender, PM status, sampled at the same time of year

25(OH)D3

Fractures

Adjusted for age

Mean 25(OH)D3 was significantly lower cases vs. ctrls.

 

Cases: 29.3 (26.5)

Ctrls: 68.75 (39), p < 0.001

BMD (FN and Tr) (DXA)

Belgium

 

 

 

 

25(OH)D < 30 nmol/L:

64% of cases vs. 8% ctrls within the same 4 mo sampling period (no relation b/w 25(OH)D and mo of sample collection).

Public

 

 

PTH (IRMA)

 

 

 

CPBA

 

 

100% female

 

 

 

 

Cases: 74.2 (7.8) y

Ctrls: 75.8 (5.6) y

 

 

 

FN and Tr BMD were significantly lower in cases than ctrls.

 

NR

 

 

 

No significant relation b/w the 25(OH)D3-PTH axis and BMD when analyzed separately. In multiple regression analyses of pooled data, models using 25(OH)D3 and PTH were predictive of FN BMD (R2=32%, p<0.001).

Cooper (1989)145

41 Hip fractures 40 Healthy ctrls (20 inpatient and 20 outpatient)

Age (cases and one of the two control groups similar), gender

25(OH)D^

Fracture patients: 23.5 (14.5),

Inpatient ctrls: 35.75 (23.5)

Outpatient ctrls: 48.5 (25)

Hip fractures

Age and albumin

 

PTH (immunoreactive, C-terminal)

Mean 25(OH)D was significantly lower in cases vs. ctrls (p<0.01). When age and albumin were used as covariates in the analysis, there was no residual difference in serum 25(OH)D levels.

UK

NR

100% female

 

 

Cases 77.4 (8.6) y

Ctrls 73.3 (10.5) (inpatients), and 66.9 (11.8) y (outpatients)

 

 

 

 

 

25(OH)D <20 nmol/L):

Cases: 49% vs.

Ctrls: 10 – 15%

 

More hip fracture cases (49%) had 25(OH)D levels <25 nmol/L vs. 15% of inpatient and 10% of outpatient ctrls.

 

NR

 

RIA

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Diamond (1998)150

41 Men with hip fracture 82 healthy ctrls (41 in-patient and 41 out-patient)

Age, gender

25(OH)D^

Hip fractures

Age, body weight, comorbidity score, smoking history, alcohol intake, serum calcium, albumin, 25(OH)D and free testosterone.

 

 

Cases 45.6, range 36.9-52.3

Inpatients ctrls 61.1 (range 50.0-72.2)

Outpatients ctrls 65.9 (range 59.0-72.8), p = 0.007 for cases vs. combined ctrls

 

Australia

 

 

NR

100% male

 

 

Men with hip fractures had significantly lower 25(OH)D levels vs. ctrls (p=0.007). 25(OH) D < 50 nmol/L: 63% of fracture patients vs. 25% of combined ctrls, OR 3.9 (95% CI 1.74 - 8.78).

 

Cases: 79.6 y

Ctrls: 78.7 y and 77 y

 

 

 

NR

 

 

 

 

 

 

RIA

 

 

 

 

 

 

 

Multiple regression analysis showed that serum 25(OH)D level < 50 nmol/L was strongest predictor of hip fracture (r = 0.34 (0.19), p=0.013).

Age was the best determinant of a serum 25(OH)D level < 50 nmol/L, p=0.028

Erem (2002)137

21 Women with hip fractures and 20 healthy PM women, all independent community-dwellers

Age, gender, PM status

25(OH)D^

Cases 26.9 (25.0)

Ctrls: 24.9 (20.5)

Hip fractures

NR

Turkey

 

 

Non significant difference in 25(OH)D levels in hip fracture patients vs. ctrls

Public

 

CPBA

 

 

 

 

 

 

25 (OH)D levels in all groups < 37.5 nmol/L

 

100% female

 

 

 

 

 

Cases: 76.7 (6.5) y Ctrls: 75.4 (6.3) y

 

 

 

 

 

Far Eastern

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Landin-Wilhelmsen, (1999)140

128 PM women with osteoporosis

227ctrls from outpatient clinic

Age, gender, PM status

25(OH)D3

Cases: 88 (30)

Ctrls: 96 (32)

Fractures

NR

 

BMD and BMC: LS, TB and FN (DXA)

25(OH)D significantly lower in osteoporotic women vs. ctrls (p<0.05); PTH significantly higher in osteoporotic women vs. ctrls (p < 0.001)

Sweden

 

 

RIA

 

 

100% female

 

 

PTH (IRMA)

Public

 

 

 

 

 

 

osteoporotic women: 59 (6) y

ctrls: 59 (5) y

 

 

 

Fracture history in 56% of osteoporotic women vs. 4% of ctrls, p<0.001

 

 

 

 

 

osteoporotic women had lower body weight and BMI vs. ctrls (p<0.001).

 

NR

 

 

 

Lau, (1989)144

200 hip fracture patients in hospital and 427 community-living ctrls

Ethnicity

25(OH)D^

Hip fractures

NR

25(OH)D levels were significantly lower in cases vs. ctrls (p<0.01).

Hong Kong

 

Men

cases <70 y: 56.3 (18) and 70 y: 46.3 (17.3)

Ctrls <70 y: 84.8 (25.5) and 70 y: 80.5 (21.5

 

NR

NR

 

 

Hip fracture patients with low 25(OH)D male < 36.5 nmol/L, female, < 34.3 nmol/L, defined by lower limit of 95% CI for ctrls) were less mobile than those with normal 25(OH)D; 33% with low 25(OH)D could walk outdoors without an aid vs. 61% of those with a normal 25(OH)D level.

 

Age range: 49-93 y (cases), 60-90 y (ctrls)

 

 

 

Asian

 

 

 

 

 

 

Women

cases <70 y: 44.5 (13.8) and 70 y: 42.8 (15.5)

ctrls <70 y: 72.5 (15.5) and 70 y: 65 (17)

 

 

 

 

CPBA

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

LeBoff (1999)29

98 community-dwelling women

30 with hip fracture and osteoporosis (OP) (group 1);

68 women admitted for elective joint replacement with (17) or without (51) osteoporosis (group 2)

Gender, PM status, setting, surgical procedure OP in group 1 and subset of group 2

25(OH)D^

median: Group 1: 32.4, Group 2: OP 49.9; non-OP 55.0

Hip fractures

Adjusted for age and estrogen replacement therapy.

U.S.

BMD: LS, FN, Tr, total body (DXA)

 

 

 

Women with hip fracture and OP had significantly lower 25(OH)D vs. women with OP admitted for surgery (p=0.01) and vs. women without OP admitted for surgery (p=0.02).

Public

 

 

 

RIA

 

 

 

 

 

 

% of women with 25(OH)D < 30 nmol/L: Signficantly more in group 1 (50%) vs. OP or non-OP group 2 (graph only ~ 5% for OP and 10% for non-OP) (p < 0.002).

 

100% female

 

 

 

 

Group 1: 77.9 y

Group 2: OP 69.9 y; non-OP 64.4 y

 

 

 

Mean BMD (LS, FN, Tr) was significantly less in women with acute hip fracture/OP vs. elective surgery non-OP ctrls.

 

NR

 

 

 

Lips (1983)147 and Lips (1987)146

125 consecutive patients with femoral neck fracture and 74 healthy community ctrls

Age

25(OH)D^

Hip fractures

Adjusted for age and sex

 

Cases: 18.5 (10.6) Ctrls: 32.9 (13.6)

 

Serum 25(OH)D levels lower in cases vs. ctrls (p<0.001).

The Netherlands

 

 

 

 

 

Cases: 67% female

Ctrls: 73% female

 

 

 

 

 

 

serum 25(OH)D < 20 nmol/L:

Cases: 62%

Ctrls: 16%

 

 

Public

 

 

 

 

 

Cases: 75.9 (11) y

Ctrls: 75.6 (4.2) y

 

 

 

 

NR

 

CPBA

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Lund (1975)149

67 consecutive cases of proximal femur fractures ctrls: milddle aged (30-59 y) N = 27 and elderly healthy individuals (60-95 y) N = 67 at same time of year

Age

25(OH)D^

Proximal femur fractures

There was no statistically significant difference in serum 25(OH)D levels vs. either ctrl.

Denmark

 

range 7.5-195 nmol/L

N=12 (18%) <25 nmol/L

 

NR

 

 

 

 

 

CPBA

 

 

 

NR

 

 

 

 

 

NR

 

 

 

 

 

NR

 

 

 

 

Punnonen (1986)148

40 cases of hip fracture and 25 ctrls (from gynecological clinic)

Age, gender, setting

25(OH)D^

Hip fractures (FN)

NR

 

 

Cases: 18.2 (13.2)

Ctrls: 53.3 (24.1)

 

25(OH)D levels were significantly lower in cases vs. ctrls, (p<0.01).

Finland

 

 

 

 

 

100% female

 

 

 

 

NR

 

 

 

 

 

 

Cases: 77.1 (8.6) y

Ctrls: 73.8 (8.4) y

 

CPBA

 

 

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Thiebaud, (1997)141

179 Hip fracture patients; 180 hospital ctrls; 55 community ctrls

Age, setting (for cases and one control group)

25(OH)D^

Women:

Fracture cases: 25.5 (20.5)

Hospital ctrls: 31.5 (26.5)

Community ctrls: 53 (23)

Fractures

Adjusted for age, sex, and creatinine

 

 

BMD: FN, TH and Tr (DXA)

Women and men with hip fractures had significantly lower 25(OH)D levels vs. ctrls. Fracture patients had lower hip (TH, FN) BMD vs. either ctrl group (p < 0.001).

Switzerland

 

 

 

Cases: 76% female Hospital Ctrls: 75% female Community ctrls: 85% female

 

 

Public

 

 

 

 

 

 

In multivariate logistic regression of the risk for hip fracture, serum albumin and PTH were significant. In women, BMD was weakly correlated with 25(OH)D and the only significant association was at the Tr (r=0.13, p < 0.05).

 

Cases: women 81.0 y; men 77.7 y

Hospital ctrls: women 80.9, men 76.9 y

Community ctrls: women 71.7 y, men 71.3 y

 

Men

Fracture cases: 17.25(18.5)

Hospital ctrls: 27.75 (21.5)

Community ctrls: 31.5(22.8)

 

 

 

 

RIA

 

 

Note:

^ total 25(OH)D or either isoform of 25(OH)D (isoform not specified);

BMC, bone mineral content; BMD, bone mineral density; ctrls, controls; DXA, dual energy X-ray absorptiometry; FN, femoral neck; PM, post menopausal; RIA, radioimmunoassay; SD, standard deviation; SPA, single-photon absorptiometry; TH, total hip; Tr, trochanter; wks, weeks; y years

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 7. Serum 25(OH)D Levels and Falls and/or Performance Measures in Postmenopausal Women and Older Men

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Intervention

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Jadad

AC

RCTs

Bischoff-Ferrari (2003)114

122 Elderly women in long-stay geriatric care

IG: 800 IU D3 + 1200 mg Calcium carbonate daily

CG: 1200 mg

Ca daily

25(OH)D^

Median (IQR): baseline

IG1: 30.75 (23-55)

CG: 29 (23-55)

values < 30

nmo/L: 50%.

Falls

Age, height, weight, BMI, number of falls in pre-treatment period, being a faller in the pre-treatment period, prior vit D use, comorbidity index. muscle strength, use of walking aid, baseline 1,25-(OH)2D, 25(OH)D, iPTH, albumin and observation time during treatment

3

 

iPTH (RIA)

Unclear

 

drop outs

IG1: 31%

CG: 25%

 

 

Switzerland

 

 

 

Public and private

 

 

 

 

100% female

 

 

 

 

 

 

 

12 wks (6 wk pre-treatment)

End of study

IG1: 65.5 (49.75-82.75)

CG: 28.5 (24.5-41.5)

 

Vit D + Ca accounted for 49% reduction in falls (−0.68; 95% CI 14-71%, p=0.01) after adjustment for age, number of falls in pretreatment period, being a faller in pre-treatment period, baseline 1,25-(OH)2D, and 25(OH)D. Predictors other than treatment were being a faller, number of falls in pre-treatment period and age.

