- Click here for explanation of classification scheme.

To review and synthesize the literature in the association of specific circulating 25(OH)D concentrations with bone health outcomes in children, women of reproductive age and post-menopausal women and elderly men. 

General Inclusion Criteria

• Randomized control trials (RCTs)
• Prospective cohort studies
• Case-control studies
• Before-and-after studies.

Infant and Children Inclusion Criteria

• Studies involving children from birth to 12 months (defined as infancy) and young children one to five years of age
• Participants must have been healthy and free of conditions known to affect calcium metabolism.

Older Children and Adolescent Criteria

• Children six years of age and older
• Participants must have been healthy without co-morbidities.

Pregnant and Lactating Women Criteria

Women must be pregnant or lactating.

Post-Menopausal Women and Elderly Men Criteria

• Subjects must be post-menopausal women or elderly men
• No classification of age was given.

Infants and Children Exclusion Criteria

• Presence of a co-morbidity
• Not within the age confines of the particular study.

Recruitment

The following databases were searched:

• MEDLINE (1996 to third week of June 2006)
• Embase (2002 to 25th week of 2006)
• CINAHL (1982 to 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 trial (RCTs) to limit bias. Prospective cohorts, case-control and before-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 (this was the unit used for data synthesis)
• For the pooling of BMD results, the percentage change in BMD from baseline in the treatment vs. control or placebo was used as the unit of analysis.

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

• Assessment of serum PTH
• BMC
• BMD
• Bone status, measured by DXA
• Serum 25(OH)D measurements
• Fractures
• Falls
• Performance measures.

Independent Variables

Circulating serum 25(OH)D concentration.

Control Variables

• Age
• Gender
• Diagnosis.

Infants and Young Children Data Sample

• 13 total studies
  • One RCT
  • Eight case-control
  • Four before-after.
• 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, all the children were non-white except for two subjects in the North American study
• Sample sizes ranged from nine to 123 participants, with an average of four
• Gender was mixed in 12 of the 13 studies
• All studies except for one case-control study with nine participants were outside North America.

Infant Study

• Seven total studies
  • Three RCT studies
  • Four case-control studies.
• For the RCTs, age at enrollment was within a few days of birth
• Age range was from birth to 12 months
• Participants must have been healthy and free of conditions known to affect calcium metabolism.

Older Children/Adolescents Study

• Seven total studies
  • Two RCTs
  • Three prospective cohorts
  • One case-control
  • One before-after.
• Older children age range was from eight to ten years with mixed gender
• Adolescent studies ranged in age from nine to 16 years
• All patients in the adolescent study were at least Tanner Stage Two for pubertal development with the exception of one study
• Participants involved either female, male or mixed genders
• Participants were reported as healthy without known co-morbidities in two of the four studies. 

Pregnant and Lactating Women Study

• Five total studies
  • Four case-control studies
  • One before-after study.
• Three prospective cohort studies reported on vitamin D status during pregnancy, one included assessment six weeks postpartum and one measured 25(OH)D concentrations postpartum and during lactation
• A prospective cohort study 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.

 Post-Menopausal Women and Elderly Men Study

• 41 total studies in 42 published reports
  • 10 RCT
  • 14 Prospective cohort
  • 18 case control.
• 15 studies reported on the relation between serum 25(OH)D and fractures
  • Three were single prospective cohort studies
  • 12 were case-control studies.
• Two cohorts were females only
• One cohort included both genders
• Six case-control studies included females
• One case-control included males only
• Four case-control studies included both genders
• One case-control study did not specify gender.

 

Findings

Post-Menopausal Women and Elderly Men

• Seven studies (three RCTs and four cohorts) assessed the relationship between 25(OH)D and performance-related measures
  • The overall quality of the evidence from RCTs and cohorts was fair to good
  • Two RCTs and two cohorts reported an association between 25(OH)D and performance measures
  • Two cohorts and one RCT did not find an association between 25(OH)D and performance measures.
• Five studies (one RCT, three cohorts and one case-control) evaluated the association between 25(OH)D concentration and falls
  • The RCT and three cohorts were of good quality and the case-control study was of fair quality
  • There is fair evidence of an association between lower serum 25(OH)D concentrations and an increased risk of falls in institutionalized elderly
  • PTF may be an important co-founder
  • One study suggested a specific serum 25(OH)D concentration of 39nmol per L, below which risk of fall is increased.
• 15 studies (three prospective cohorts and 12 case-controls) reported on the association between serum 25(OH)D and fractures
  • The quality of the prospective cohorts and case-controls ranged from poor to good
  • One of the three cohorts reported an inverse association between serum 25(OH)D and fractures and nine of 12 case-control studies found lower 25(OH)D concentration in cases vs. 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.

Pregnant and Lactating Women Study Findings

• Four studies (no RCTs, three cohorts, and one before-after study) assessed vitamin D status at various time points in pregnancy with vitamin D deficiency being observed in 0% to 50% of subjects
• Only one study (N=115) included maternal BMD as an outcome and there was no relation between vitamin D status and postpartum changes in BMD
  • 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
  • Two studies observed no change in vitamin D status during pregnancy, where another observed a decline in serum 25(OH)D from first to third trimester
  • There was insufficient evidence on the association between 25(OH)D and a change in bone density during pregnancy
  • 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.

Older Children and Adolescents Study Findings

• Seven Studies (two RCTs, three cohorts, one case-control, one before-after study)
  • The two RCTs each scored greater than three out five on the Jadad scale and therefore were of higher quality
  • Most observational studies were of fair quality
  • 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 and baseline BMD and change in BMD or BMC indices from the studies in older children and adolescents
  • The results from the two randomized trials of vitamin D supplementation have not confirmed a consistent benefit on BMD or BMC across site and age groups.  

Infant Study Findings

• Seven total studies
• A rise in PTH was either not observed with 25(OH)D concentrations above 27nmol to 30 nmol per L or occurred at a lesser rate than at lower values, suggesting a threshold value may exist somewhere above 27nmol per L
  • The three RCTs were of fair to high quality and the four case-controls were of fair quality.
• There is inconsistent evidence for an association between a specific concentration of serum 25(OH)D and bone health outcomes 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 27nmol per L (measured by CPBA). 

Infant and Child Study Findings

• Six studies reported mean or median 25(OH)D concentrations less than 30nmol per L in children with rickets whereas the other studies reported mean or median values above 30nmol per L and up to 50nmol per L
• In seven of eight case-control studies serum 25(OH)D values were lower in the children with rickets, compared to controls
  • The study quality of the RCT, four before-after and eight case-control studies ranged from poor to fair. 
• 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.

Infants and Children Conclusion

• 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.

Infants Conclusion

• 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 27nmol per L (measured by CPBA).

Pregnancy and Lactation Conclusion

• Two studies observed no change in vitamin D status during pregnancy, whereas another observed a decline in serum 25(OH)D from the first to the third trimester
• There was insufficient evidence on the association between 25(OH)D and change in bone density during pregnancy
• Once 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.  

Post-Menopausal and Elderly Men Conclusion

• 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 were measured increased ranged from 50nmol to 87nmol per L.

Government:

NIH

• Extensively comprehensive review
• Individual study quality subject to some reviewer interpretation.