Assessment of Efficacy of Zoledronic Acid in the Treatment of Bone Marrow Edema Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assessment of Efficacy of Zoledronic Acid in the Treatment of Bone Marrow Edema Syndrome (NCT01348269), a randomized phase 3 study. The primary outcome is Reduction of the Edema Area.

2. Clinical Question

The clinical question is about a measured imaging outcome as well as symptoms. The primary endpoint is the percentage reduction in edema volume, while secondary outcomes include pain, quality of life, subjective estimation of medical condition, and additional medicinal visits. These outcomes address different aspects of the study and should not be treated as interchangeable. An imaging difference does not by itself establish a corresponding difference in pain or quality of life. The registry record describes the study as a prospective, bicentric, randomized, double-blind, placebo-controlled phase III study. It does not report detailed eligibility criteria, the treatment schedule beyond the single intravenous dose, or the original rationale for choosing the endpoint and follow-up time.

3. Trial Design

The registry describes a prospective, bicentric, randomized, double-blind, parallel-group, placebo-controlled phase III study. The listed sponsor is Wuerzburg University Hospital. The study is marked completed, and the registry lists enrollment of 48. The listed start is 2011-05 and primary completion is 2015-08-26.

The primary outcome compares two arms: zoledronic acid and placebo. The primary outcome results report 34 participants for zoledronic acid and 13 for placebo. Elsewhere, the safety results list 34 participants at risk in the zoledronic acid group and 14 in the placebo group. These differing counts are not reconciled in the registry record. It does not report the reasons for any difference between enrollment and the outcome-specific counts, nor does it specify whether participants were excluded from particular analyses.

Randomization is intended to make treatment groups comparable on average, while masking is intended to reduce the influence of treatment knowledge on participant experience, care, and outcome assessment. Those are general features of these design choices; details of sequence generation, allocation concealment, or how masking was maintained are not reported in the registry record. The official title describes the study as bicentric, but the record does not identify the participating centers in the information summarized for the trial.

The primary outcome was assessed at week 6 after a single intravenous administration. Secondary outcomes include pain at week 3 and week 6, quality of life measured with the Qualeffo-41 Questionnaire, subjective estimation of medical condition using PDI, and the number of additional medicinal visits. The registry lists 13 outcome measures and 2 analyses. A full protocol, the original sample-size justification, prespecified analysis populations, and a detailed statistical analysis plan 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.

Baseline

Treatment | Core Study (Until Week 6)

Follow-up (Until Week 12)

Reasons for not completing this period:

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 Reduction of the Edema Area, measured over Week 6 after administration of a single intravenous dose of zoledronic acid (5 mg).

The primary endpoint is titled “Reduction of the Edema Area” and is defined as percentage reduction in edema volume. Edema volume was measured by MRI before treatment and six weeks after treatment. Screening edema volume was set to 100%, and the follow-up measure was expressed as percentage reduction compared with that screening value. The endpoint therefore represents a change in an imaging measurement, not a direct measure of pain or daily function.

The registry reports the group means and standard deviations for this continuous measure. Mean reduction was 64.53 in the zoledronic acid arm and 23.97 in the placebo arm. The reported unit is percentage of edema volume. The registry record does not explain how MRI volumes were measured, who assessed the images, or whether image assessors were masked to treatment assignment.

Imaging provides a quantitative way to assess change in the targeted edema measure. In general, a prespecified primary endpoint helps focus the main comparison and reduces the risk of selecting a favorable result from many outcomes after data collection. The registry identifies the edema reduction measure as primary, but does not report further endpoint-selection rationale or the original protocol language defining the analysis. A difference in this imaging endpoint should be interpreted as evidence about the measured edema outcome; it does not, on its own, answer whether pain, quality of life, or other outcomes differed.

7. Results Posted in the Registry

• Zoledronic Acid: mean 64.53 versus 23.97 on control; difference 40.56 (95% CI 11.61 to 69.51), standardized effect d = 0.94; z-test p = 0.006.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Reduction of Pain (VAS)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Zoledronic Acid: mean 25.50 versus 25.60 on control; difference -0.10 (95% CI -14.99 to 14.79), standardized effect d = -0.00; z-test p = 0.989.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Zoledronic Acid and the control. The interval gives the range of effects that remain compatible with the data.

Reduction of Pain

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Zoledronic Acid: mean 25.00 versus 38.50 on control; difference -13.50 (95% CI -32.03 to 5.03), standardized effect d = -0.46; z-test p = 0.153.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Zoledronic Acid and the control. The interval gives the range of effects that remain compatible with the data.

