• Increase Font Size
  • Decrease Font Size
  • View as PDF

NSUP: Vitamin D (2008)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To determine if supplementation with vitamin K1 (phylloquinone) had an independent or additive effect on bone health in healthy, older and non-osteoporotic women supplemented with vitamin D3 and calcium.

Inclusion Criteria:
  • Healthy non-osteoporotic women
  • 60 years and above.
Exclusion Criteria:
  • Clinical osteoporosis 
  • Chronic disease (e.g., diabetes mellitus, cardiovascular disease, cancer, fat malabsorption syndromes)
  • Routine medication that interferes with vitamin K, vitamin D or bone metabolism (notably warfarin and steroids)
  • Consumption of nutrient supplements that provided in excess of 30mcg vitamin K, 10mcg (400 IU) vitamin D, or 500mg calcium daily.
Description of Study Protocol:

Recruitment

Healthy women 60 years of age and older were recruited from the general population to provide approximately equal numbers in the age groups 60 to 64 years, 65 to 69 years, 70 to 74 years and 75 years and older.

Design

244 women randomized to receive either:

  • Placebo
  • 200mcg per day vitamin K1
  • 10mcg (400 IU) vitamin D3 plus 1,000mg calcium per day
  • Combined vitamins K1 and D3 plus calcium.

Blinding Used

To ensure double blinding, an independent statistician who had no connection to the study provided a computer-generated randomization list to the researchers.

Intervention

Vitamin K1, vitamin D3 and calcium.

Statistical Analysis

  • Correlation and linear regression procedures were used to study relationships between variables
  • ANOVA and X2 tests were used to detect differences between groups and distributions
  • Cross-sectional multiple regression analysis was used to reveal factors contributing to variance in BMD and BMC at baseline and other time-points
  • Repeated-measures ANOVA and general linear model procedures were used initially to study the significance of changes in BMC and BMD within and between the intervention groups, with appropriate adjustment for covariates (including baseline age, bone area, weight, height, physical activity, total energy intake, calcium and other nutrient intakes, serum markers of vitamin D and vitamin K status, and markers of bone turnover).
Data Collection Summary:

Timing of Measurements

At baseline and every six months for two years:

  • Weight
  • Height
  • Smoking habits
  • Sunshine exposure
  • Adherence to protocol by pill counting
  • Dietary intake assessed using a FFQ
  • Bone densitometry of the hip and wrist
  • Markers of bone turnover
  • Vitamin status.

Dependent Variables

BMC and BMD.

Independent Variables

Vitamin K1, vitamin D3 and calcium.

Description of Actual Data Sample:
  • Initial N: 244
  • Attrition (final N): 209
  • Age: 60 years and above
  • Ethnicity: Scottish.

Anthropometrics

  Placebo Vitamin K1 Vitamin D + Calcium Vitamins K and D + Calcium
Final N (N at Recruitment) 56 (61) 54 (60) 50 (62) 49 (61)
Baseline Characteristics Age (years) 67.8±6.0 67.7±4.9 69.4±6.4 67.8±5.4
Age at menopause (years) 47.8±4.8 49.8±4.3 48.3±8.4 49.5±4.1
Weight (kg) 66.0±8.5 67.5±9.3 64.9±8.4 64.5±9.0
BMI (kg/m2) 26.2±3.3 26.4±3.7 25.8±3.4 26.1±3.7
Basal Nutrient Intakes Vitamin D (mcg/day) 5.0±2.3 5.4±2.6 5.6±3.2 5.9±3.1
Vitamin K (mcg/day) 83.0±24.5 86.9±29.6 82.0±26.8 87.1±28.8
Calcium (mg/day) 1068±280 1046±244 1078±248 1026±219

Location

Scotland.

Summary of Results:
Interval (Months) Placebo Vitamin K1 Vitamin D + Calcium Vitamins K and D + Calcium ANOVA from Baseline
Femoral Neck BMD (mg/cm2) 0-24
0.7
(-10.2, 11.6)
-4.2
(-15.6, 7.2)
1.9
(-6.5, 10.3)
1.0
(-8.0, 10.1)
 NS
Femoral Neck BMC (mg) 0-24
-32.1
(-127, 0.6)
-49.6
(-141, 42.0)
25.8
(-59.7, 111)
9.9
(-86.6, 66.8)
 NS
Femoral Trochanter BMD (mg/cm2) 0-24
8.9
(-3.9, 21.6)
4.3
(-9.1, 17.8)
7.8
(-2.3, 17.8)
6.9
(-3.9, 17.7)
 NS
Femoral Trochanter BMC (mg) 0-24
63.0*
(218, 1,040)
346
(-100, 793)
460*
(158, 763)
549*
( 207, 890)
 P<0.01
Femoral Ward's BMD (mg/cm2) 0-24
0.1
(-19.6, 19.4)
2.2
(-20.1, 16.2)
11.4
(-6.3, 29.2)
6.0
(-21.8, 9.9)
 NS
Femoral Ward's BMC (mg) 0-24
-36.7
(-143, 70.3)
-30.9
(-126, 64.5)
39.9
(-60.3, 140)
25.6
(-106, 54.5)
 NS
Mid-Distal Radius BMD (mg/cm2) 0-24
-20.4**
(-25.4, -15.3)
-18.6**
(-26.7, -10.5)
-16.6**
(-23.3, -9.9)
16.9**
(-23.7, -10.1)
 P<0.001
Mid-Distal Radius BMC (mg) 0-24
-20.4**
(-25.4, -15.3)
-16.3**
(-22.1, -10.6)
-14.9**
(-20.8, -9.0)
-14.1**
(-20.7, -7.6)
 P<0.001
Ultradistal Radius BMD (mg/cm2) 0-24
3.6
(-0.2, 7.4)
-1.9
(-7.5, 3.8)
1.7
(-3.1, 6.5)
6.2*
(2.6, 9.8)
 P<0.01
Ultradistal Radius BMC (mg) 0-24
7.2
(-4.9, 19.3)
-6.3
(-20.8, 8.3)
-1.5
(-17.4, 14.4)
30.7*
(15.2, 46.2)
 P<0.01

* Signficant bone gain from baseline
** Significant bone loss from baseline.

Other Findings

  • At the ultradistal radius, there were significant increases in BMC and BMD from baseline in women who received combined calcium, vitamin D and vitamin K
  • No evidence that vitamin K1 taken alone at high dietary intakes had any influence on maintaining bone loss.
Author Conclusion:
  • Dietary supplementation with a combination of nutritionally-relevant amounts of vitamin K with vitamin D and calcium in healthy older women was associated with a modest but significant increase in BMC at one site, consisting predominately of trabecular bone
  • Changes were not observed in either the vitamin K group alone or in the calcium plus vitamin D group, suggesting a synergistic role of the combination as suggested by previous reports
  • Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius.
Funding Source:
Government: UK Food Standards Agency
Reviewer Comments:

Power of study diminished by wide inter-individual variation in BMD at baseline and by the lower than expected rate of bone loss in the placebo group.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? ???
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? No
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) No
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? No
  4.4. Were reasons for withdrawals similar across groups? ???
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? No
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? ???
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes