Clodronate With or Without Chemotherapy and/or Hormonal Therapy in Treating Women With Stage I or Stage II Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clodronate With or Without Chemotherapy and/or Hormonal Therapy in Treating Women With Stage I or Stage II Breast Cancer (NCT00009945), a randomized phase 3 study. The primary outcome is Disease Free Survival..

2. Clinical Question

The trial’s rationale was to evaluate clodronate in preventing metastatic disease in early-stage breast cancer. The registry lists skeletal metastasis-free survival, overall survival, relapse-free survival, and incidence of non-skeletal metastasis as secondary outcomes. These broaden the clinical questions beyond the primary composite outcome, but do not replace it: each measures a different aspect of survival or disease spread.

The registry record does not report separate primary comparisons within chemotherapy or hormonal-therapy subgroups. It also does not report the eligibility details beyond women with stage I or stage II breast cancer. Accordingly, the posted comparison addresses the randomized groups as recorded, not a particular subgroup or background-treatment combination.

3. Trial Design

This was a randomized, phase III, parallel-group trial with quadruple masking. The registry lists NSABP Foundation Inc as the sponsor and records enrollment of 3323. The trial status is completed. Those design features identify the broad structure of the study, but do not fill in details about the allocation procedure, the identities of the masked parties, or how concealment was implemented; those details are not reported in the registry record.

Participants were assigned to clodronate or placebo. Each arm description specifies 2 tablets once daily for 3 years. The official title describes the comparison in patients receiving systemic chemotherapy and/or hormonal therapy or no therapy, and the brief summary similarly describes clodronate with or without those treatments. However, the registry record does not report the number of participants in each background-treatment category or the manner in which those treatments were selected.

The posted primary outcome is disease-free survival, expressed as the percentage of patients disease free at 8 years. The record defines an event as any recurrence, second primary, or death. Secondary outcomes include skeletal metastasis-free survival, overall survival, relapse-free survival, and incidence of non-skeletal metastasis. Posted results are present for the first three secondary survival outcomes; results for incidence of non-skeletal metastasis are not reported in the registry record.

The arm sizes accompanying the primary outcome are 1655.0 for clodronate and 1656.0 for placebo. These outcome denominators should not be assumed to describe every stage of follow-up or every analysis population. The registry record does not report participant flow, exclusions after randomization, the handling of missing outcome data, or the analysis population used for the posted estimates. It also does not report the trial’s original statistical analysis plan, including its intended modeling approach or whether any interim analyses were conducted.

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

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 Disease Free Survival., measured over 8 years.

The primary endpoint is disease-free survival at 8 years, reported as the percentage of patients. The registry’s description defines an event as recurrence, a second primary cancer, or death, and describes the measure as time to the first such event. The posted result is therefore a fixed-time summary of whether participants remained disease free through the stated follow-up point, rather than a breakdown of event types or a display of the full event-time experience.

A composite endpoint combines multiple kinds of events into one outcome. This can capture several clinically important ways in which disease-free status may end, but it also means that the overall result does not reveal which event types contributed most. The registry record does not report the separate counts for recurrence, second primary cancer, or death within the primary endpoint, nor does it give a definition of recurrence or second primary cancer beyond the brief description.

A fixed-time percentage is useful for describing the proportion disease free at a clinically specified point in follow-up. It gives a direct group-level summary, but does not on its own show when events occurred, how follow-up varied between participants, or how censoring and incomplete follow-up were handled. Those analysis details are not reported in the registry record. The endpoint should therefore be interpreted as the posted percentage at 8 years, with the stated event definition, rather than as a complete account of the survival analysis.

7. Results Posted in the Registry

• Arm 1: Clodronate: 81.0% (1341/1655) versus 79.6% (1318/1656) on control; risk difference 1.4 percentage points (95% CI -1.3 to 4.1), risk ratio 1.02 (0.98–1.05); unadjusted two-proportion z-test p = 0.298.

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.

Skeletal Metastasis Free Survival

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Arm 1: Clodronate: 95.7% (1584/1655) versus 94.6% (1567/1656) on control; risk difference 1.1 percentage points (95% CI -0.4 to 2.5), risk ratio 1.01 (1.00–1.03); unadjusted two-proportion z-test p = 0.146.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm 1: Clodronate and the control. The interval gives the range of effects that remain compatible with the data.

Overall Survival

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Arm 1: Clodronate: 90.6% (1499/1655) versus 89.3% (1479/1656) on control; risk difference 1.3 percentage points (95% CI -0.8 to 3.3), risk ratio 1.01 (0.99–1.04); unadjusted two-proportion z-test p = 0.227.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm 1: Clodronate and the control. The interval gives the range of effects that remain compatible with the data.

Relapse Free Survival

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Arm 1: Clodronate: 89.9% (1488/1655) versus 88.3% (1462/1656) on control; risk difference 1.6 percentage points (95% CI -0.5 to 3.7), risk ratio 1.02 (0.99–1.04); unadjusted two-proportion z-test p = 0.134.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm 1: Clodronate and the control. The interval gives the range of effects that remain compatible with the data.

The reported secondary survival outcomes follow a pattern broadly aligned with the primary result: their point estimates are positive for clodronate, and their unadjusted confidence intervals include no difference. They address different outcomes, so they add context rather than simply repeating the primary question. Overall survival concerns death, while skeletal metastasis-free survival and relapse-free survival concern other aspects of disease course, as indicated by their registry outcome names.

The secondary outcomes relate to the primary result because they provide additional views of survival and metastasis during the same stated follow-up period. Consistency in the direction of the point estimates can be noted, but should not be treated as proof of a common effect or as a collection of independent replications. The outcomes may be related, and the registry record does not report their correlation or the full definitions used to classify events.

Unadjusted secondary results generally carry less inferential weight than a prespecified primary result because multiple outcome tests increase the chance of at least one apparently notable result occurring by chance. In general, multiplicity procedures can address that issue, but the registry record does not report whether an adjustment was planned or used. The posted comparisons are therefore best interpreted as descriptive, endpoint-specific results rather than as a definitive set of confirmatory claims.

Incidence of non-skeletal metastasis is listed as a secondary outcome, but its result is not reported in the registry record. This missing result limits the completeness of the secondary-outcome picture. No inference about that endpoint can be made from the survival summaries or from the other posted secondary results.

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

• Skeletal Metastasis Free Survival
• Overall Survival
• Relapse Free Survival
• Incidence of Non-skeletal Metastasis

9. Statistical Interpretation

10. Statistical Methods Explained

The posted outcome is a percentage, and the associated comparison is expressed as a risk difference. These measures answer related but distinct questions. The percentage describes each randomized group separately; the risk difference describes the difference between the group proportions on the proportion scale. A positive estimate indicates a larger proportion in the clodronate group for this endpoint, while a negative estimate would indicate a smaller proportion. The comparison reported for the primary outcome is 0.014.

What does a confidence interval describe?

In general, a confidence interval describes the uncertainty around an estimate under a stated statistical method. A narrower interval indicates greater precision under that method; a wider interval indicates less precision. For a risk difference, the value corresponding to no difference is zero. The primary interval, from -0.013 to 0.042, spans zero, so the posted summary is compatible with differences in either direction. This does not mean every value in the interval is equally likely, and it does not account for sources of uncertainty that the calculation did not model.

The intervals and p-values accompanying these comparisons are unadjusted re-calculations from posted summary statistics. They should not be mistaken for the trial’s original analysis. The registry record does not report the trial’s original statistical methods, such as whether the primary endpoint was analyzed using a time-to-event model, how censoring was handled, or whether covariates were included. It also does not report the planned test, significance threshold, or model diagnostics. Without those details, the re-calculated comparisons are useful summaries but cannot reproduce or verify an unreported trial analysis.

Why is a binary summary not the whole time-to-event result?

The primary outcome description refers to time to the first event, but the posted measure is the percentage of patients disease free at 8 years. A time-to-event analysis can use the timing of events and account for participants whose event status is not observed throughout follow-up through methods such as censoring. A single percentage does not reveal the event-time distribution or show how those features were handled. This is a general distinction between a fixed-time percentage and a full time-to-event analysis; the registry record does not report the actual analysis method used for the primary endpoint.

The listed secondary outcomes are also reported as percentages at 8 years. Their definitions and analysis details are not fully described in the registry record. For example, the record gives the names skeletal metastasis-free survival, overall survival, and relapse-free survival, but does not provide full operational definitions for each. It is therefore safest to interpret the outcome labels as posted, without assuming additional event rules or methods.

What does an unadjusted comparison leave out?

An unadjusted comparison uses the posted group summaries without accounting for additional variables. It does not necessarily reproduce a stratified or covariate-adjusted analysis. Random assignment is intended to support a fair group comparison, but an unadjusted re-calculation does not reveal how the trial’s planned analysis may have treated baseline characteristics, stratification factors, or background therapy. The registry record does not report such details, so no claim about their role in the official analysis can be made.

The unadjusted p-value for the primary comparison is 0.298. In general, a p-value assesses compatibility between data and a statistical null hypothesis under the calculation’s assumptions. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of the observed difference. Its interpretation depends on the analysis plan, and the registry record does not report whether the trial’s own analysis used this test or how it handled testing across outcomes.