Quality of Life (Qualeffo-41 Questionnaire)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Zoledronic Acid: mean 2.10 versus 2.10 on control; difference 0.00 (95% CI -0.34 to 0.34), standardized effect d = 0.00; z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Zoledronic Acid and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover symptoms, quality of life, subjective estimation of medical condition, and additional medicinal visits. Posted numerical results include week 3 pain reduction, week 6 pain reduction, and week 3 quality of life. The overall pattern is not a uniform replication of the primary imaging result: the reported comparisons vary in estimated direction, magnitude, and precision. The registry lists additional secondary outcomes but does not provide numerical results for all of them in the information recorded.

These measures can add context to the primary result because they address experiences and outcomes distinct from MRI-measured edema volume. However, they do not serve as interchangeable confirmations. An imaging change and a patient-reported outcome may differ in timing, measurement error, and clinical meaning. The registry does not report a validated threshold for a clinically important difference in the secondary measures, and the posted summaries alone cannot establish whether an observed change matters to participants.

Unadjusted secondary results carry less weight when many outcomes are assessed. In general, testing many comparisons increases the chance that at least one appears unusual under its null model by chance. A multiplicity plan can specify how to interpret related tests and control that risk. The registry record lists 13 outcome measures and does not report a multiplicity adjustment or testing hierarchy. This does not make the secondary outcomes irrelevant, but it means their p-values and estimates should be treated as exploratory unless a prespecified analysis plan establishes otherwise.

The record also does not provide complete outcome-specific analysis populations, missing-data handling, or numerical results for every listed secondary measure. Those gaps limit any attempt to make a comprehensive comparison across the secondary endpoints. The appropriate overall reading is that secondary outcomes offer separate, incomplete evidence and do not independently settle the interpretation of the primary imaging comparison.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Reduction of Pain (VAS)
• Reduction of Pain
• Quality of Life (Qualeffo-41 Questionnaire)
• Quality of Life (Qualeffo-41 Questionnaire)
• Subjective Estimation of Medical Condition (PDI)
• Subjective Estimation of Medical Condition (PDI)
• Number of Additional Medicinal Visits
• Number of Additional Medicinal Visits

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous, so the registry reports a mean and standard deviation for each group. A mean describes the group’s average result. A standard deviation describes how spread out individual results are around that average. These summaries are useful for comparing groups, but they do not show the full distribution or identify how many participants improved by a particular amount.

What does the mean difference represent?

The reported primary mean difference is 40.56 percentage points, calculated as the zoledronic acid group mean minus the placebo group mean for percentage edema reduction. A positive difference therefore indicates a larger mean reduction in the zoledronic acid arm on this measure. The difference is expressed in the endpoint’s units, which makes it distinct from a standardized effect size. It is a comparison of group averages, not a statement that each participant’s edema changed by that amount.

What does the t-test assess?

The sponsor reports a two-sided t-test for the primary comparison, with p = 0.006. In general, a two-sample t-test assesses whether the observed difference in group means is compatible with a null model in which the population means are equal. “Two-sided” means that departures in either direction count as evidence against that null model. The test’s interpretation depends on its assumptions, including how observations are distributed and whether the variance approach is appropriate. The registry does not report diagnostic checks, whether a pooled-variance or unequal-variance version was used, or a detailed justification of the chosen test.

A p-value is not the probability that the result occurred by chance, nor is it the probability that the treatment is ineffective. It is calculated under a specified null model and summarizes how incompatible the data are with that model. A small p-value does not show that the estimated effect is precise or important by itself. The estimate and its interval are needed to understand magnitude and uncertainty.

Why is a rank-based test also reported?

The registry also reports a Wilcoxon (Mann-Whitney) result, p = 0.015. In general, this rank-based method compares the ordering of observations between groups rather than directly testing a difference in means. It can be useful when a comparison based on ranks is desired, though its interpretation is not automatically a test of medians in every setting. The registry does not report why this additional analysis was selected, whether it was prespecified, or which analysis was designated as primary in the statistical analysis plan.

What does the interval add?

The primary difference is reported with limits of 11.61 and 69.51. A confidence interval is a range of values compatible with the data and the interval’s statistical procedure. In general, wider intervals represent less precision than narrower intervals. The limits are both positive, but the registry record does not state the confidence level or the method used to construct the interval. The interval should therefore be read with that reporting gap in mind rather than assigned a confidence level not stated in the record.

Why do dispersion and sample size matter?

