Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing (NCT02786498), a randomized phase 2 study. The primary outcome is Fracture Healing Will be Assessed Clinically Using Function IndeX for Trauma (FIX-IT).

2. Clinical Question

The trial asked whether different vitamin D3 supplementation strategies were associated with differences in clinical fracture-healing function at 3 months post-injury. The comparison involved three active regimens and a control group receiving placebo loading and daily doses. The primary outcome was the mean score on the Function IndeX for Trauma, or FIX-IT.

The registry describes the objective as determining the effect of vitamin D3 supplementation on fracture healing at 3 months. The posted results address clinical function on the specified score; they do not by themselves describe every aspect of bone healing or establish the effects of supplementation outside the trial’s recorded outcome and follow-up.

3. Trial Design

This was a randomized, triple-masked, parallel-group phase 2 trial sponsored by the University of Maryland, Baltimore. The registry records a total enrollment of 102 and a completed status. The study began on 2016-11-21, and primary completion is recorded as 2019-08. The allocation procedure beyond the description as randomized, and the identities of the parties covered by triple masking, are not reported in the registry record.

There were four parallel groups. The High Loading Dose group received vitamin D3 loading doses of 150,000 IU at enrollment and 6 weeks, with daily placebo. The High Daily Dose group received 4,000 IU vitamin D3 per day and loading-dose placebo. The Low Daily Dose group received 600 IU vitamin D3 per day and loading-dose placebo. The Control Group received placebo for both loading and daily doses. The arm descriptions specify a 3-month duration for the regimens.

The primary endpoint was clinical fracture healing assessed using FIX-IT at 3 months post-injury. The posted arm summaries include 27 participants in High Loading Dose, 24 in High Daily Dose, 24 in Low Daily Dose, and 27 in Control Group. These are the group counts attached to the outcome summaries; the registry record does not explain the relationship between these counts and the full enrollment or describe any exclusions from the outcome analysis.

The registry also identifies serum 25(OH)D, adherence, adverse events, serum calcium, parathyroid hormone, and completion of blood and radiographic measures as secondary outcomes. Detailed protocol procedures, the full statistical analysis plan, and the trial’s original sample-size justification are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Fracture Healing Will be Assessed Clinically Using Function IndeX for Trauma (FIX-IT), measured over 3 months post-injury.

The primary endpoint was fracture healing assessed clinically with the Function IndeX for Trauma (FIX-IT) at 3 months post-injury. FIX-IT is described as a standardized measure of weight-bearing and pain in patients with lower extremity fractures, specifically tibia and femur fractures. The total score combines two equally weighted domains: ability to bear weight and pain at the fracture site.

The weight-bearing domain assesses single-leg standing and ambulation. The pain domain uses palpation and stress procedures. Each domain can contribute up to 6 points, and the total scale ranges from 0 to 12 points. The maximum score of 12 indicates the highest level of function. Thus, the outcome represents clinical function related to the fracture rather than a direct imaging measure alone.

A continuous score allows the mean outcome in each group to be summarized and compared. The posted results report group means and standard deviations, along with unadjusted mean differences against the control group. These summaries describe average scores and the spread of individual scores within each group; they do not show how every participant scored or whether changes occurred for particular individuals. The registry record does not report a separate primary imaging result or details of how the clinical outcome was collected beyond the FIX-IT description.

7. Results Posted in the Registry

• High Loading Dose: mean 10.10 versus 9.00 on control; difference 1.10 (95% CI -0.34 to 2.54), standardized effect d = 0.41; z-test p = 0.135.
• High Daily Dose: mean 9.70 versus 9.00 on control; difference 0.70 (95% CI -0.87 to 2.27), standardized effect d = 0.25; z-test p = 0.381.
• Low Daily Dose: mean 9.30 versus 9.00 on control; difference 0.30 (95% CI -1.41 to 2.01), standardized effect d = 0.10; z-test p = 0.732.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: FIX-IT is a numerical score, and the registry specifies that the reported measure is a mean with standard deviation. The mean summarizes the group’s average score. The standard deviation describes the spread of participant scores around that average; it is not the uncertainty in the estimated mean and is not an interval for the treatment comparison.

The arm means and standard deviations were 10.1 and 2.5 for High Loading Dose, 9.7 and 2.8 for High Daily Dose, 9.3 and 3.3 for Low Daily Dose, and 9.0 and 2.9 for Control Group. The corresponding group counts were 27, 24, 24, and 27. These summaries show both the central scores and their within-group variability. The posted comparison estimates express the difference in mean score between each active group and control, without adjustment. Positive estimates indicate a higher average score in the active group because the score direction is defined so that higher function receives a higher score.