 

 

85.3 y

range 63-99

 

 

 

NR

 

 

 

 

 

 

RIA

 

 

Corless (1985)112

82 Elderly hospital patients with serum 25(OH)D < 40 nmol/L

IG1: 9,000 IU/d D2

CG: placebo

25(OH)D^

Mean (SEM):

ADLs: muscle strength and independence index

NR

5

 

 

No significant correlation between change in 25(OH)D and change in muscle strength’ (r=0.12, p>0.3) or independence’ indices (r=0.26, p>0.1).

Unclear

U.K.

 

 

Baseline IG1: 16.6 (2.1)

CG: 17.6 (2.05)

% < 20 nmol/L:

IG1: 66%

CG: 70%

 

 

Drop outs

IG1: 9/41 (22.1%),

CG: 8/41 (19.5%)

9 mo

 

 

Public

 

 

 

 

 

IG1: 78.1% female

CG: 78.8 % female

 

 

 

 

 

 

 

End of study: graph only (IG1: ~ 110 nmol/L)

 

 

 

 

IG1: 82.3 (6.0) y

CG: 82.6 (6.9) y

 

 

 

 

 

NR

 

CPBA

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Intervention

Duration

Serum 25(OH)D

Mean (SD) (nmol/L)

Assay

Bone Health Outcomes

Covariates

Summary of Results

Jadad

AC

Dhesi, (2004)115

139 Ambulatory older adults with a history of falls and 25(OH)D <30 nmol/L

IG1: 600,000, D2 (injection) CG: placebo

25(OH)D^

Baseline

IG1: 26.8 (25.5-28)

CG: 25 (23.8–26.3)

Falls, postural sway, reaction time, aggregate functional performance time and quadriceps strength

NR

5

 

Significant correlation between 25(OH)D and ∆ aggregate functional performance time in both groups (r=0.19, p=0.03).

Unclear

U.K.

 

 

 

 

6 mo

 

Public

Drop outs

IG1: 8/70 (11.4%), CG: 8/69 (11.6%)

 

 

 

 

 

End of study

IG1: 43.8 (41.3-46.3)

CG: 31.5 (28.5-34.5)

 

 

 

 

IG1: 75.7% female

CG: 79.7% female

 

 

 

 

 

IG1: 77.0 (6.3) y

CG: 76.6 (6.1) y

 

 

 

 

 

 

RIA

 

 

 

 

Caucasion

 

 

 

 

 

Kenny (2003)113

65 Healthy, community-dwelling men with normal 25(OH)D

IG1: 1,000 IU

D3 + 500 mg

Ca

CG: 500 mg

Ca daily

25(OH)D^

Baseline

IG1: 65 (17.5)

CG: 60 (17.5)

Ability to rise from a chair, static balance, 8-foot walk, TUG, timed supine to stand test and PASE questionnaire.

NR

4

 

 

Association between baseline 25(OH)D and single-leg stance time (r=0.245, p<0.05) and PASE Score (r=0.360, p<0.01).

Adequate

U.S.

 

 

 

IG1: 4/33 (12.1%), CG 1/32 (3.1%)

 

 

Public

 

End-of-study (graph only)

IG1: ~ 83

CG: ~ 50

 

 

 

 

 

6 mo

 

 

 

 

 

100% male

 

 

 

 

 

 

IG1: 77 y

CG: 75 y

 

 

 

 

 

 

 

CPBA

 

 

 

 

NR

 

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Prospective Cohorts

Faulkner (2006)134

9,704 Older community-dwelling women (from the Study of Osteoporotic Fractures), and 389/400 (97.2%) drawn at random entire cohort for serum measures

4 y

25(OH)D3

Median (IQR)

Falls; GS, quadriceps strength, chair-stand time, walking speed, reaction time and balance-walk time measured in subset of 389

Adjusted for age, height, BMI, clinical site, season of serum collection, education, ethnicity, physical activity, smoking, alcohol use, housebound status, dietary calcium intake, orthostatic hypotension, stroke, Parkinson’s disease, arthritis, diabetes, osteoporosis, hyperthyroidism, cognitive impairment, visual acuity, self-rated health, use of estrogen, thyroid hormones, calcium supplements, corticosteroids, diuretics, and CNS-active medications.

U.S.

 

Total cohort: 62.5 (47.5-77.5) Women using vit D supplements (N=4,273): 67.5 (52.5 - 85)

Women not using vit D supplements (N=5,253): 55 (42.5-70)

Public

 

 

100% female

 

 

 

 

 

 

% < 25 nmol/L

Women using vit D supplements: 0.6%

Women not using vit D supplements: 4.2%

 

 

Median (IQR): 70 (67-75) y

 

 

 

 

 

 

There was a trend toward higher 25(OH)D3 concentrations associated with weaker grip strength (p=0.017) vs. women in the first quartile.

 

66% Northern European (excluded African Americans)

 

 

 

 

RIA

 

 

 

 

 

 

25(OH)D3 was not associated with neuromuscular function, ∆ neuromuscular function (grip strength, chair stand time, walking speed and balance walk time) or fall rates.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Flicker (2003)123

1,619 Institutionalized elderly, both low (N=667) and high level care (N=952)

145 d (low level care) and 168 d (high level care subjects)

25(OH)D^

Low level care:

WA (32°S): 39.3 (20.1)

NSW (34°S): 43.7 (22.5)

Victoria (38°S) 38.4 (19.6) p<0.05

High level care:

WA (32°S): 33 (17.3)

NSW (34°S): 32.4 (22.4)

Victoria (38°S): 30.7 (19.4)

Falls

Adjusted for weight, cognitive status, psychotropic drug use, prior wrist fracture and presence of wandering behavior

Australia

 

Public

All 1,619 included in analysis

 

After excluding bed bound residents and adjusting for above covariates, log serum 25(OH)D level was independently associated with time to first fall: adjusted HR 0.74 (95% CI, 0.59-0.94, p=0.01).

 

100% female

 

 

 

Low level care: 83.7 (8.7) y

High level care: 83.7 (9.1) y

 

 

 

 

% < 25 nmol/L:

Low level care: 22%

High level care: 45%

 

20% reduction in risk of falling with doubling of 25(OH) D level.

 

NR

 

 

 

 

 

 

 

RIA

 

 

Gerdhem (2005)131

1,044 Ambulatory independently living women

3 y

25(OH)D^

95 (30)

< 50 nmol/L: 4.4%

< 75 nmol/L: 26%

Gait speed, Romberg balance test, lower extremity strength

NR

 

 

25(OH)D correlated with: gait speed r=0.17, p<0.001), Romberg balance test (r=0.14, p<0.001), self-estimated activity level (r=0.15,p<0.001), thigh muscle strength (r=0.08, p=0.02).

Sweden

 

 

 

 

58/1,044 (6%) did not complete

 

 

 

Public

 

CPBA

 

 

100% female

 

 

 

 

 

 

 

 

 

5% of the variability in 25(OH)D explained by fall-related and anthropometric variables multiple regression).

 

75 (75-75.9) y

 

 

 

 

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Sambrook (2004)122

646 Ambulatory residents of institutional care facilities (hostels and nursing homes) > 65 y

1 y

25(OH)D^

Fallers: 28.8 (14.2)

Non-fallers: 33.2 (16.5)

Falls

Adjusted for age, incontinence, illness severity; Interactions between PTH, 25(OH)D and other variables were tested.

Australia

 

 

 

% <39 nmol/L: 73.6%

Men: 64.5%, Women: 75.8%

 

NR

 

 

 

After adjusting for age, incontinence and illness severity, serum 25(OH)D was no longer a significant predictor of falls.

 

9/646 (1%) did not complete

 

 

 

 

 

RIA

 

 

Fallers: 84% female

Non-fallers: 79% female

 

 

 

 

 

 

 

 

25(OH)D was related to balance. There was a 1.65X increased risk of falls in group with 25(OH)D < 39 nmol/L and PTH > 66 pg/mL compared to those with 25(OH)D > 39 nmol/L and PTH < 66 pg/mL.

 

Fallers: 86.6 y (6.5) y

Non-fallers: 85.1 (6.4) y

 

 

 

 

NR

 

 

 

 

Visser (2003)124

1,509 Older individuals from longitudinal study of aging 501/1509 (33%) did not complete

3 y

25(OH)D^

NR

GS and ASMM Sarcopenia defined as a loss of GS > 40%, and ASSM > 3%

Adjusted for sex, age, BMI, physical activity level, chronic disease, creatinine, season of data collection and smoking.

The Netherlands

 

< 25 nmol/L: 9.6% <12.5 nmol/L: 1.3%

 

 

 

 

 

Separate analysis adjusted for weight change. Interactions explored between PTH and 25(OH)D

Public

NR

 

CPBA

 

 

Stable GS: 74.2 (6.1) y

Loss of GS: 76.9 y (6.5)

Stable ASMM: 73.7 (5.9) y

Loss of ASMM: 74.9 (6.4) y

 

 

 

 

 

 

 

Individuals with 25(OH)D <25 nmol/L vs. levels >50 nmol/L were more likely to experience loss of GS (adjusted OR 2.57, 95% CI 1.40-4.70, p<0.05); loss of ASMM, NS.

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Verreault (2002)125

1,002 Elderly women, ≥ 65 y with moderate to severe disability living in community

3 y

25(OH)D^

Mean: 52.9 % <25 nmol/L: 12.4%

Lower extremity strength, GS, walking speed, repeated chair stands. Disability in activities involving mobility and upper extremity function.

Adjusted for: baseline performance, age, BMI, comorbidity and other confounders associated with a decline in performance. (Cox proportional hazard model) age, race, education, smoking and baseline BMI, season and presence of comorbidity.

U.S.

 

Public

374/1002 (37%)

 

RIA

 

100% female

 

 

No association between low 25(OH) D levels and loss of muscle strength or declines in mobility or disability. Results were similar when 25(OH)D and PTH were both included in the model.

 

NR

 

 

 

 

NR

 

 

 

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Case-Control Studies

Stein (1999)138

83 ambulatory nursing home and hostel residents grouped as fallers 33) vs. never fell (50)

Age, setting, level of independence

25(OH)D^

Median:

Cases: 22

Ctrls: 29

Falls

Adjusted for PTH; interactions sought between weight and gender

Australia

 

 

Serum 25(OH)D lower in patients who had a fall vs. those who did not (95% CI for difference in medians: 1 - 13 nmol/L, p=0.019).

 

 

CPBA

 

Public

 

 

 

 

 

 

 

 

 

Bivariate OR (95% CI) for falling vs. never falling for Ln 25(OH)D was 0.33 (0.13-0.83). Neither Ln 25(OH)D or 1,25-(OH)2D were independent predictors after adjusting for PTH.

 

66% female

 

 

 

 

 

 

 

 

 

Median age (IQR): 84 (79-89) y

 

 

 

 

NR

 

 

 

 

AC, allocation concealment; ADLs, activities of daily living; ASMM, appendicular skeletal muscle mass; BMI, body mass index; CPBA, competitive protein binding assay; CI, confidence interval; ctrls, controls; GS, grip strength; IQR, interquartile range; NS, not significant; OR, odds ratio; PTH, parathyroid hormone; RIA, radioimmunoassay; SD, standard deviation; y, years

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 8. Serum 25(OH)D Levels and BMD/BMC in Postmenopausal Women and Older Men

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Intervention

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Jadad

AC

RCTs

Aloia (2005)117

208 Post menopausal women

IG: 800 IU D3 for 2 y, then 2,000 IU for 1 y + 1200 - 1500 mg Ca CG: 1200 - 1500 mg Ca

25(OH)D^

BMD: LS, total hip, total body, mid radius (DXA)

NR

5

 

 

Baseline:

IG1: 48.3 (20.9)

CG: 43 (16.6)

No association between serum 25(OH)D and ∆ BMD. Analyses examining those with low baseline 25(OH)D or high PTH showed no influence of 25(OH)D on ∆ BMD.

Adequate

U.S.