Observed variability affects how precisely a group mean and the between-group difference can be estimated. Greater variability generally makes a comparison less precise if other features remain the same. Unequal group sizes can also affect precision. Here, the primary outcome counts differ between arms, and the reported standard deviations are sizable. General statistical practice would consider the effects of these features and the analysis assumptions; the registry record does not report a fuller assessment of them.

Over-dispersion is a general concern when observed variability is greater than a statistical model expects. In that situation, standard errors may be too small and intervals or tests may appear more certain than warranted. The primary outcome is analyzed as a continuous measure, and the registry does not report an over-dispersion assessment. This concept is not evidence that over-dispersion occurred in this trial; it illustrates why model assumptions and diagnostic information matter.

The arm summaries and comparison are unadjusted in the simple recalculation. No adjustment for covariates is reported in the registry’s primary analysis results. Randomization supports a group comparison, but does not remove the need to describe the analysis population, missingness, and prespecified methods. Those details are not reported in the registry record. The registry also does not report an original sample-size justification, interim analysis plan, or whether any analysis choices changed after the study began. Those omissions limit how fully the reported tests can be assessed, but do not alter the values the registry reports.

11. Confidence Intervals and Precision

The primary mean difference is 40.56 percentage points, with reported limits from 11.61 to 69.51. The interval spans a range of positive values, so the posted estimate is not pinpoint precise. It allows for a range of possible magnitudes, from a smaller to a larger difference in mean edema reduction. The confidence level and interval-construction method are not reported in the registry record, so they should not be inferred.

Precision is also informed by the variability and the number of observations. The primary outcome summaries include 34 participants in the zoledronic acid arm and 13 in the placebo arm, with standard deviations of 41.92 and 46.52. The difference between these group sizes, together with the spread of values, is relevant to the uncertainty in the estimated contrast. The registry does not provide individual-level data or additional analyses that would show how robust the interval is to distributional assumptions.

The p-value of 0.006 and the interval answer related but different questions. The p-value summarizes compatibility with a null model; the interval describes a range of effect values compatible with the data and the interval procedure. Neither conveys the full clinical meaning of the imaging change. The endpoint measures percentage reduction in edema volume, and there is no reported threshold defining a clinically important difference.

Some secondary outcome intervals are wide and include zero, whereas the primary interval does not. This illustrates that evidence and precision vary across outcomes. A result that is not statistically distinguishable from zero does not prove no effect, just as a primary result with an interval above zero does not establish effects on unmeasured outcomes. Details on missingness and the exact analysis populations are not reported, so their potential influence on precision cannot be evaluated from the registry record.

12. 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 illustrations based on the observed effect, not a reconstruction of the trial’s original design. They assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set in turn to 100%, 75%, or 50% of the observed effect. These are hypothetical planning scenarios, not observed outcomes or the actual design assumptions for the trial; the original sample-size justification and assumptions are not reported in the registry record.

For these continuous-outcome calculations, the figures represent participants per arm. The separate convention for time-to-event calculations would be total events, but the primary endpoint is continuous, so the per-arm interpretation applies. The 80% power column gives the illustrated number of participants per arm for an 80% chance of detecting the specified effect under the planning assumptions if that effect is real. The 90% power column gives the corresponding number for a 90% chance. Higher target power generally requires more participants, all else held constant.

The planning values use the observed effect as a starting point, and the scenarios for smaller effects require more participants. This pattern is expected because a smaller group difference is harder to distinguish from random variation. The very large figures for the week 3 pain comparison arise in a scenario where the observed mean difference is close to zero; they should not be read as a recommendation for a future study without a clinically justified target effect and an appropriate design plan.

This is not observed power. It is a planning illustration conditional on its assumptions and the chosen effect size. It does not tell whether the trial was adequately designed, and it cannot establish the probability that a result is true.

13. 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 = 40.560; pooled standard deviation σ = 43.195.
2. n = 2 × (1.96 + 0.842)² × 43.195² / 40.560² = 17.8, rounded up to 18 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 <- 40.56                      # observed difference in means
sigma <- 43.1945922541237                     # 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(1348269)
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 = 18 (80% power), 24 (90% power)
 75% of observed effect: n per arm = 32 (80% power), 43 (90% power)
 50% of observed effect: n per arm = 72 (80% power), 96 (90% power)
power.t.test: 18.8 
Simulated power at n = 18 per arm: 0.787 (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.