The mean differences were 1.1 for High Loading Dose, 0.7 for High Daily Dose, and 0.3 for Low Daily Dose. Their accompanying intervals give a range of values consistent with the estimated comparison under the calculation used. The registry record does not identify the inferential test or model used for the sponsor’s original analysis. The posted comparisons are marked as unadjusted recalculations from summary statistics, rather than sponsor analyses. The registry record lists zero analysis entries, so the recalculations should not be read as a substitute for a prespecified analysis that is not reported.

The comparison summaries also include pooled standard deviations and standardized effect estimates. The pooled standard deviation is a combined measure of score variability across the two groups in a comparison. A standardized effect expresses the mean difference relative to that variability, which can help describe the magnitude on a scale independent of the original score units. The posted standardized effects are 0.406 for High Loading Dose, 0.245 for High Daily Dose, and 0.097 for Low Daily Dose. These summaries do not replace the mean differences in FIX-IT points, and their interpretation still depends on the study context and uncertainty.

Standard errors quantify the estimated sampling uncertainty of a group mean. The posted standard errors for the control mean are 0.558 in each comparison; those for the active groups are 0.481, 0.572, and 0.674 for High Loading Dose, High Daily Dose, and Low Daily Dose, respectively. A standard error is distinct from a standard deviation: the former concerns precision of an estimated mean, while the latter describes variation among scores. Neither should be mistaken for a range containing all participant scores.

The intervals around the mean differences and the unadjusted p-values provide different presentations of inferential uncertainty. The interval shows a range of plausible values under the method used, while the p-value measures how unusual the observed data would be under a null hypothesis, conditional on the assumptions of its test. The registry record does not name that test or give the interval confidence level. The p-values are 0.135, 0.381, and 0.732 for the three active-versus-control comparisons. They should be interpreted alongside the estimated differences and intervals, not as measures of effect size.

Over-dispersion is a concern when variability exceeds what a statistical model assumes; in general, underestimating variability can make uncertainty appear smaller than it is. For this continuous endpoint, the group standard deviations describe observed score spread, but the registry record does not report a diagnostic assessment of model assumptions or any adjustment for unusual distributions. No additional distributional details are reported, so it is not possible to assess those assumptions from the registry summaries alone.

The posted planning illustrations use the observed mean difference as a reference and consider fractions of that effect. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. These are planning assumptions for an illustration and are not reported as the trial’s original design assumptions. The original sample-size justification and the trial’s planned statistical analysis are not reported in the registry record.

In general, power is the probability that a statistical procedure will detect a specified effect under the assumptions of a planning calculation. Planning for a smaller effect generally requires more participants, because a smaller difference is harder to distinguish from random variation. The calculations depend on the assumed variability, target effect, allocation, and significance level. They are not evidence about the probability that this completed trial detected an effect. The sample-size reading explains their intended interpretation separately.

Several outcomes were included beyond FIX-IT. The registry names serum 25(OH)D, adherence, adverse events, serum calcium, parathyroid hormone, and completion of blood and radiographic measures among secondary outcomes. The record indicates 11 outcome measures and 7 posted secondary outcomes, but numerical results for those outcomes are not reported in the registry record in the information summarized for this analysis. Accordingly, they cannot be incorporated into the interpretation of the primary endpoint.

10. Confidence Intervals and Precision

Precision is reflected in the uncertainty around a mean difference, not only in the point estimate. The posted intervals are -0.344 to 2.544 for High Loading Dose versus control, -0.866 to 2.266 for High Daily Dose versus control, and -1.415 to 2.015 for Low Daily Dose versus control. Each interval includes zero, so the summaries do not pin down a single direction of difference. They also include positive values, with the ranges extending across different possible magnitudes.

The High Loading Dose estimate is 1.1 points, with an interval spanning from -0.344 to 2.544. The High Daily Dose estimate is 0.7 points, with an interval from -0.866 to 2.266. The Low Daily Dose estimate is 0.3 points, with an interval from -1.415 to 2.015. The interval endpoints should be considered together with the estimate: an estimate is the center of the comparison, while the interval conveys uncertainty around it.

The registry record does not identify the confidence level or calculation method for these intervals. They are therefore best described as the posted intervals rather than assigned a confidence percentage that is not recorded. Their inclusion of zero does not prove that the groups are identical; it indicates that the estimates remain compatible with no mean difference under the interval calculation. Nor does the interval alone indicate whether a difference would matter clinically. The record does not report a threshold for a clinically important FIX-IT difference.

The outcome group counts range from 24 to 27 participants, and the group standard deviations range from 2.5 to 3.3. In general, estimates based on limited data can remain uncertain, particularly when participant scores vary. The intervals are a more informative guide to the precision of these comparisons than ranking the groups solely by their means. No adjusted intervals or direct comparisons between active regimens are reported in the registry record.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for 80% power and participants per arm for 90% power. They do not represent total events: the distinction in the planning assumptions says that time-to-event calculations would give total events, while all other calculations give participants per arm. FIX-IT is a continuous outcome, so the figures are participants per arm.