IG1: 3/104 (2.9%), CG: 3/104 (2.9%) did not complete

 

 

Public

 

PTH (IA, Allegra)

 

 

 

3 mo 800 IU D3 IG1: 70.8 (95% CI 66.4-76.1)

 

 

 

100% female

 

3 mo 2000 IU D3 IG1: 86.9 (95% CI 80.1-94.1)

CG: no significant change

 

 

 

 

 

3 y

 

 

 

 

 

IG1: 59.9 (6.2) y

CG: 61.2 (6.3) y

 

 

 

 

 

 

100% African American

 

 

 

 

 

 

 

RIA

 

 

 

Cooper (2003)120

187 Post menopausal women not on HRT

IG1: 10,000 IU Vit D2/wk + 1000 mg Ca/d CG: 1000 mg Ca/d

25(OH)D^

BMD: LS, FN, Ward’s triangle, Tr, proximal forearm (DXA)

NR

4

 

 

IG1: 82.6 (27.0)

CG: 81.6 (24.4)

No significant correlation between baseline 25(OH)D concentration and ∆ BMD at any site or between ∆ 25(OH)D and ∆ BMD at any site.

Unclear

Australia

IG1: 20/93 (21.5%), CG: 14/94 (14.9%) did not complete

 

 

Public and private

RIA

 

 

 

2 y

 

 

 

 

 

100% female

 

 

 

 

 

 

IG1: 56.5 (4.2) y

CG: 56.1 (4.7) y

 

 

 

 

 

 

Caucasian

 

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Intervention

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Jadad

AC

Dawson-Hughes (1995)118

247 Healthy, ambulatory postmenopausal women

IG1: 700 IU D3 + 500 mg Calcium citrate malate CG: 100 IU D3 + 500 mg Ca daily

Baseline: NR

BMD LS, FN and total body (DXA)

NR

3

End of study

IG1: 100.1 (24.5)

CG: 66.3 (25.5)

Difference in means: 33.8 (95% 27.6, 40.1)

25(OH)D concentrations during either season did not correlate with ∆ BMD at any site.

Unclear

US

 

 

 

 

IG1: 5/128 (4%), CG: 8/124 (6%) did not complete

 

 

 

Public and private

 

 

 

 

 

2 y

CPBA

 

 

 

 

100% female

 

 

 

 

 

 

IG1: 63.0 y

CG: 64.0 y

 

 

 

 

 

 

Caucasion

 

 

 

 

 

Ooms (1995)119

348 Elderly women

IG1: 400 IU D3 CG: placebo daily

25(OH)D^

Median (25th and 75th percentiles):

IG1: 27 (19-36) CG: 26.0 (19-37)

BMD: FN, Tr and distal radius (DXA)

Season

4

 

IG1: 51/177 (28.8%)

CG: 53/171 (31.0%)

Effect of vitamin D supplementation was independent of baseline 25(OH)D as well as 25(OH)D corrected for season.

Unclear

The Netherlands

 

 

 

100% female

2 y

 

 

 

Public

 

 

1 y followup:

IG: 62 (52-70)

CG: 23 (17-31)

 

 

 

 

IG1: 80.1 (5.6) y

CG: 80.6 (5.5) y

 

 

 

 

 

NR

 

CPBA

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age

Ethnicity

Intervention

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Jadad

AC

Schaafsma (2002)121

85 Healthy, postmenopausal women 50 - 70 y

IG1: eggshell powder + 200 IU D3 IG2: Ca carbonate + 200 IU D3 CG: placebo

25(OH)D^

IG1: 97.1 (24.1)

IG2: 83.1 (22.4) CG: 91 (36.5)

BMD: LS, hip (DXA)

NR

4

 

 

No significant correlation between 25(OH)D and BMD.

Unclear

The Netherlands

 

 

 

12/85 (14%) did not complete

 

 

 

 

 

 

% change:

IG1: 25.1 (29.8)

IG2: 43.8 (27.3)

CG: 11.1 (22.7)

 

 

 

NR

 

 

 

 

 

 

100% female

12 mo

 

 

 

 

IG1: 60.5 y

IG2: 59.5 y

CG: 63.5 y

 

 

 

 

 

 

 

CPBA

 

 

 

 

Caucasian

 

 

 

 

 

Storm (1998)116

60 Postmenopausal women without osteoporosis

IG1: 4 glasses of fortified milk (325 IU of vitamin D/quart)

IG2: Ca carbonate

CG: placebo daily

25(OH)D^

Mean (SE): IG1: 63.5 (8)

IG2: 68.8 (7.3)

CG: 59.8 (6.8); levels dropped almost 20% during 2 winters and returned to baseline during summer

BMD: Tr, FN, LS (DXA)

Independent variables: Ca intake, 25(OH)D, bone markers, PTH, insulin growth factor I, age, BMI, thiazide use, smoking, and baseline BMD

4

The Netherlands

Unclear

 

7/60 (12%)

 

 

Public

 

 

Serum 25(OH)D was not a significant determinant of FN BMD at baseline, during winter (p=0.23) or over the entire study period.

 

 

100% female

 

 

 

IG1: 71 y

IG2: 72 y

CG: 71 y

2 y

End of study mean (SE): pooled: 67.8 (3.5)

 

 

 

 

 

CPBA

 

 

 

 

Caucasian

 

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Attrition

Mean age (SD)

Ethnicity

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Prospective Cohorts

Bischoff-Ferrari (2005)132

327 Individuals with knee OA

1 - 2 y

25(OH)D^

69.5 (30.5) nmol/L

BMD FN (DXA Lunar DPX-L)

Adjusted for age, sex, BMI, knee pain, physical activity, cohort and disease severity.

 

64% female

 

 

U.S.

 

 

% with values< 37.5 nmol/L: 15%

% with values 40-80 nmol/L: 51%

% with values > 80 nmol/L: 34%

 

 

 

228 complete data

 

 

Significant positive association between 25(OH)D and BMD independent of age, sex, BMI, knee pain, physical activity, and disease severity.

Public

 

 

 

 

74.4 (11.1) y

Females: 76.6 (9.9) y

Men: 70.6 (12.1)

 

 

 

 

 

 

Significant trend between being in a higher serum 25(OH)D group and having higher BMD (p<0.04)

 

NR

 

RIA

 

del Puente (2002)129

139 Active, non-institutionalized females (109 menopausal and 30 pre-menopausal)

2 y

25(OH)D^

Age 45-49 y: 57.7 (14.7)

Age 50-59 y -59.2 (19.2)

Age 60-69 y: 54.2 (16.7)

Age 70-79 y: 54.5 (19)

BMD LS and FN (DXA)

Adjusted for age, menopausal status, current smoking status and BMI.

Italy

 

 

 

25(OH)D independent predictor of BMD change at FN and LS (FN ∆ BMD (beta 0.26 0.13), p=0.04 and LS ∆ BMD (beta 0.07 0.03), p=0.04).

 

124 at followup

15/139 (11%) did complete

 

 

Public

 

 

 

 

 

 

<37.5 nmol/L: 17.3%; (range 9.1 to 27.5% across age groups).

 

 

100% female

 

 

 

 

 

 

 

In stepwise analysis discrimination models only FN significant (partial R2=0.26, p=0.04).

 

58 (9) y

 

 

 

 

 

 

CPBA

 

 

 

Caucasian

 

 

 

 

Dennison (1999)127

316 Healthy adults age 60-75 y

4 y

NR

BMD: LS and proximal femur (DXA)

Adjusted for adiposity

 

All 316 included in analysis

 

CPBA

No association between baseline 25(OH)D and BMD at LS and proximal hip beta=0.002 spine, 0.001 hip) and no association between 25(OH)D and bone loss after adjustment for adiposity.

U.K.

 

 

 

45% female

 

 

 

Public

 

 

 

 

 

 

Women: 65.6 (2.8) y

Men: 66.1 (3.2) y

 

 

 

 

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Gerdhem (2005)131

1,044 Ambulatory independently living women

3 y

25(OH)D^

95 (30)

BMD: FN and LS (DXA)

NR

 

 

 

 

No association between baseline 25(OH)D and BMD.

Sweden

58/1044 (6%) did not complete

 

% with values < 50 nmol/L: 4.4%

% with values < 75 nmol/L: 26%

 

 

Public

100% female

 

 

See other tables for other outcomes

 

75 (75-75.9) y

 

 

 

 

 

 

 

CPBA

 

 

 

NR

 

 

 

 

Melin (2001)126

64 Healthy, independent elderly individuals

1 y

25(OH)D^

BMD: FN (DXA)

Adjusted for BMI

Sweden

 

 

Outdoor exposure ≥ 3 h/wk (N=49); males: 67.5 (15) females: 60 (27.5) nmol/L.

Indoor exposure < 3 h/wk females (N=14): 40 (12.5)

% with values < 77.5 nmol/L: 78%

 

FN BMD associated with serum 25(OH)D after summer (r=0.38, p=0.003) and winter (r=0.37, p=0.003). After adjusting for BMI, 25(OH)D remained a significant determinant after winter (adjusted R2=0.14, p=0.005).

 

All 64 included in analysis

 

 

Public

 

 

 

 

81% female

 

 

 

83.7 y

 

 

 

Caucasian

 

 

 

 

 

 

RIA

 

 

Rosen (1994)135

18 Healthy independently living elderly women

2 y

25(OH)D^

Baseline: 72.5 (6.7)

BMD LS and FN (DXA)

NR

 

 

 

 

 

∆ 25(OH)D between summer and winter was associated with LS BMD in 2nd y (r=0.59, p=0.04) but not FN BMD.

U.S.

3/18 (17%)

 

6 mo: 63 (3)

12 mo: 88 (7.8)

18 mo: 70.9 (8.5)

 

Public

100% female

 

 

 

 

77 (2) y

 

CPBA

 

 

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Attrition

Gender

Mean age (SD)

Ethnicity

Duration

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Stone (1998)128

261 Healthy elderly females > 65 y random sample -subcohort of individuals not on HRT from Study of Osteoporotic Fractures

42 - 71 mo

25(OH)D^

65.5 (24.5)

BMD TH (DXA) calcaneal (SPA)

Adjusted for age, weight, clinic site, current use of Ca supplements, multivitamins containing vitamin D, physical activity, smoking status and season. Controlled for levels of other hormones.

U.S.

 

 

 

 

RIA

Public

 

 

 

 

30/261 (11%) without calcaneal BMD; 43/261 (16%) without hip BMD

 

 

 

Significant association between lower 25(OH)D levels and TH BMD loss. Lower 25(OH)D levels associated with increased loss at TH after adjusting for estradiol, testosterone, and SHBG, season, and use of supplements.

 

100% female

 

 

 

 

71.3 (4.8) y

 

 

 

 

 

 

 

 

25(OH)D not associated with calcaneal BMD after adjusting for age and weight.

 

Caucasian

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Case-control studies

Al-Oanzi (2006)152

56 Men with idiopathic osteoporosis 114 male ctrls

NR

25(OH)D3

Cases: 44.7 (21)

Ctrls: 43.3 (17)

BMD diagnosis of osteoporosis based on T-score FN and LS

NR

 

 

No significant difference between plasma 25(OH)D in cases and ctrls, but mean free plasma 25(OH)D was about 33% lower in men with OP vs. ctrls (p<0.0001).

U.K.

 

 

 

 

 

100% male

 

RIA

 

Public

 

 

 

 

 

Cases: 59.6 (13.6) y

Ctrls: 62.4 (10.4) y

 

 

 

 

 

Caucasion

 

 

 

 

Boonen (1999)139

100 Postmenopausal women 50 hip fracture patients, 50 ctrls

Age, PM status, sampled at same time of year

25(OH)D^

BMD FN and Tr (DXA) Fractures

Adjusted for age

 

Cases 29.25 (26.5)

Ctrls: 68.75 (39)

 

Mean 25(OH)D3 was lower in cases vs. ctrls (p<0.001).

Vitamin D deficiency (< 30 nmol/L): 64% of cases vs. 8% ctrls within the same 4 mo sampling period (no relation b/w 25(OH)D and mo of sample collection). FN and Tr BMD were significantly lower in cases than ctrls. No significant relation found b/w the 25(OH)D3-PTH axis and BMD in cases and ctrls. In multiple regression of pooled data, models using 25(OH)D3 and PTH were highly predictive of FN BMD (R2=32%, p < 0.001).