14. Analyses Reported by the Sponsor

The sponsor’s reported primary analyses are a two-sided t-test with p = 0.006 and a Wilcoxon (Mann-Whitney) analysis with p = 0.015. The simple unadjusted recalculation from the posted group summaries gives a mean difference of 40.56 percentage points, with limits from 11.61 to 69.51, and a t-test p-value of 0.006. The recalculated t-test p-value matches the sponsor’s reported t-test value at the precision shown.

The recalculation is a check based on summary statistics, not a replacement for the sponsor’s trial analysis. It does not include participant-level data, adjustment for covariates, or information about exclusions and missing outcomes. The sponsor’s own analysis takes precedence if a discrepancy arises; the registry indicates no discrepancy for this comparison. The registry does not provide a reported effect estimate or interval alongside the sponsor’s p-values, so the sponsor’s reported tests and the summary-based estimate contribute different information.

The additional Wilcoxon result offers a rank-based comparison, but the record does not explain whether it was prespecified or how the two tests were intended to be used together. Without the protocol or statistical analysis plan, it is not possible to identify an unreported hierarchy or determine whether one test was confirmatory and the other supportive.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures, including the primary edema endpoint and multiple secondary outcomes. It reports two primary comparison analyses, a t-test and a Wilcoxon (Mann-Whitney) test. The record does not report a multiplicity adjustment, a hierarchy for testing outcomes, or a statistical analysis plan that explains how multiple tests were intended to affect interpretation.

In general, when many outcomes or tests are examined, the chance of at least one apparently notable result can increase even if all corresponding null hypotheses are true. Prespecified outcome priorities and multiplicity procedures help distinguish confirmatory evidence from exploratory patterns. Without those details, the primary endpoint remains the outcome identified as primary in the record, while secondary findings should be interpreted cautiously and in the context of the number of outcomes considered.

Information on missing data is also limited. The record does not report the number of participants with missing primary outcome measurements, reasons for missingness, imputation methods, or sensitivity analyses. It does not specify an intention-to-treat population, a per-protocol population, or other analysis-population definitions. The primary outcome counts are 34 for zoledronic acid and 13 for placebo, while safety counts are 34 and 14. The reasons for this difference and any effect on analysis populations are not reported in the registry record.

These omissions matter because missing outcomes and choices about which participants to include can affect estimates and their uncertainty. They do not establish that the reported comparison is biased, but they prevent a full assessment of how the analysis handled incomplete follow-up or deviations from assigned treatment. Interim analyses, stopping rules, and any associated statistical adjustments are also not reported in the registry record. The original protocol and detailed analysis plan would be needed to resolve these questions.

16. 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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: generalised tonic-clonic seizure (7.1%), hypertensive crisis (2.9%), post-traumatic neck syndrome (2.9%), paraesthesia (2.9%), osteoarthritis (2.9%).

The safety results list 34 participants at risk in the zoledronic acid group and 14 in the placebo group. Serious adverse events affected 4 and 1 participants, respectively. No deaths are listed in either group. The record also lists other adverse events affecting 34 participants in the zoledronic acid group and 11 in the placebo group. These counts describe the posted safety summaries; they do not by themselves establish that an event was caused by treatment.

The registry lists serious-event terms with percentages, including Generalised tonic-clonic seizure at 7.1%, and Hypertensive crisis, Post-traumatic neck syndrome, Paraesthesia, Osteoarthritis, and Back pain each at 2.9%. The record as summarized does not make clear how these term percentages relate to treatment arms or whether participants could contribute more than one event. They should not be interpreted as arm-specific risks.

Safety comparisons require attention to the number at risk, duration of observation, event definitions, and completeness of reporting. The registry does not provide detailed event narratives, timing, severity beyond the serious-event classification, or a causal assessment. The group counts are also not equal, and the safety placebo count differs from the primary outcome placebo count. These figures are descriptive and do not provide a complete comparative safety analysis.

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

The posted results show a greater mean reduction in MRI-measured edema volume in the zoledronic acid arm than in the placebo arm at week 6. The reported mean difference is 40.56 percentage points, with limits from 11.61 to 69.51, and the sponsor reports p = 0.006 for the two-sided t-test. The rank-based test is also reported, with p = 0.015. These statistics describe evidence about the primary imaging endpoint in the participants included in the posted analysis.

That finding does not establish that every participant experienced a reduction of the same size, or that the imaging difference translates into a particular improvement in pain, quality of life, or function. Secondary outcomes are separate measurements, and their posted results do not show a consistent pattern that can simply be equated with the primary result. The registry does not report a threshold for a clinically important change in edema volume.