The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each calculation targets a stated fraction of the observed effect. Rows for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect illustrate how the required sample size changes as the target effect changes. Smaller effects need more participants to be detected under the same planning assumptions.

For example, planning for 100% of the observed effect in the High Loading Dose comparison gives 96 participants per arm for 80% power and 128 participants per arm for 90% power. For that comparison, planning for 75% of the observed effect gives 170 participants per arm for 80% power and 227 participants per arm for 90% power; planning for 50% gives 381 and 510 participants per arm, respectively. The other active-versus-control comparisons have their own estimates and requirements because their observed effects differ.

The 80% and 90% columns describe the target probability of detecting the specified effect if the calculation’s assumptions hold. The higher target probability requires more participants for a given effect. These figures are planning illustrations based on observed effects, not observed power and not the trial’s original design justification. The trial’s own sample-size assumptions are not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 1.100; pooled standard deviation σ = 2.707.
2. n = 2 × (1.96 + 0.842)² × 2.707² / 1.100² = 95.1, rounded up to 96 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 1.1                      # observed difference in means
sigma <- 2.70739727413618                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2786498)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 96 (80% power), 128 (90% power)
 75% of observed effect: n per arm = 170 (80% power), 227 (90% power)
 50% of observed effect: n per arm = 381 (80% power), 510 (90% power)
power.t.test: 96.1 
Simulated power at n = 96 per arm: 0.800 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

There are three posted active-versus-control comparisons for the primary FIX-IT outcome: High Loading Dose, High Daily Dose, and Low Daily Dose. The registry record does not report whether the original analysis plan treated these as a family of comparisons or adjusted for making multiple comparisons. The reported p-values are unadjusted, and no multiplicity-adjusted estimates or intervals are reported. Because repeated comparisons can increase the chance of at least one apparently unusual result, the p-values should not be interpreted as if a multiplicity procedure had been applied.

The registry lists 11 outcome measures and identifies 7 secondary outcomes as posted. Named secondary outcomes include serum 25(OH)D, adherence, adverse events, calcium, parathyroid hormone, and completion of blood and radiographic measures. Their numerical results and any hierarchy among the outcomes are not reported in the registry record. It is therefore not possible to determine from these summaries which outcomes were designated as key secondary endpoints, whether any outcomes were exploratory, or whether multiplicity across outcomes was addressed.

Missing-data procedures are not reported in the registry record. The endpoint summaries include 27 participants in High Loading Dose, 24 in High Daily Dose, 24 in Low Daily Dose, and 27 in Control Group. The record does not explain whether all randomized participants had an evaluable FIX-IT result, why the group counts differ, or how incomplete outcome data were handled. No imputation method, sensitivity analysis, or missingness pattern is reported.

The analysis population is also not described. It is not reported whether the estimates follow an intention-to-treat, per-protocol, or another population definition, or whether participants were analyzed in their assigned groups. The registry describes randomized allocation, but that fact alone does not establish which participants entered a particular analysis. Without these details, the posted group summaries cannot be linked confidently to a specific analysis population or missing-data strategy.

The original statistical analysis plan, including the prespecified primary comparison, any covariate adjustment, and any interim analysis procedures, is not reported in the registry record. No conclusions about those procedures can be drawn from the unadjusted recalculations.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse event counts and counts of participants with other adverse events by group. For serious adverse events, the count was 0 in each group: High Loading Dose, High Daily Dose, Low Daily Dose, and Control Group. The numbers at risk for this reporting were 27, 24, 24, and 27, respectively. Deaths were recorded as 0 in every group, and no serious adverse event terms are listed.

For other adverse events, the reported participant counts were 9 of 27 in High Loading Dose, 10 of 24 in High Daily Dose, 11 of 24 in Low Daily Dose, and 14 of 27 in Control Group. These are counts of participants, not counts of every individual event. The registry record does not report event descriptions, severity details for these other events, timing, or attribution to study treatment.

A reported count of zero serious adverse events means none were recorded in the corresponding group in this registry entry; it does not establish that an event is impossible or rule out events beyond the recorded follow-up and reporting. The safety summaries are descriptive and do not constitute a statistical comparison between groups. The registry record does not report a formal safety analysis or adjusted estimates.

15. What the Result Does, and Does Not, Mean

The posted results describe average FIX-IT function scores at 3 months post-injury. All three vitamin D3 groups had higher mean scores than the control group in the unadjusted comparisons, with mean differences of 1.1 for High Loading Dose, 0.7 for High Daily Dose, and 0.3 for Low Daily Dose. Higher scores indicate a higher level of function on the described scale.