Belgium

 

 

 

 

 

 

 

Public

100% female

 

% with values < 30 nmol/L

cases: 64%

ctrls: 8%

 

 

Cases: 74.2 (7.8) y

Ctrls: 75.8 (5.6) y

 

 

 

NR

 

CPBA

 

 

 

 

 

 

Landin-Wilhelmsen (1999)140

128 PM osteoporotic pts, 227 age matched ctrls from outpatient clinic

Age, gender, PM status

25(OH)D3:

Cases: 88 (30)

Ctrls: 96 (32)

BMD and BMC: LS, TB and FN (DXA)

NR

 

25(OH)D significantly lower in OP pts vs. ctrls (p<0.05).

 

 

RIA

Fractures

 

Sweden

 

 

 

 

 

 

100% female

 

 

 

OP pts had lower body weight and BMI vs. ctrls (p<0.001).

Public

 

 

 

 

 

 

Cases 59 (6) y

Ctrls 59 (5) y

 

 

 

 

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Villareal (1991)143

98 Ambulatory, independently living PM women 49 women with low (<38 nmol/L) 25(OH)D and 49 Ctrls.

Age, gender, PM status, ethnicity, season, independence status, geographical location

Cases: 23 (7)

Ctrls: 58.9 (19)

BMD (LS, T12-L3) QCT

NR

 

 

 

Women with low 25(OH)D levels had a reduced LS BMD. In the low 25(OH)D group, LS BMD correlated with 25(OH)D (r=0.41, p < 0.01).

U.S. (Mid West)

CPBA

iPTH (RIA)

NR

 

 

In multivariate analysis, iPTH was the major determinant of a decrease in LS BMD.

 

100% female

 

 

 

 

 

Cases: 64 y

Ctrls: 63 y

 

 

 

 

 

Caucasion

 

 

 

 

Thiebaud (1997)141

179 Hip fracture patients (136 women and 43 men) 180 hospital ctrls (136 women and 44 men) 55 community ctrls (47 women and 8 men)

Age, setting (for cases and one control group)

25(OH)D^

Fracture cases:

women 25.5 (20.5)

men 17.25(18.5)

Hospital ctrls:

women 31.5 (26.5)

men 27.75 (21.5)

Community ctrls:

women 53(23)

men 31.5 (22.8)

BMD FN, TH and Tr DXA)

Adjusted for age, sex, and creatinine 25(OH)D levels generally low especially in hospital ctrls and hip fracture cases.

Switzerland

Fractures

 

 

 

 

Women and men with hip fractures significantly lower 25(OH)D levels vs. ctrls. Fracture patients had lower hip BMD vs.ctrls (p < 0.001).

Public

 

 

 

 

 

 

Significant biochemical markers in the multivariate logistic regression model of the risk for hip fracture were serum albumin and PTH.

 

% female

hip fracture cases: 76%

hospital ctrls: 76%

community ctrls: 85%

 

 

 

 

 

 

RIA

 

 

 

 

 

 

 

In women FN, Tr BMD weakly correlated with 25(OH)D and the only significant association was at the Tr (r=0.13, p < 0.05).

 

Cases: 81.0 y (women) and 77.7 y (men); Hospital ctrls: 80.9 y (women) and 76.9 y (men); Community ctrls: 71.7 y (women) and 71.3 y (men)

 

 

 

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country

Funding

Population, N

Gender

Mean age (SD)

Ethnicity

Matching Variables

Serum 25(OH)D

Mean (SD) nmol/L

Assay

Bone Health Outcomes

Covariates

Summary of Results

Yan (2003)136

352 Older individuals (60-83 y)

Age, ethnicity

Chinese men 27.1 (11.5), women 30.9 (13.5); and British men: 36.6 (12.1), women 34.7 (13.7)

BMC: FN (DXA)

Adjusted for bone area, weight, height, age and sex

China 42° N and U.K. 52 °N

 

 

 

 

% female

Chinese: 50.5%

British: 50%

 

 

Significantly higher 25(OH)D levels in British subjects. Weak association (r=0.054, p=0.05) b/w 25(OH)D and FN BMC in British subjects after adjusting for size but not in Chinese subjects.

Public

 

 

 

Chinese:

male 67.9 (3.6) y

female 65.2 (3.7) y

 

% with values <25 nmol/L: Chinese: men 53%, women 39%; British: men 20.9%; women 28.4%.

 

 

British:

male 69.1 (6.1) y

female 68.2 (6.5) y

 

 

 

 

 

 

RIA

 

 

 

64% Chinese (Asian), 36% British (Caucasion)

 

 

 

 

^ total 25(OH)D or either isoform of 25(OH)D (isoform not specified);

∆, change in; b/w, between; ctrls, controls; AC, allocation concealment; DXA, dual-energy X-ray absorptiometry; FN, femoral neck; IA, immunoassay; NR, not reported; OA, osteoarthritis; OP, osteoporosis; N, north; PTH, parathyroid hormone; QCT, quantitative computed tomorgraphy; RIA, radioimmunoassay; S, south; TH, total hip; Tr, trochanter; vit, vitamin; y, year;

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Question 2. How Does Dietary Intake of Vitamin D, Sun Exposure, and/or Vitamin D Supplementation Affect Serum 25(OH)D Concentrations?

For each vitamin D source (dietary intake from fortified foods, vitamin D supplementation or sun exposure), our objectives were to determine the effect on circulating levels of 25(OH)D and to determine whether the effect is altered by specified individual or environmental characteristics.

Question 2A. Does Dietary Intake from Foods Fortified with Vitamin D Affect Concentrations of Circulating 25(OH)D?

Overview of Relevant RCTs

When evaluating the effect of food fortification on circulating 25(OH)D concentrations, it is important to acknowledge the potential confounding effect generated by the food source, the assay used to measure 25(OH)D and potential differences in the bioavailability and/or metabolism of vitamin D2 versus vitamin D3. Most studies in this review used dairy products as the source of fortified food. There is potential for study contamination through altered intake of other nutrients such as calcium, phosphate and acid load that can affect bone and mineral homeostasis.

Study characteristics. A total of 13 RCTs, 12 parallel design,116,155-165 and one factorial design,166 studied the effect of dietary sources of vitamin D on circulating 25(OH)D concentrations. Two of the 13 trials did not provide the vitamin D content of the dietary source and were excluded.116,162 Therefore, the following summary includes a total of 11 trials (Table 9).155-161,163-166

Within the included trials, there were a total of 697 subjects in the vitamin D dietary intervention groups and 584 in the control groups for a total of 1,281 subjects.155-161,163-166


Population characteristics. All trials were in adults. Two trials studied young adults,158,160 one included young women,164 three involved postmenopausal women,155,157,159 one included elderly men,163 and the remaining four studied elderly individuals of both genders.156,161,165,166 Four out of the six trials that included both males and females provided the gender breakdown156,158,165,166 and the percentage of females ranged from 51165 to 83158 percent. The ethnicity of the study population was reported in four trials,155,157,159,163 and BMI was also reported in four trials.155,163,164,166 The vitamin D dietary intake was evaluated at baseline in three trials161,164,166 and sunlight exposure was assessed in three studies.156,158,166 The studies did not provide an assessment of skin type of participants. Sunlight exposure was assessed in only three of the 11 trials although several others excluded subjects who had recent or planned exposure to higher-than-usual levels of sunshine. Methods of ascertainment included a sunlight exposure score during the summer in a subsample,158 the percentage of participants who were outside daily during sunny period and the percentage who avoided sunlight166 and an outdoor score to reflect the average exposure to sunlight per day per season.156 Results showed that sunlight

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

exposure did not predict post therapy serum 25(OH)D in the total sub-sample,158 that there was no significant difference in sunlight exposure between groups at baseline166 or during the study.156 Participants were community-dwelling in all of the included trials.155-161,163-166

Interventions and comparators. The vitamin D dietary interventions included fortified milk,155-159,163 nutrient dense fruit and dairy based products,166 high vitamin D diet,165 fortified orange juice,160 fortified cheese,161 and fortified bread.164 The RCT with a factorial design had two other intervention groups that included an exercise program and a combined program of exercise and nutrient dense products.166


The type of vitamin D administered within the described vitamin D dietary interventions was vitamin D3 in eight trials,155,157-161,163,164 and was not specified in three.156,165,166 The vitamin D content was 200 - 1,000 IU. Seven trials also specified the calcium content within the dietary intervention.155-160,163


The comparators within the included trials were as follows: usual diet or no intervention,155,157,163,165,166 unfortified liquid milk,156,158 fortified milk with a lower dose of calcium but same dose of vitamin D compared to intervention group,159 unfortified orange juice,160 unfortified cheese or no cheese,161 and regular wheat bread or regular wheat bread and a vitamin D3 supplement.164


The duration of the intervention ranged from three weeks164 to 24 months.155,157,163


Compliance was reported in four trials and was reported to be greater than 85 percent.155,156,161,163


Study quality. Six out of the 11 trials had a methodological quality score of ≥ 3/5 on the Jadad scale (Table 9).156,157,159-161,163 Ten trials reported the percent lost to followup,155-159,161,163-166 and of these, only one reported losses greater than 20 percent.166 In all trials, the description of allocation concealment was unclear.155-161,163-166


Intention-to-treat analysis. One trial carried out an intention-to-treat analysis,165 eight trials did not,155-160,163,164,166 and the type of analysis was unclear in one trial.161

Outcomes

Vitamin D status by serum 25(OH)D. Seven trials measured total 25(OH)D (i.e., D2 and D3),155,157,158,161,163,164,166 whereas four trials specifically measured 25(OH)D3 levels.156,159,160,165 Refer to Table 9 for baseline, end of study and absolute change in serum 25(OH)D levels in addition to other measurement details.


Harms. None of the studies reported adverse side effects related to the consumption of the dietary intervention under investigation.155-161,163-166

Study Selection for Meta-Analysis

Meta-analysis was conducted to quantify the effects of dietary sources with vitamin D with/without calcium versus placebo or calcium on serum 25(OH)D levels. Seven of the 11 included trials that reported (or provided sufficient data to calculate) the absolute change in total 25(OH)D or 25(OH)D3 concentrations were included in the meta-analysis.155,156,158,160,164-166 The

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

other four RCTs were excluded due to insufficient data required to calculate the change in 25(OH)D levels,157,163 between group differences in baseline 25(OH)D levels,161 or the intervention and control groups receiving equal amounts of vitamin D.159

Quantitative Data Synthesis

Combining all seven trials that investigated the effect of food fortification or dietary sources of vitamin D (with/without calcium) versus control was not possible due to heterogeneity of the treatment effect (I2 = 79.2 percent). However, the individual weighted mean differences (WMD) demonstrated a clear trend toward a significantly higher absolute change in serum 25(OH)D in the treatment group versus control (Figure 3).155,156,158,160,164-166 Potential sources of heterogeneity are the different 25(OH)D assays used (two studies each used HPLC, RIA or CPBA, and one study did not report the assay), the dietary vehicles used, study populations, the type or dose of vitamin D (unclear in one trial165), and the outcome employed (i.e., total 25(OH)D versus 25(OH)D3).

Figure 3. Forest Plot on the Effect of Dietary Sources of Vitamin D (with/without calcium) vs. Control on Absolute Change in Total Serum 25(OH)D or 25(OH)D3.

Combined data from two trials (N = 275) that were similar in the dietary vehicle used (fortified skim milk), population studied (postmenopausal women and young adults), dose of vitamin D (400 and 480 IU daily), type of vitamin D (D3), 25(OH)D assay (RIA), and outcome (total 25(OH)D) demonstrated a significantly higher absolute change in serum 25(OH)D (WMD 15.71, 95% CI 12.89, 18.53, heterogeneity I2 = 0 percent) in the treatment group155,158 (Figure 4). Similarly, a significantly higher percent change in serum 25(OH)D was demonstrated in the treatment group (WMD 19.13, 95% CI 15.32, 22.95). However, heterogeneity of the treatment effect was high (I2 = 54.1 percent).155,158 The study by McKenna et al. demonstrated a decrease in 25(OH)D levels in both groups as a result of seasonal decline. However, food fortification reduced the degree of seasonal decline in the treatment group.158

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Figure 4. Forest Plot on the Effect of Vitamin D3Fortified Skim Milk (with calcium) vs. Control on Absolute Change in Total Serum 25(OH)D.