The result also does not settle how well the finding generalizes beyond this study. Eligibility details, full analysis-population definitions, missing-data methods, and the original sample-size rationale are not reported in the registry record. The primary endpoint counts differ from the enrollment figure and the safety counts, and the reasons are not given. The confidence level for the primary interval is not stated.

Statistical evidence on an outcome is not the same as a treatment recommendation. The figures support a difference in the recorded group averages under the reported comparison, while uncertainty and reporting gaps remain. The trial record does not establish all benefits and harms, nor does it answer questions beyond its measured outcomes and follow-up timeframe. Interpretation should remain specific to the posted comparison rather than extending it to unreported populations, outcomes, or longer-term effects.

18. Why This Trial Matters Statistically

This trial illustrates why an imaging endpoint, a statistical test, and a clinically experienced outcome need to be distinguished. The primary result is a comparison of mean percentage reduction in MRI-measured edema volume, while the secondary measures address pain and quality of life among other outcomes. A statistically notable difference on one measure does not automatically imply a parallel difference on another.

It also illustrates the value of reporting an effect estimate with an interval rather than relying only on a p-value. The mean difference and its limits communicate both direction and a range of uncertainty, while the p-value summarizes compatibility with a null model under a specified test. The substantial standard deviations and unequal primary outcome counts are relevant context for that precision.

The record presents two different types of analysis for the primary comparison: a mean-based t-test and a rank-based Wilcoxon analysis. Their reported p-values are both available, but the reason for using both and their prespecified roles are not described. This makes protocol transparency important when readers assess whether results were confirmatory or supportive.

Finally, the record demonstrates why trial interpretation depends on more than a completed status and a favorable-looking primary comparison. The enrollment figure, outcome-specific counts, and safety counts are not fully reconciled; the handling of missing data and multiplicity is not reported; and the original sample-size rationale is unavailable. These gaps do not negate the posted numerical findings, but they define what can and cannot be concluded from the registry record alone.

19. 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.

Several trial-specific reporting limitations affect interpretation. The registry lists enrollment of 48, while the primary outcome results include 34 participants in the zoledronic acid arm and 13 in the placebo arm. Safety summaries instead list 34 and 14 at risk. The record does not explain these differences or report outcome-specific participant flow, exclusions, or reasons for missing measurements.

The primary endpoint description identifies MRI measurement before treatment and at six weeks, but the record does not give measurement procedures, assessor details, or image-reading reliability. It also does not report the confidence level or construction method for the interval accompanying the mean difference. The posted result is therefore interpretable as an estimate and limits, but some technical details needed to reproduce or fully assess it are unavailable.

The sponsor reports both a t-test and a Wilcoxon analysis, but does not report the reason for both methods or their relative prespecified status in the registry results. Multiplicity handling across the 13 listed outcome measures is not reported. Neither the original sample-size justification nor the trial’s own design assumptions are reported, so the planning illustrations should not be treated as a record of the study’s design process.

Detailed eligibility criteria, allocation procedures, masking implementation, analysis-population definitions, missing-data methods, interim analyses, and longer-term follow-up are not reported in the registry record. The secondary results summarized in the record are incomplete relative to all listed measures. These limitations restrict assessment of robustness and generalizability; they do not provide evidence that any particular unreported method was or was not used.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Assessment of Efficacy of Zoledronic Acid in the Treatment of Bone Marrow Edema Syndrome — NCT01348269.
• Registry record last updated 2024-08-13; status last verified 2024-08.
• Results first posted 2024-08-13.
• 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.

23. Record Summary

NCT01348269 is a completed, prospective, bicentric, randomized, double-blind, placebo-controlled phase III study sponsored by Wuerzburg University Hospital. It assessed a single intravenous dose of zoledronic acid against placebo for bone marrow edema syndrome. The registry lists enrollment of 48 and primary completion on 2015-08-26.

The primary outcome was percentage reduction in MRI-measured edema volume at week 6. Mean reduction was 64.53 in the zoledronic acid arm and 23.97 in the placebo arm. The reported mean difference was 40.56, with limits from 11.61 to 69.51; sponsor analyses reported p = 0.006 by two-sided t-test and p = 0.015 by Wilcoxon (Mann-Whitney).

Secondary outcomes included pain, quality of life, subjective estimation of medical condition, and additional medicinal visits. Serious adverse events affected 4 of 34 participants in the zoledronic acid group and 1 of 14 in the placebo group; no deaths were listed. The registry does not report a full statistical analysis plan, original sample-size justification, multiplicity approach, or detailed missing-data handling.