The estimates are uncertain. Each interval includes zero and spans values on either side of zero, and the registry record does not report the interval confidence level. The posted p-values are 0.135, 0.381, and 0.732. These results do not establish that the groups have identical outcomes, but they also do not provide precise evidence of a mean difference. The registry summaries do not identify a clinically important difference threshold, so statistical estimates cannot be translated into a judgment about clinical importance from this record alone.

The comparisons address each active regimen against placebo control. They do not directly test whether one vitamin D3 regimen is better than another. The differences among the point estimates should not be treated as proof that the regimens differ, particularly because the intervals overlap and no active-versus-active analysis is reported.

The results are limited to the posted endpoint, the recorded follow-up, and the analysis summaries. They do not establish a result for later fracture healing, other fracture types, or outcomes not numerically reported. The registry lists biochemical, adherence, safety, and measurement-completion outcomes, but their numerical results are not reported in the registry record in the information. These data therefore cannot answer questions about those outcomes.

In general, a randomized comparison can support an estimate of between-group differences when the analysis follows the randomized groups and handles missing data appropriately. The registry record does not report the analysis population or missing-data procedures, so those conditions cannot be assessed from the available summaries. The appropriate interpretation is descriptive: the posted means, differences, intervals, and p-values characterize the recorded trial results but do not justify a broader claim about treatment effects.

16. Why This Trial Matters Statistically

This trial is statistically informative because it reports continuous outcome summaries for four randomized groups, including means, standard deviations, participant counts, and active-versus-control comparisons. That combination makes it possible to distinguish the estimated size of a difference from the variability of the scores and the precision of the estimate. Reporting only a p-value would not show the size or direction of the differences.

The three point estimates vary across the vitamin D3 regimens, while the uncertainty intervals remain broad and include zero. This illustrates why ranking group means alone is insufficient: the apparent ordering of estimates is not the same as evidence that the regimens differ. Direct comparisons between active groups, if conducted, would need their own estimates and uncertainty; such results are not reported in the registry record.

The trial also demonstrates the distinction between an observed result and a planning calculation. The sample-size illustrations use the observed effect and specified planning assumptions, whereas the original design justification is not reported. Those illustrations can help readers understand how smaller target effects require more participants, but they cannot establish whether the trial was designed with a particular power target or whether it had adequate power for its actual analysis.

Finally, trial interpretation depends on more than endpoint values. Multiplicity handling, missing-data methods, analysis populations, and protocol-specified procedures affect how estimates should be understood, yet those details are not reported in the registry record. Clear reporting of these elements would help readers assess how the posted estimates relate to the randomized design and how much confidence to place in comparisons across multiple outcomes.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary endpoint summaries come from groups with 27, 24, 24, and 27 participants. The registry record does not explain the differences in those counts or whether any participants lacked an evaluable FIX-IT score. Missing-data handling and analysis-population definitions are not reported, limiting assessment of possible bias from incomplete outcomes or departures from the randomized groups.

The posted active-versus-control comparisons are unadjusted recalculations from summary statistics. The sponsor’s analysis results are not included in the analysis entries, and the registry record does not report the original statistical analysis plan, the inferential test, covariate adjustment, or multiplicity handling. The reported intervals do not have a stated confidence level in the record. These omissions make it difficult to align the summaries with the trial’s prespecified analysis decisions.

The registry describes the trial as phase 2 and exploratory, with a primary clinical outcome at 3 months post-injury. Longer-term results are not reported. The record’s description of FIX-IT refers specifically to lower extremity fractures, including tibia and femur fractures, but detailed eligibility criteria and the exact fracture composition of enrolled participants are not reported. Generalization beyond the participants and outcome recorded cannot be assessed from these summaries.

The registry names secondary outcomes, including laboratory measures, adherence, adverse events, and completion of measurements, but their numerical results are not reported in the registry record in the information. Safety counts are descriptive, and event details and attribution are not reported. The record also does not report the trial’s original sample-size justification or any interim analysis procedures. These are limitations of what can be concluded from the registry summaries, rather than evidence that a particular procedure was or was not used.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing — NCT02786498.
• Registry record last updated 2022-03-31; status last verified 2022-03.
• Results first posted 2021-04-01.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

NCT02786498 is a completed, randomized, triple-masked, parallel-group phase 2 trial sponsored by the University of Maryland, Baltimore. The registry records enrollment of 102 participants and a primary completion of 2019-08. The trial compared three vitamin D3 supplementation strategies with a placebo control.

The primary endpoint was mean FIX-IT score at 3 months post-injury. The unadjusted mean differences versus control were 1.1 for High Loading Dose, 0.7 for High Daily Dose, and 0.3 for Low Daily Dose. All three posted intervals include zero. Unadjusted p-values were 0.135, 0.381, and 0.732, respectively.

The registry record does not report the original statistical analysis plan, sample-size justification, analysis population, missing-data procedures, or multiplicity handling. The posted estimates are most appropriately read alongside their uncertainty and the limits of the registry entries.