In an attempt to explain the heterogeneity found in the overall analysis, the following subgroups were analyzed: (1) younger versus older individuals; (2) all trials that administered 400 IU/day (the most common dose); (3) the use of total 25(OH)D versus 25(OH)D3 and (4) the type of vitamin D assay (RIA, HPLC versus CPBA). The subgroup analysis that included studies of younger individuals demonstrated a significant absolute increase in 25(OH)D levels (4 trials, N = 323, WMD 17.02, 95% CI 12.49, 21.56, heterogeneity I2 = 44.4 percent).155,158,160,164 However, combining trials within all of the other subgroup analyses was not possible as the heterogeneity of the treatment effect was high. A meta-regression to further explore heterogeneity was not carried out due to the limited number of trials with sufficient data.


Publication Bias. We were not able to evaluate the possibility of publication bias given the limited number of trials with sufficient data required to conduct such an investigation.

Qualitative Data Synthesis

Results from the four trials157,159,161,163 that were excluded from the quantitative analysis are described below.


Daly et al. (2006) explored the effect of fortified milk (800 IU vitamin D3 plus 1000 mg of calcium) versus no additional milk in older Caucasian, ambulatory men (mean age 62 years) over a two year period. Serum 25(OH)D was increased in the milk supplementation group relative to controls (27 percent, p<0.001). Baseline characteristics did not differ between groups.163


Johnson et al. (2005) investigated the effects of vitamin D fortified cheese (600 IU D3 daily) on serum 25(OH)D versus unfortified cheese or no cheese for two months in older men and women.161 Serum 25(OH)D measured at the beginning of the study demonstrated a significant difference between the fortified cheese versus control groups. Overall compliance with consumption of 85 grams of cheese per day was high (96.2 percent) with no difference between groups. Results demonstrated that, despite a significantly higher total vitamin D dietary intake in the fortified cheese versus the two control groups (unfortified cheese and no cheese groups), the end of study serum 25(OH)D decreased by a mean of 6 (SD 2) nmol/L (p<0.001) in the fortified cheese group. While not a clinically significant decrease, the authors speculated that this decrease reflected the higher baseline serum 25(OH)D in the fortified cheese group.161

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Lau et al. (2001) investigated the benefits of milk supplementation (240 IU D3 plus 800 mg Ca) in postmenopausal Chinese women over a two year period.157 At 12 months, serum 25(OH)D was higher in the milk supplementation group compared to baseline (p<0.05). Baseline and followup serum 25(OH)D for the control group, a comparison of serum 25(OH)D between the intervention and control group, and participants’ sunlight exposure and vitamin D intake were not reported.157


Palacios et al. (2005) assessed the effect of consuming milk enriched with calcium and vitamin D (1,200 mg Ca plus 228 IU D3) versus milk with lower calcium content but the same amount of vitamin D (900 mg Ca plus 228 IU D3) daily for six months in healthy postmenopausal women. Serum 25(OH)D3 increased from baseline in those women who consumed the milk enriched with calcium (which also contained phosphorus and lactose) even thought the amount of vitamin D was similar (p <0.001). The calcium enriched milk group had significantly higher serum 25(OH)D3 at the end of study than the non-enriched group (p = 0.007). These results led the authors to speculate that calcium may affect the absorption of vitamin D. However, compliance was not measured. The participants’ sunlight exposure and vitamin D intake were also not reported.159


Dose response of serum 25(OH)D to dietary interventions. The positive direction of the treatment effect of dietary interventions with foods fortified with vitamin D is consistent. Based on our synthesis of the data from the individual trials, the treatment effect may be dependent on baseline serum 25(OH)D levels (Table 10). Those trials with low baseline 25(OH)D levels (i.e., < 50 nmol/L)156,160,164-166 consistently demonstrated a greater percent increase in 25(OH)D levels at the end of study compared to trials with higher baseline 25(OH)D levels (i.e., > 50 nmol/L).155,157-159,161 Observations from such indirect comparisons need to be interpreted cautiously due to differences in baseline characteristics of the study populations, the bioavailability of the vitamin D in the various food sources and the different measures of serum 25(OH)D used.

Summary

Despite the possibility of study contamination by altered intake of other nutrients contained within the different food sources that affect bone and mineral homeostasis, food sources enriched with vitamin D in the form of milk, orange juice or other dairy and fruit based products (i.e., yogurt, custard and fruit juice) significantly improved vitamin D status in vitamin D deficient, insufficient or sufficient populations including young adults, postmenopausal women and elderly men. This was demonstrated by a significant rise in serum 25(OH)D in individuals that received vitamin D enriched dietary interventions compared to controls on an individual trial basis,155-160,163-166 and by combining trials that permitted a quantitative analysis.155,158


Increases in serum 25(OH)D from vitamin D enriched dietary interventions may depend on baseline 25(OH)D levels as well as vitamin D dose. However, this observation is based on indirect comparisons of the individual trials and should be interpreted with caution. It was not possible to determine if results vary with age, BMI and ethnicity given the limited data available and the between trial differences in terms of population characteristics, dietary interventions and measurement of serum 25(OH)D levels.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Summary. Serum 25(OH)D levels and dietary intake of vitamin D


Quantity: There were eleven RCTs (N = 1,281) of which seven (N = 668) permitted a quantitative analysis. However, due to significant heterogeneity of the treatment effect, only two trials (N = 275) could be combined.


Quality: Mean quality score (Jadad) for the 11 RCTs was 2.8/5 with scores ranging from 1 to 4 (six trials had a score ≥ 3). In all trials, the description of allocation concealment was unclear. Only one trial reported losses to followup > 20 percent.


Consistency: The majority (10/11) of individual trial results were consistent with a significant effect of dietary intake from foods fortified with vitamin D on 25(OH)D concentrations. The individual treatment effects of the seven trials ranged from 15 (95% CI 11-18) to 40 (95% CI 25-55) nmol/L (fortification consisting of 100 - 1,000 IU of vitamin D) and the combined treatment effect from the two trials (dose 400-480 IU vitamin D3) was 16 (95% CI 13-19) nmol/L.


There is good evidence that dietary intake of vitamin D increases serum concentrations of 25(OH)D.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 9. Serum 25(OH)D Levels and Fortified Foods

Author (year)

Country (latitude)

Population, N

Mean age (SD)

Ethnicity

Dietary Source

Vit D daily dose; Ca

Duration

Absolute change in mean serum

25(OH)D

(SD) (nmol/L)

Assay

Fasting sample (Y/N)

Season of sample

Jadad Score+

Chee (2003)155

173 Postmenopausal women (IG1 91, CG 82)

IG1: Skim milk powder (400 IU D3 + 1200 mg Ca)

CG: usual diet

25(OH)D^

IG 17.3 (13.3)

CG 2.8 (13.1)**

RIA

2

Malaysia (3° 7' N)

 

 

Y

 

 

59 (3) y

24 mo

 

 

 

 

 

 

 

NR

 

 

Asian (Chinese)

 

 

 

 

Daly (2006)163

149 Ambulatory men ≥ 50 y (IG1 76, CG 73)

IG1: fortified milk (800 IU D3 + 1000 mg Ca)

CG: usual diet

25(OH)D^

IG1: 5.7

CG: –15.1

RIA

3

Australia (37° 47’S)

 

 

Y

 

 

61.9 (7.7) y

24 mo

 

 

 

 

 

 

 

NR

 

 

Caucasian

 

 

 

 

de Jong (1999)166

71 Elderly individuals (IG1 37, CG 34)

2 nutrient dense vs. regular products

400 IU vit D

25(OH)D^

IG1: 35 (18)

CG: 5 (9)

CPBA

2

The Netherlands (51°58' N)

 

 

Y

 

78.8 y

4 mo

 

 

 

 

 

 

 

NR

 

 

Dutch (Caucasian)

 

 

 

 

Johnson (2005)161

110 Adults > 60 y (IG1 33, IG2 34, CG 33)

IG1: fortified cheese (600 IU D3)

IG2: unfortified cheese

CG: no cheese

25(OH)D^

IG1: −6.0 (11.49)

IG2: 3.5 (7.29)

CG: 0.75 (10.05)*

RIA

4

U.S. (45° 25′ N)

 

 

Y

 

 

NR

 

 

 

 

 

2 mo

 

Winter

 

 

NR

 

 

 

 

Keane (1998)156

42 Elderly individuals (IG1 18, CG 24)

IG1: fortified milk (200 IU vit D + 800 mg Ca)

CG: unfortified milk (4 IU vit D + 600 mg Ca)

25(OH)D3

IG1: 22.25 (10.90)

CG: 6.75 (10.92)*

CPBA

4

Ireland (53° 22' N)

 

 

NR

 

 

78.1 y (range 66-91)

12 mo

 

 

 

 

 

 

 

Late winter

 

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country (latitude)

Population, N

Mean age (SD)

Ethnicity

Dietary Source

Vit D daily dose; Ca

Duration

Absolute change in mean serum 25(OH)D (SD) (nmol/L)

Assay

Fasting sample (Y/N)

Season of sample

Jadad Score

Lau (2001)157

185 Postmenopausal women (IG1 95, CG 90)

IG1: Milk powder (240 IU D3 + 800 mg Ca)

CG: no intervention

25(OH)D^

IG1: 23.2 (13.2)**

CG: not estimable

CPBA

3

China (22°17' N)

 

NR

 

 

 

24 mo

 

 

 

 

56.9 y

IG1: 57.1 (1.78) y

CG: 56.8 (1.5) y

 

 

NR

 

 

Asian (Chinese)

 

 

 

 

McKenna (1995)158

102 Younger adults (IG1 52, CG 50)

IG1: fortified skim milk 480 IU D3 + 1525 mg Ca/L, 2L/wk)

CG: unfortified skim milk (12 IU D3 + 1270 mg Ca/L, 2L/wk)

25(OH)D^

IG1: − 15 (21.1), CG: − 31 (24.2)**

RIA

2

Ireland (53° 22' N)

 

NR

 

 

median (range) 22.6 y (17 – 54)

 

 

 

 

 

5 mo

 

Late winter (baseline) & summer (end of study)

 

 

NR

 

 

 

 

Natri (2006)164

41 Women 25-45 y (IG1 11, IG2 10, IG3 9, CG 11)

IG1: fortified wheat bread (400 IU D3)

IG2: fortified rye bread (400 IU D3)

IG3: regular wheat bread + vit D3 supplement 400 IU D3)

CG: regular wheat bread

25(OH)D^

IG1: 16.3 (21.89)

IG2: 14.9 (19.61)

IG3: 19.5 (30.3)

CG: −0.3 (13.27)*

RIA

1

Finland (60° 10' N)

Y

 

 

29.1 y

 

 

Feb – March

 

 

NR

3 wks

 

 

 

Palacios (2005)159

69 Postmenopausal women (IG1 34, CG 35)

IG1: fortified Ca-enriched skim milk (228 IU D3 + 1,200 mg Ca) (also contained phosphorus, lactose)

IG2: fortified skim milk (228 IU D3 + 900 mg Ca)

25(OH)D3

IG1: 13.9 (30.0)

CG: 0.7 (34.3)**

RIA

4

Spain (37° 8' N)

 

Y

 

 

62.7y

6 mo

 

NR

 

 

Caucasian

 

 

 

 

Panunzio (2003)165

232 Elderly individuals (IG1 98, CG 134)

IG1: diet with vit D (400 IU D)

CG: diet without vit D

25(OH)D3

IG1; 41.1 (71.6)

CG: 0.7 (28.5)**

NR

2

Southern Italy (41° 27' N)

 

Y

 

 

 

10 wks

 

 

 

 

NR; range 65-74 y

 

 

NR

 

 

NR

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country (latitude)

Population, N

Mean age (SD)

Ethnicity

Dietary Source

Vit D daily dose; Ca

Duration

Absolute change in mean serum 25(OH)D (SD) (nmol/L)

Assay

Fasting sample (Y/N)

Season of sample

Jadad Score

Tangpricha (2002)160

26 Healthy adults aged 19-60 y (IG1 14, CG 12)

IG1: fortified orange juice (1,000 IU D3 + 350 mg Ca)

CG: unfortified orange juice (350 mg Ca)

25(OH)D3

IG1: 57.0 (26.19)

CG: 22.3 (17.32)*

CPBA

4

U.S. (42°22' N)

NR

 

 

29.0 (9.0) y

 

 

Spring

 

 

 

3 mo

 

 

 

 

NR

 

 

 

 

*SEM or 95% CI converted to SD;

