- Click here for explanation of classification scheme.

To review and synthesize the literature in the association of the effect of Vitamin D supplementation on specific circulating 25(OH)D concentrations.

Randomized controlled trials, parallel design studies and factorial design studies regarding the effect of Vitamin D supplementation on circulating 25(OH)D serum levels. 

• Studies examining supplementation of vitamin D and serum 25(OH)D concentration that did not provide the vitamin D content of the dietary sources
• Studies that did not examine the effect of vitamin D supplementation on serum 25(OH)D levels. 

Recruitment

The following databases were searched:

• MEDLINE (1996 to the third week of June 2006)
• Embase (2002 to the 25th week of 2006)
• CINAHL (1982 to the fourth week of June 2006)
• AMED (1985 to June 2006)
• Biological Abstracts (1990 to February 2005)
• The Cochrane Central Register of Controlled Trials (CENTRAL; second quarter 2006). 

No language restrictions were applied and studies were restricted to human subjects.

Design

Studies for inclusion were limited, whenever possible, to randomized controlled trials (RCTs) to limit bias. Prospective cohorts, case-control and before-and-after studies were included due to the lack of studies addressing the association between serum 25(OH)D concentrations and bone health outcomes. 

The results of the search were assessed using a three-step process. First, bibliographic records (including title, keywords and abstract) were screened by one reviewer. Potentially relevant records were then screened independently by two reviewers using the full-text report and strict eligibility criteria. Conflicts were discussed and resolved through consensus or adjudication by a third reviewer. Relevant studies were subsequently assessed for study design and categorized by question. 

Statistical Analysis

• Meta-analysis of RCTs that assessed interventions, populations and outcomes (e.g., fractures or falls) was concluded using a random effects model, with an assessment of statistical heterogeneity
• For continuous outcomes [e.g., serum 25(OH)D concentrations and Bone Mineral Density (BMD)], the difference in means between treatment groups was used for the meta-analyses
  • The absolute change in 25(OH)D concentrations was used for quantitative pooling. A weighted average was used to calculate the 25(OH)D values for the combined treatment and placebo group. The difference in means was then calculated using the weighted averages for the two combined groups. 
• To avoid differences in the reporting of units for 25(OH)D concentrations, (i.e., nmol per L, ng per ml) all values were converted to nmol per L that was the unit used for data synthesis.

Timing of Measurements

The results of the search were assessed using a three-step process. First, bibliographic records, including title, keywords and abstract were screened by one reviewer. Potentially relevant records were then screened independently by two reviewers using the full-text report and strict eligibility criteria. Conflicts were discussed and resolved through consensus or adjudication by a third reviewer. Relevant studies were subsequently assessed for study design and categorized by question. 

Dependent Variables

Serum 25(OH)D concentrations.

Independent Variables

Vitamin D supplementation.

Control Variables

• Age
• Sunlight exposure (in some studies).

• A total of 74 RCTs in 81 published reports evaluated the effect of vitamin D supplementation on circulating 25(OH)D concentrations
• 69 studies were parallel design randomized trials
• Four were crossover trials
• One was a factorial trial
• Baseline BMI was reported in 19 trials and ranged from 24.8kg to 32.8kg per m²
• Five trials received a rating of five out of five on the Jahad scale
• 13 trials received a rating of four out of five on the Jahad scale
• 17 trials received a rating of three out of five on the Jahad scale
• 39 trials received a rating of less than or two out of five on the Jahad scale: More than half the studies were of lower quality
• Seven trials used infants
• Six trials used pregnant or lactating women: All trials were of low methodological quality.
• Four trials examined vitamin D supplementation on children and adolescents
• 10 trials included pre-menopausal women and younger men
• 44 trials were conducted on post-menopausal women and elderly men: 14 of these trials took place in institutional settings.

Findings

• Infants
  • Most trials were of low methodological quality
  • One trial suggested that 200 IU of vitamin D₂ may not be enough to prevent vitamin D deficiency in some infants in northern latitudes
  • 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
  • All trials were of low-methodological quality
  • 1,000 IU to 3,000 IU per day of Vitamin D₂ and 1,000 IUper day of vitamin D₃ resulted in significant increases in serum 25(OH)D concentration in lactating mothers and in cord blood
  • One trial found that the 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 Adolescents
  • The study quality was less than or equal to three in three trials
  • There were consistent increases in 25(OH)D concentrations ranging from eight nmol per L (200 IU), 16.5 (with 600 IU of vitamin D₃) to 60nmol per L (2,000 IU of vitamin D₃). 
• Pre-Menopausal Women and Younger Men
  • The methodological quality of eight out of 10 studies was considered to be poor
  • The trials found that vitamin D₂ and vitamin D₃ in healthy adults may have different effects on 25(OH)D concentrations
  • Vitamin D₂ appeared to have a smaller effect on serum 25(OH)D which may have been due to more rapid clearance or different metabolism than vitamin D₃
  • One trial compared 1,000 IU vitamin D₂ orally vs. injection and found a greater variability in response with the intramuscular preparation.  A dose-response effect was noted in those trials that used multiple doses of vitamin D₃. 
• Elderly Populations
  • Methodological quality was greater or equal to three in 24 trials
  • One trial found that wintertime declines in serum 25(OH)D were prevented with 500 IU daily
  • A dose response with increasing doses of vitamin D₃ was noted although there was a variability in response to similar doses across trials that may have been due to differences in serum 25(OH)D assay or baseline 25(OH)D status
  • It was difficult to comment on how these results differed by assay, since there were often other differences between trials such as the dose used.  Similarly although some trials suggested a greater response to vitamin D in populations that were vitamin D deficient at baseline compared to those who were not, this was difficult to assess due to heterogeneity of assays.

• 17 trials of vitamin D₃ provided sufficient data to conduct a quantitative analysis
• The treatment effect of oral vitamin D₃ supplementation increases with increasing doses. Combining trials by different clinical and methodological characteristics did not change the direction of this effect nor did it reduce the heterogeneity found.
• Meta-regression results demonstrated a significant association between dose and serum 25(OH)D levels (P=0.04)
• The meta-regression (exploratory only) results suggested that 100 IU of vitamin D₃ will increase the serum 25(OH)D concentrations by one to two nmol per L
• This suggests that doses of 400 IU to 800 IU daily may be inadequate to prevent vitamin D deficiency in at-risk individuals
• Vitamin D₃ doses of 700 IU daily or more significantly and consistently decreased serum concentrations of PTH in vitamin D-deficient populations
• Given limitations in measurement of 25(OH)D concentrations and the lack of standardization and calibration, it is difficult to suggest precise recommendations for adequate intakes, especially since optimal levels of serum 25(OH)D have not been defined.

Government:

HHS

There was no possibility to evaluate for population bias because there were a limited number of trials with sufficient data.