**Absolute change calculated from baseline and end of study data;

^ refers to total (both isoforms) 25(OH)D or isoform not specified;

+Jadad score out of 5; allocation concealment for all studies in the table was rated as “unclear”; NR, not reported

Ca, calcium; CG, control group; CPBA, competitive protein binding assay; IG, intervention group; IU, international units; mo, month(s); N, north; NR, not reported; S, south; vit, vitamin; Y, yes; y, year

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 10. Absolute and % Change in Serum 25(OH)D for the Intervention Group in Supplementation Trials (grouped by vitamin D dosages < 400 IU vs. ≥ 400 IU/d)

Author (year)

Daily Vitamin D Dose

IG Baseline 25(OH)D (nmol/L)

IG End of Study 25(OH)D (nmol/L)

Absolute (%) Change in 25(OH)D (nmol/L)

Jadad Score+

< 400 IU/d

Keane (1998)156

200 IU vit D^

24*

46.25*

22.3 (92.9)*

4

Lau (2001)157

240 IU D3

66

89.2

23.2 (35.1)

3

McKenna (1995)158

137 IU D3

77

62

−15 (−19.5)

2

Palacios (2005)159

228 IU D3

109.9*

123.9*

14 (12.7)*

4

≥ 400 IU/d

Chee (2003)155

400 IU D3

69.1

86.4

17.2 (25.0)

2

Daly (2006)163

800 IU D3

77.2

NR

NR

3

de Jong (1999)166

400 IU D^

37

72

35 (94.6)

2

Johnson (2005)161

600 IU D3

57.5

52.5

−5 (−8.7)

4

Natri (2006)164

400 IU D3

29

45.3

16.3 (56.2)

1

Panunzio (2003)165

400 IU D^

40.2*

81.3*

41.1 (102.2)*

2

Tangpricha (2002)160

1,000 IU D3

37*

94*

57 (154)*

4

Note:

*25(OH)D3 ;

^isoform of vitamin D not specified;

+Jadad score out of 5; allocation concealment was rated as “unclear” for all studies listed in the table; IG, intervention group; IU, international units; NR, not reported

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Question 2B. What is the Effect of UV Exposure on Circulating 25(OH)D Concentrations?

Overview of Relevant RCTs

Study characteristics. Eight randomized trials evaluated the effect of ultraviolet exposure on serum 25(OH) D concentrations.167-174


Within these eight parallel design trials, there were a total of 337 subjects with 197 subjects in the intervention group and 140 subjects in the comparator groups. Four trials evaluated the effect of natural sun exposure,168,169,171,172 and four trials evaluated the effect of artificial UV exposure167,170,173,174 on circulating 25(OH)D concentrations.


Population characteristics. There were seven trials in adult populations and one in infants.172 Three trials involved younger or middle-aged adults169,170,174 and four trials included older adults.167,168,171,173 The percentage of females ranged from 17170 to 100 percent,167 and one trial had only male participants.174 In the trial in infants, 55 percent were female.172


Body Mass Index was not reported in any of the trials. Skin type was reported in two trials: Matsuoka170 in which all individuals were skin type III (i.e., sometimes burn, always tans) and Falkenbach included skin types II (i.e., always burns, sometimes tans) and III.174 Another trial reported that skin pigmentation varied from fair to medium.168


Vitamin D intake. One trial reported daily dietary vitamin D of 3.1 nmol or 48 IU168 and another estimated dietary intake of 100 IU of vitamin D plus 1,000 mg of calcium per day.167 Dietary intake was not reported in the remaining six trials.170-175


Vitamin D deficiency. In four of the eight trials, the proportion of subjects with vitamin D deficiency at baseline (< 30 nmol/L) was reported.167-169,172 In two trials of elderly nursing home residents, 93 percent of subjects were vitamin D deficient (<30 nmol/L) in one trial,167 and 50 percent in the other trial.168 In contrast, in a trial on community-dwelling adults in Australia, only 10 percent were vitamin D deficient.169 In the infant trial,172 20 percent of infants were deficient and 11 percent were diagnosed with rickets. Baseline concentrations and type of vitamin D assay are presented in Table 11.


Interventions. In the four trials that used solar exposure,168,169,171,172 the dose was one minimal erythemal dose (MED) in one trial,168 and a geometric mean of 138 J/m2 in another trial.169 In two trials, the exact dose was not reported but described as 2 hours of sunshine per day with face and hands exposed172 or 15 versus 30 minutes with head, neck and arms exposed.171 All trials were conducted in southern latitudes, except for the infant trial.172 In the four trials that used artificial UV,167,170,173,174 the description of the dose was as follows: (1) one suberythematous dose of 27 mJ/cm2 to the whole body,170 (2) 1/2 MED at doses from 30 to 140 mJ/cm2;167 (3) high energy versus low energy UV-B to provide suberythematous doses,174 and (4) a dose of 160 mJ/cm2 per week.173


The frequency of UV exposure was a single exposure in one trial,170 one173 to three times per week,167 ten times over a 12 day period,174 and daily in four trials.168,169,171,172 The duration of the intervention varied from a single exposure,170 to 12 days in one trial,174 28 days in two

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

trials,171,172 and 12 weeks in three trials.167,168,173 Marks et al. used sunscreen as the intervention.169


Ascertainment of UV exposure. Three of the four trials that used natural sun exposure reported the method of ascertainment of UV-B exposure. Ho et al. used a sunshine diary to record minutes outdoors per day and used the average weekly UV score for September to October.172 Lovell used UV sensitive polysulphone badges and readings on a UV meter coupled to a sensor.168 Marks also used polysulphone film badges in addition to a sun exposure and clothing diary.169


Comparators. In four trials, the comparator was a placebo.169,171-173 Two trials included a comparator arm of vitamin D3 400 IU167 or two dosages of vitamin D3; 289 IU or 867 IU.168 The two remaining trials used lower energy UV-B,174 or UV-B with 50,000 IU vitamin D2 versus vitamin D2 alone as comparators.170


Compliance. Compliance was reported in only two trials.167,174 In the Chel trial167 three patients in the UV-B group did not complete the treatment and in the other trial174 one subject did not comply with treatment.


Study quality. Study quality scores on the Jadad scale ranged from 1 to 4 out of a possible 5, with all except two trials having a score of less than 3.169,171 A description of trial withdrawals was adequately reported in six of the trials.167-169,172-174 In all eight trials, the description of allocation concealment was unclear. One challenge with trials of UV exposure is the difficulty of blinding study participants to the intervention.


Type of analysis. Three trials performed an intention-to-treat analysis.170,171,174 In five trials an intention-to-treat analysis was either not performed or the type of analysis was unclear.167-170,173


Qualitative data synthesis. Quantitative synthesis of the trials of UV exposure and serum 25(OH)D was not possible due to the heterogeneous study populations, the interventions (e.g., length and area of exposure, and dose) and lack of complete data.


Outcomes. Followup serum 25(OH)D or 25(OH)D3 concentrations were evaluated in six trials167,168,171-174 (Table 11). The change in serum 25(OH)D concentrations from baseline was significant in all of the six trials.


Reid (1986) compared the effect of sun exposure in 15 Caucasian older men and women living in residential homes in New Zealand. The subjects were randomized into three groups of five each; controls who did not change their daily routine and the two intervention groups (outside daily for either 15 or 30 minutes for four weeks). Body surfaces exposed included head, neck, legs and forearms. Mean baseline serum 25(OH)D concentrations were different across groups: 35 nmol/L (15 minute group); 60 nmol/L (30 minute group), and; 60 nmol/L (control group). Serum 25(OH)D increased in both the 15 and 30 minute groups, however the increase (18.5 nmol/L) was only significant in the 30 minute group.171


Lovell (1988) studied the effect of sun exposure in Caucasian elderly nursing home residents in Australia compared to vitamin D3 (either 289 IU or 867 IU/day) over a three month period. The median increase (11.0 nmol/L) in serum 25(OH)D concentrations was significant after the second month of treatment in the UV-B group and the lower dose vitamin D group and after the first month, with 867 IU vitamin D3.168

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

In Asian breast-fed infants aged one to eight months who were not receiving supplemental vitamin D, Ho (1985) assessed the effect of two hours of sunshine per day for two months (face and hands uncovered) versus the usual amount of sunshine. Infants in the intervention group received 115 minutes of sunshine per day compared to controls who received an average of 63 minutes. There was a significant increase in serum 25(OH)D in the treatment group, but not in the infants receiving usual sunshine exposure. Serum 25(OH)D concentrations correlated with UV exposure scores, even after adjusting for age. The estimated UV score needed to maintain serum 25(OH)D at 27.5 nmol/L was 24 minutes per day with only the face uncovered.172


Marks et al. (1995) conducted a seven-month RCT in Australia of daily sunscreen use (SPF of 17) compared to placebo in 113 subjects over age 40 years. Participants were recruited from a random sample of a trial designed to evaluate the effect of regular sunscreen use in subjects with solar keratoses. Sunscreen was applied daily to the head, neck, forearms and dorsum of each hand. The mean baseline serum 25(OH)D3 was 54.2 nmol/L. When the results were stratified by age, serum 25(OH)D3 increased less in subjects over 70 years in the sunscreen group (7.4 nmol/L) versus those younger than 70 years (15.9 nmol/L) but the differences were not significant. Overall serum 25(OH)D3 concentrations increased by the same amount in the sunscreen and non-sunscreen groups with a difference of 0.99 nmol/L (95% CI −7.0, 5.0). Nine out of 11 subjects with serum 25(OH)D3 below the reference range had values within the reference range by the end of the study. The absence of a difference between groups may have been due to incomplete compliance with sunscreen use.169


In a 12 week trial, Toss (1982) studied the effect of artificial UV exposure on 42 elderly nursing home residents compared to vitamin D2 450 IU plus calcium 600 mg daily, calcium alone, or placebo. Front and back were exposed to UVR for 1 minute each, then 2 minutes and followed by ten treatments of 3 minutes each. The mean UV total dose was 160 mJ/cm2. There were significant increases in serum 25(OH)D in both the UV group (end of study 25(OH)D was 59 nmol/L) and in the vitamin D2 group (42 nmol/L), compared to no change in serum 25(OH)D in the control and calcium groups.173


Chel (1998) investigated the effect of artificial UV-B irradiation in 45 elderly females in The Netherlands. The majority of subjects were vitamin D deficient (<30 nmol/L). Subjects were randomized to receive UV-B (one-half MED) three times per week, 400 IU vitamin D3 or placebo for 12 weeks. Six areas of 4 cm2 were irradiated with UV-B doses increasing from 30 to 140 mJ/cm2, and individual doses were adjusted according to skin sensitivity as determined by the MED. After 12 weeks, the median serum 25(OH)D concentrations increased to 60 nmol/L in both the UV- B (increase of 42 nmol/L) and vitamin D3 (increase of 37 nmol/L) groups (p<0.001).167


Falkenbach (1992) evaluated the effect of artificial high energy (less emission in range of 300 nm) versus low energy, shorter wavelength UV-B in healthy young men (N=24) in Germany, during the winter. Both treatment groups were treated ten times over a 12-day period in a solarium. The initial exposure was three minutes and increased by 10 percent with each session to achieve suberythemal doses, using both ventral and dorsal irradiation. Baseline serum 25(OH)D3 concentrations were higher (115-124 nmol/L) than in other trials which may reflect younger age of subjects. Fasting serum 25(OH)D3 concentrations measured three days after the last exposure increased significantly in both groups and remained elevated for four weeks, in the

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

low energy, shorter wavelength UV-B group (Table 11). Serum PTH concentrations were significantly decreased in this group.174


Matsuoka (1992) evaluated if administration of vitamin D2 interfered with the release of vitamin D3 from the skin after exposure to UV-B light. A total of eighteen subjects were randomized to receive oral 50,000 IU vitamin D2 alone, 50,000 IU vitamin D2 followed by UV-B exposure 12 hours later or UV-B alone. UV-B was given as a single dose to the whole body at a suberythematous dose of 27 mJ/cm2. Total serum 25 (OH)D concentrations (measured by CPBA) did not increase significantly in any group. Vitamin D3 concentrations (measured by HPLC) increased significantly after UV-B treatment (increase of 27.5 nmol/L). A similar increase in vitamin D3 was observed when UV-B exposure was preceded by vitamin D2, suggesting that elevated serum vitamin D2 does not interfere with release of vitamin D3 from the skin.170

Summary. Effect of UV Exposure on 25(OH)D Concentrations


Quantity: Eight RCTs evaluated the effect of UV exposure on serum 25(OH)D concentrations. Four trials used solar exposure and four used artificial UV-B sources.


Quality: The overall quality of the trials was low, with only two of eight trials having a score of ≥ 3/5 on the Jadad scale.


Consistency: There was heterogeneity in the age and gender of subjects, dose, and duration of UV exposure that made synthesis of the results difficult. In addition, it was difficult to ascertain the exact dose.


Both artificial and solar exposure increased serum 25(OH)D concentrations in vitamin D deficient and replete subjects. Three trials in elderly nursing home populations (solar or artificial UV-B exposure) demonstrated significant increases in serum 25(OH)D concentrations.167,168,171 One trial using artificial UV-B exposure in elderly females reported an increase of 42 nmol/L in serum 25(OH)D (measured by RIA) with ½ MED exposure to the lower back, three times per week.167 These results support the belief that older individuals have adequate capacity to synthesize vitamin D3 in response to UV-B exposure, despite the decreased availability of 7-dehydrocholesterol in the skin. One trial evaluated the effect of sunscreen on serum 25(OH)D concentrations and found that the UV-B response was not suppressed by sunscreen use.169


There is fair evidence that solar and artificial UV-B exposure increase 25(OH)D levels. The included trials did not address the issue of whether serum 25(OH)D response is attenuated in heavily pigmented groups. It was also not possible, to evaluate the impact of effect modifiers such as age, ethnicity, seasonality and latitude.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 11. Effect of UV Exposure on Serum 25(OH)D Levels

Author (year)

Country (Latitude)

Season

Funding

Population, N

Mean Age (SD)

% Vit D Deficient

Ethnicity

UV Exposure Comparator

Serum 25(OH)D

Assay

Baseline (nmol/L)

Serum 25(OH)D at end of trial or Absolute change (nmol/L)

Jadad Score+

Chel (1998)167

45 elderly females in nursing home

Artificial 1/2 MED on lower back 3 x/wk 12 wks

25(OH)D^

Median

60**

↑42

2

The Netherlands (52°12' N)

 

RIA

 

85 y

 

 

 

 

 

 

 

Median (25,75th percentile)

18 (12, 25)

 

 

NR

93% had values < 30 nmol/L

60% had values < 20 nmol/L

 

 

 

Public

Vitamin D3 400 IU/d

23 (14, 28)

60**

↑37

 

 

 

Control

12 (8, 18)

NS

 

 

NR

 

 

 

 

Falkenbach (1993)174

24 healthy young men

Artificial UV-B: higher energy of total UV-B but less energy at wavelengths < 300 nm compared to other group 10x in 12d

25(OH)D3

3 d after exposure: 221.3 (64.0)*

4 wks after exposure: 236.8 (56.0)**

2

 

 

RIA

 

Germany (50°11' N)

Age range 21-37 y

 

 

 

 

115.5 (88.0)

 

 

Winter

NR

 

 

 

Public

NR

Lower energy dorsal/ventral irradiation 10x in 12d

123.8 (63.8)

3 d after exposure: 196.0 (86.0)*

4 wks after exposure: 152.5 (81.3)

 

Ho (1985)172

54 infants (breast-fed)

Sunlight 2 h × 4 wks, face and hands exposed 12 wks

25(OH)D^

100 (57.5)

↑30 (37.5) **

3

China (39° 55' N)

Mean age 4.0 (1.7) mo

CPBA

 

 

Sept-October

 

 

70 (37.5)

 

 

 

20% had values < 27.5 nmol/L

Control- usual amount of sunshine

52.5 (37.5)

45 (35), NS

 

Public

 

 

 

 

Asian

 

 

 

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country (Latitude)

Season

Funding

Population, N

Mean Age (SD)

% Vit D Deficient

Ethnicity

UV Exposure Comparator

Serum 25(OH)D

Assay

Baseline (nmol/L)

Serum 25(OH)D at end of trial or Absolute change (nmol/L)

Jadad Score+

Lovell (1988)168

38 elderly nursing home residents

Daily sun exposure to arms and legs (20, 30 and 40 min in April, May and June respectively)

3 mo

25(OH)D^

↑60.6 (26.3-102.5)*

2

Australia (27° 28' S)

 

CPBA

 

 

Age 55-95 y

 

 

 

Fall/winter

 

median (range)

32.6 (18.8, 112.8)

 

 

 

50% had values < 25 nmol/L

 

 

NR

 

vitamin D3 289 IU/d

18.3 (10.8, 71.3)

47.3 (12-87.8)

 

 

Caucasian

vitamin D3 867 IU/d

41.1(15.5, 57.8)

↑24.9*

 

 

 

Control

18.9 (7.8, 77.3)

NS

 

Marks (1995)169

113 community-dwelling adults

Sunlight + sunscreen (SPF17) applied daily to hands, arms, head and neck, 7 mo

25(OH)D^

↑11.8

4

Australia (37° 03' S)

 

CPBA

 

 

Age > 40 y

 

 

 

Spring/summer

 

56.6 (95%CI 52-61.2)

 

 

 

10% had values < 30 nmol/L

 

 

 

Public

 

 

 

 

 

 

 

Sunlight + placebo mean daily UV 137.9 vs. 138.7 J/m2

51.6 (95% CI 47-56.2)

↑12.8

 

 

NR

 

 

Matsouka (1992)170

18 medical students

UV-B suberythemal dose 27mJ/cm2 x1, total body

3 d

Total and 25(OH)D3

mean (SEM)

25(OH)D3 35 (12.5)

↑ 27.5

Total 25 (OH)D: no change

1

USA (39° 53' N)

NR

HPLC CPBA

 

Winter

NR

 

mean (SEM)

25(OH)D3 – 12.5 (2.5)

 

 

NR

Caucasion

 

 

 

 

 

vit D2 50,000 IU + UV-B same dose as above

7.5 (2.5)

25(OH)D3 35 (12.5)

↑27.5

25(OH)D no change

 

 

 

50,000 IU D2

NR

25(OH)D3 no change

25(OH)D no change

 

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author (year)

Country (Latitude)

Season

Funding

Population, N

Mean Age (SD)

% Vit D Deficient

Ethnicity

UV Exposure Comparator

Serum 25(OH)D

Assay

Baseline (nmol/L)

Serum 25(OH)D at end of trial or Absolute change (nmol/L)

Jadad Score+

Reid (1986)171

15 elderly nursing home residents

Sunlight 15 min/day

Head, neck, forearms, lower legs exposed

4 wks

25(OH)D^

↑7 (2.8)

1

New Zealand (37° S )

 

CPBA

 

 

80 y

 

 

 

Spring

 

mean (SEM)

35 (5)

 

 

 

NR

 

 

 

Public

 

Sunlight 30 min/day

60 (12.5)

↑18.5 (3)*

 

 

Caucasian

Control

60 (15)

↑5 (2.8)

 

Toss (1982)173

42 elderly nursing home residents

Artificial UVR (270-400 nm) once a week for 12 wks, mean dose 160 mJ/cm2 (ventral/dorsal)

25(OH)D^

~59

1

 

 

 

 

 

Sweden (57° 43' N)

 

CPBA

 

 

85 y

 

 

 

 

 

~27 (from graph)

 

 

NR

NR

 

 

 

 

 

 

Vit D2 150 IU +Ca 600 mg 3X/wk for 12 wks

~20

~42

 

 

NR

 

 

 

 

 

Ca 600 mg

~24

NS

 

Note:

*significant change from baseline within IG;

** significant between groups and within group;

+ Jadad score out of a total of 5; allocation concealment for all studies listed in the table was rated as “unclear” CPBA, competitive protein binding assay; d, day; MED, minimal erythemal dose; min, minutes; mJ, millijoules; mo, month(s); N, north; NR, not reported; NS, not significant; RIA, radioimmunoassay; S, south; SEM, standard error of the mean; UV-B, ultraviolet-B; UVR, ultraviolet radiation; wkly, weekly; wks, weeks; y, year

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Question 2C. What Is the Effect of Vitamin D Supplementation on Circulating 25(OH)D?

Overview of Relevant RCTs

Study characteristics. A total of 74 RCTs in 81 published reports evaluated the effect of vitamin D supplementation on circulating 25(OH)D concentrations.60,61,90-93,102,105,112-115,117-121,167,168,176-185,185-236 Within the trials, five had the following companion publications: Greer93 had one companion193; Grados191 had two companion papers190,237; Dawson-Hughes184 had one companion185; Schaafsma121 has one companion221; and Sorva224 had two companion papers.225,226 For each trial in this section we refer to the primary publication (Table 12).


Sixty-nine studies were parallel design randomized trials.60,61,90-93,102,105,112-115,117-121,167,168,176-184,186-190,192,194-197,199-207,209-215,217-220,222,224,227,229-236 Four were crossover trials,198,216,223,228 and one a factorial trial.208


Baseline BMI was reported in nineteen trials and ranged from 24.8199 to 32.8 kg/m2.196


Study quality. Five trials112,115,203,210,238 received a rating of 5/5 on the Jadad scale, 13 trials received a rating of 4/592,113,119-121,178,184,190,192,206,219,223,228 and 17 trials were rated 3/5.102,114,117,177,180,183,193,197-200,215,216,218,222,229,231 Thirty-nine trials received a Jadad score of 2/5.60,61,90,91,93,118,167,168,176,179,181,182,186-189,194-196,201,202,204,205,207,209,211-214,217,220,224,227,230,232-236 These ratings indicate that more than half of the studies were of lower quality (Table 12).


Interventions. Vitamin D3 alone was the intervention in 29 trials.60,61,105,113,119,167,168,186-189,194,195,198,200,203,206,208-210,216,223,230-236


Twenty-six trials used vitamin D3 combined with calcium as the intervention.113,114,117,118,121,177,178,180,181,183,184,187,190,192,197,199,200,202,207,213,215,218,219,222,224,228


Fifteen trials used vitamin D2 alone as the intervention.90-93,102,112,115,120,176,179,196,211,212,214,227 and the type of vitamin D was not stated in four trials.168,204,217,220


Three trials had separate vitamin D2 and vitamin D3 arms.61,229,230


Qualitative data synthesis. Baseline serum 25(OH) D concentrations were reported in 61 trials.60,102,105,112-115,117,119-121,167,168,177-181,184,187-190,192,194-210,212,214-220,222-224,227-230,232-236

Twenty-one trials examined the efficacy of vitamin D supplements in vitamin D deficient populations (mean serum 25(OH)D ≤ 30 nmol/L),112,114,119,167,179,180,189,190,197,199,207,209,210,214,218,220,222,224,227,235,236 and three other trials had a subgroup of patients who were vitamin D deficient (≤ 30 nmol/L).90,91,202

Vitamin D assay. The majority of trials (N = 42) used a competitive binding protein assay to measure serum 25 (OH)D concentrations.60,91,93,102,105,112,113,118,119,121,168,176,178-184,190,194-196,198-200,202,204-207,209-211,214,215,220,224,227,232,235,236


Twenty-nine trials used an immunoassay method.61,90,114,115,117,120,167,177,186-189,192,197,201,203,208,212,213,216-218,222,223,228,230,231,233,234 and three trials used HPLC.92,219,229 No trials reported using liquid chromatography-tandem mass spectrometry to measure serum 25(OH)D concentrations.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

The qualitative results are presented by age group and additional details are presented in Table 12. For the vitamin D3 (+/- calcium) versus placebo or calcium trials that provided adequate data, the results of quantitative synthesis are presented after the qualitative section. We did not conduct quantitative analyses of vitamin D2 versus placebo due to the smaller number of trials, heterogeneity of trials and lack of adequate data.

Infants

Seven trials included term infants.90-93,182,217,236 Only two trials had a quality score of ≥ 3.92,93 Sample sizes ranged from 30 to 312 and six out of the eight trials were published prior to 1995.


Intervention. Vitamin D2 was used in four trials90-93 vitamin D3 in another236 and the isoform was not stated in three trials.182,217,220 In most trials, infants received daily doses ≤ 400 IU of vitamin D2.90,92,93,182 Zeghoud (1994) administered either 200,000 IU or 100,000 IU vitamin D3,236 and Zeghoud (1997) administered 500 IU versus 1,000 IU daily.91


Vitamin D status. Baseline serum 25(OH)D concentrations were not reported in all trials. In one trial in France, all subjects were vitamin D deficient236 and in another trial by Zeghoud 63 percent had levels <30 nmol/L.91 In another trial the mean cord serum 25(OH)D concentrations were < 27.5 nmol/L in 95 percent of infants90 (Table 12). Serum 25()H)D assays included CPBA in four trials, immunoassay in two and HPLC in one trial.


Zeghoud et al. (1994) randomized 30 healthy formula-fed neonates to receive either 200,000 IU of vitamin D once at birth or 100,000 IU at birth, 3 and 6 months. Mean (SD) serum 25(OH)D concentrations increased to 150 (55) nmol/L with 200,000 IU and to 92 (42) with 100,000 IU, 15 days post dose. In the 100,000 IU treatment arm, the mean (SD) 25(OH)D concentrations 3 months after each dose were 43.7 (24.7), 52.2 (29.2), and 67.5 (30) nmol/L.236

In another trial, Zeghoud (1997) randomized 80 healthy full term neonates to receive either 500 or 1000 IU of vitamin D2/day from birth to three months of age. At birth, 63.7 percent of neonates had serum 25(OH)D concentrations ≤ 30 nmol/L (mean 17.9, SD 7.8), the majority born to mothers who had not received vitamin D supplement. Twenty-seven percent of the mothers had received an oral dose of 100,000 IU vitamin D2 in the sixth to seventh month of pregnancy. Neonates were grouped by 25(OH)D concentration; group 1 (N = 14) had a total vitamin D (both D2 and D3 measured) concentration ≤ 30 nmol/L and elevated serum PTH (> 6.4 pmol/L); group 2 (N = 36) had low 25(OH)D concentrations (mean 22.7 (6.5) nmol/L) without PTH elevation and group 3 (N = 29) had serum 25(OH)D concentrations > 30 nmol/L. One month after beginning the 1,000 IU dose of vitamin D, mean 25(OH)D concentrations ranged from 65 to 70 nmol/L and PTH concentrations were similar amongst the three groups. In the 500 IU arm, mean 25(OH)D concentrations increased and ranged from 58 to 63 nmol/L. However, the levels attained by the vitamin D deficient group were significantly lower than the other groups and serum PTH concentrations remained elevated in 14.3 percent of infants in this group. These results suggest that neonates with vitamin D deficiency may respond differently and require higher doses of supplemental vitamin D.91 This trial had a 35 percent loss to followup. Specker et al. in a trial of 312 term infants from two northern and southern cities in China evaluated three dosages of vitamin D (100, 200 or 400 IU vitamin D2/day for six months) for the prevention of rickets. Mean cord serum vitamin D concentrations at baseline were lower in northern infants than those in the south (12.5 versus 45 nmol/L, samples drawn in the fall). At 6 months, serum 25(OH)D concentrations increased in a dose response manner in the

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

northern children (30, 38 and 63 nmol/L respectively). However, some infants in the 100 and 200 IU dose arms, remained vitamin D deficient, suggesting that these doses may be inadequate for infants residing in northern latitudes.90


Greer et al. randomized 18 term exclusively breast-fed infants to either 400 IU of vitamin D2 or placebo. After 12 weeks, the mean serum 25(OH)D concentration was 95 nmol/L in vitamin D supplemented compared to 50 nmol/L in controls (p<0.01).93 Similar concentrations of 25(OH)D were seen at the end of 6 months (93 (30) versus 58.8 (25) nmol/L) in another trial by Greer conducted in Caucasian, breast-fed infants with the same dose of vitamin D2.92


In Turkey, Pehlivan randomized 40 breast-fed infants to 400 or 800 IU of vitamin D (isoform not stated). Ninety-five percent of the mothers had 25(OH) D levels below 40 nmol/L, due to lack of sun exposure (mean 25(OH)D level 17.5), and 80 percent had levels <25 nmol/L. The mean serum 25(OH)D was 83.7 (SD 53.7) and 24 percent of the infants had baseline serum 25(OH)D levels below 40 nmol/L. Followup mean (SD) serum 25(OH)D at 16 weeks was 76.9 (35.4) and 91.8 (61.5) nmol/L for the 400 IU and 800 IU groups respectively, and 79.5 percent of infants had 25(OH)D levels within the normal range.217


Chan (1982) randomized 91 term infants into one of three groups, 1) breast-fed alone, 2) breast-fed with 400 IU vitamin D and 3) fed with Similac containing 400 IU/L of vitamin D. Lactating mothers were supplemented with 400 IU vitamin D. After 6 months, mean serum 25(OH)D (SD) levels in the three groups were 47.5 (23.4), 57.5 (40.5), and 45.0(31.6) nmol/L, respectively. There were no significant differences in 25(OH)D between nursing mothers who were supplemented and those who were not.182

Summary. Vitamin D supplementation on 25 (OH)D levels in Infants


Quantity: Seven trials included infants and few trials used vitamin D3.


Quality: Most trials were of lower methodological quality.


Consistency: One trial suggested that 200 IU of vitamin D2 may not be enough to prevent vitamin D deficiency, in some infants residing at northern latitudes. A dose-response was noted in this same 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.

Pregnant Women and Lactating Mothers

There were six trials of vitamin D supplementation in pregnant or lactating women.176,179,186,201,211,220 All trials scored either 1/5 or 2/5 on the Jadad scale. Sample sizes ranged from 40 to 126 women.


Intervention. Three trials administered 1,000 IU vitamin D2 daily176,179,211 and the remaining trials used vitamin D3. Dosages ranged from 400 to 1,000 IU.


Vitamin D status. Assays for circulating 25(OH)D were CPBA in four trials and RIA in two. Brooke included women who were vitamin D deficient, with a mean serum 25(OH)D

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

concentration of 20 nmol/L179 and the mean serum 25(OH)D at baseline was < 30 nmol/L in another trial.220


Brooke compared 1,000 IU vitamin D2 versus placebo given at 28 weeks to 126 Asian women who were vitamin D deficient and reported large increases in both serum and cord blood with 25(OH)D levels of 168 (increase of 148) versus 16.2 nmol/L in the controls (Table 12). This dose also improved neonatal serum calcium (five infants in the control group had symptomatic hypocalcemia versus none in the vitamin D group). The serum 25(OH)D values in this trial were not, however, replicated in other trials and may be related to the fact that an older CPBA assay was used.


Rothberg et al. randomized nursing mothers to 500 IU or 1,000 IU vitamin D daily (isoform not stated) versus placebo for six weeks post delivery. By day four, serum 25(OH)D (mean, SD) levels in the mothers were 34 (13.5), 36.8 (12.3) and 25(13.8) nmol/L respectively. These mean concentrations were lower than in the other trials and could be due to the fact that the mothers did not receive vitamin D fortified milk or D supplemented diets. By six weeks, the mean 25 (OH)D concentrations were significantly lower in the unsupplemented mothers (26.5 nmol/L) than in supplemented mothers (35 nmol/L). Maternal serum 25(OH)D concentrations correlated directly with infant serum 25(OH)D values.220


In a trial of 77 women conducted in winter, Mallet compared 1,000 IU vitamin D2 to a single dose of 200,000 IU vitamin D2 given in the last trimester versus placebo.211 Mallet reported mean maternal plasma concentrations of 25.3 nmol/L with 1,000 IU, 26.3 nmol/L with 200,000 IU dose compared to 9.4 nmol/L in the controls, levels that were lower than those achieved in the Brooke trial. Cord blood levels increased, but were lower than serum concentrations.


Delvin administered 1,000 IU vitamin D3 to mothers during the last six months of pregnancy compared to no supplement and reported that mean serum 25(OH)D increased significantly to 55 nmol/L versus 27.5 in controls (cord serum 25(OH)D: 45 and 17.5 respectively). Serum 25(OH)D concentrations in infants at 4 days of age were 32.5 (2.5) in the supplemented and 12.5 (2.5) nmol/L in controls.


In a small trial of 18 lactating women, Hollis administered 2,000 IU (1600 IU vitamin D2 and 400 IU vitamin D3 prenatal) versus 4,000 IU vitamin D (1,600 IU D2 and 400 IU D3 prenatal) for 3 months. The serum 25(OH)D concentrations increased by 36.1 nmol/L in the 1,600 IU group (to 90.3 nmol/L) and 44.5 nmol/L with 3,600 IU group (111.3 nmol/L).201 In this trial, serum 25(OH)D levels ranged from 69.5 to 77 nmol/L with 1,600 and 3,600 IU vitamin D2, respectively.


The mean value of 25(OH)D achieved in the treated groups was less than 45 nmol/L in all studies except one in which serum 25(OH)D in mothers at delivery was 168 ± 12.5 nmol/L.179


In a 20 week trial of 100 breast-fed infants in Finland, Ala-Houhala (1985) compared three supplementation protocols in healthy term infant- mother pairs: 1,000 IU or 400 IU of vitamin D2 given to the infants, or 1,000 IU daily provided to the lactating mothers. The mean serum 25(OH)D concentration in the infants receiving 1000 IU increased to 57.5 (28) nmol/L compared to 45 (21) nmol/L with 400 IU vitamin D2. Infants who did not receive supplementation but whose mothers received 1000 IU vitamin D2 during lactation had a mean serum 25(OH)D serum concentration of only 14 (9.4) nmol/L.176 Therefore, supplementing lactating mothers with 1,000 IU during winter months did not increase serum 25(OH)D concentrations in the infant.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

There were no randomized trials evaluating the efficacy of 400 IU of vitamin D3 in lactating women.

Summary. Vitamin D supplementation on 25 (OH)D levels in Pregnant or Lactating Women


Quantity: There were six small trials of vitamin D supplementation in pregnant or lactating women. No randomized trials studied the effect of 400 IU vitamin D3. Three trials used 1,000 IU of vitamin D2 and one trial used 1,000 IU of vitamin D3.


Quality: All trials were of low methodological quality.


Consistency: 1,000-3,600 IU/day of vitamin D2 and 1,000 IU/d of vitamin D3 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 1,000 IU of vitamin D2 during winter months did not increase serum 25(OH)D concentrations in the infants.

Children and Adolescent Populations

Four trials examined the effect of vitamin D supplementation in children or adolescent populations. Two trials were conducted in pre-pubertal children,102,223 one included both prepubertal and post-pubertal children,105 and one was 100 percent adolescent males.194 Sample sizes ranged from 20223 to 179.105


Study quality (Jadad score) was ≥ 3/5 in three trials.102,105,223


Intervention. The intervention was vitamin D2 in one trial,102 and vitamin D3 in the other three trials.105,194,223 Doses ranged from 200 to 2,000 IU per day.


Serum 25(OH)D assays used were CPBA in three trials and RIA in one.


Ala-Houhala administered 400 IU of vitamin D2, 5-7 times per week for a year in Finnish children aged 8-10 years and reported a mean increase in serum 25(OH)D of 22 nmol/L with supplementation compared to a decrease of 2.7 in the placebo group. There was no change in PTH levels. In a crossover trial during winter, Schou et al. administered 600 IU vitamin D3 to 20 healthy children (mean age 9.8 years) and reported in the group given placebo first that the 25(OH)D concentration was 33.7 (SD 10.4) nmol/L, increasing to 50.2 (SD 14.2) nmol/L during vitamin D supplementation. There was no significant effect on PTH concentrations.


In a trial in females aged 10-17 years, 200 IU or 2,000 IU of vitamin D3 were given. The mean increases in serum 25(OH)D concentrations ranged from 8 nmol/L (end of study 43 nmol/L) with 200 IU daily, to 60 nmol/L with 2,000 IU vitamin D3 daily compared to a decrease of 5 nmol/L in controls.105


Guillemant administered 100,000 IU vitamin D3 every two months to adolescent male jockeys and reported that with low dietary calcium intakes, vitamin D3 prevented the wintertime decrease in serum 25(OH)D and rise in serum PTH. The mean increase in serum 25(OH)D was 35 nmol/L.

Suggested Citation:"Appendix C: Methods and Results from the AHRQ-Ottawa Evidence-Based Report on Effectiveness and Safety of Vitamin D in Relation to Bone Health." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×