Why does over-dispersion matter in general?

For outcomes modeled as counts or rates, over-dispersion means that variation is greater than a model expects. If ignored, standard errors may be too small and intervals too narrow. This is a general modeling issue, not a feature established for the posted binary endpoint. The primary result is a percentage, and the registry record does not report a count or rate model, dispersion estimate, or any over-dispersion assessment. It would not be appropriate to attribute an over-dispersion correction to this trial.

Likewise, the record does not report interim monitoring, stopping rules, multiplicity adjustments, prespecified subgroup analyses, or a sample-size justification. Absence from the registry is not proof that such procedures were never used; it means their use and details are not reported in the registry record. The statistical interpretation should remain anchored to the posted arm summaries and clearly identified unadjusted re-calculations.

11. Confidence Intervals and Precision

The primary estimate is 0.014, with a 95% confidence interval from -0.013 to 0.042. Since the interval includes zero, the summary data do not distinguish a difference from no difference under this unadjusted calculation. The interval also extends in both directions, so the point estimate should not be read as a precise estimate of the underlying group contrast.

In general, a confidence interval reflects sampling uncertainty under the method used to calculate it. It does not automatically incorporate every uncertainty relevant to the result, including uncertainties about outcome measurement, missing follow-up, model choice, or selective reporting. The registry record does not report enough analysis detail to assess those issues for the trial’s original analysis. The reported interval is thus best read as precision for the simple unadjusted re-calculation from the posted summaries.

There are no confidence limits beside the separate arm percentages in the record. The comparison interval is more informative about the group contrast than comparing the two percentages in isolation, because it directly quantifies uncertainty around their difference. However, it should not be extended to claims about a particular subgroup, a particular event type, or a different follow-up time.

The secondary comparisons also have intervals that include zero. Their precision differs by endpoint, but their results are not independent tests of one underlying question. Looking across several outcomes makes the full inferential picture broader, while also raising the issue of multiplicity. The registry record does not report an adjustment for multiple comparisons, so the unadjusted intervals should be interpreted as endpoint-specific summaries rather than as a family of jointly controlled inferences.

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 sample-size display is a planning illustration based on the observed effect, not the trial’s own original design justification. For these binary percentage outcomes, the displayed figures are participants per arm. No event-total interpretation should be applied: the listed assumption for these outcomes specifies participants per arm, whereas the general note about total event counts applies to time-to-event planning displays.

The listed planning 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 set to a stated fraction of the observed effect. The registry record does not report the assumptions used for the trial’s original design, so these illustrations should not be taken as a reconstruction of its planning.

The 80% power column gives the planned number of participants per arm for a hypothetical study to have an 80% chance of detecting the specified effect under the stated assumptions, if that effect is real and the assumptions hold. The 90% power column gives the corresponding planning target for a 90% chance. These are design calculations, not probabilities that the trial result is correct and not a measure of the trial’s achieved ability to detect an effect.

Rows planning for 100%, 75%, and 50% of the observed effect show how the illustrative target changes as the assumed effect becomes smaller. Smaller effects need more participants to be detected with the same target power, all else held to the listed assumptions. These figures are not observed power; they are planning illustrations that depend on the effect selected and the specified calculation assumptions.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.796; treatment proportion p₁ = 0.810; average p̄ = 0.803.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5624 = 1.1023.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5623 = 0.4732.
4. n = (1.1023 + 0.4732)² / (0.0144)² = 12,006.9, rounded up to 12,007 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
p0 <- 0.795893719806763                          # control proportion
p1 <- 0.810271903323263                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(9945)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 12,007 (80% power), 16,074 (90% power)
 75% of observed effect: n per arm = 21,494 (80% power), 28,773 (90% power)
 50% of observed effect: n per arm = 48,690 (80% power), 65,181 (90% power)
power.prop.test: 12006.9 
Simulated power at n = 12,007 per arm: 0.800 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and several secondary outcomes, but it does not report how the trial handled multiple statistical tests. When multiple outcomes are tested, the chance of finding at least one apparently unusual result can rise. In general, a prespecified testing hierarchy or adjustment can control that issue, but the registry record does not report whether either was used. The secondary p-values and intervals should therefore be read as unadjusted endpoint-specific summaries, not as results with documented family-wise error control.

The registry record also does not report an analysis plan describing how missing outcome data were handled. It gives no account of loss to follow-up, censoring rules, imputation, or sensitivity analyses. For a fixed-time survival percentage, these details can affect how participants with incomplete follow-up contribute to the estimate. The posted outcome denominators do not, by themselves, explain the status or follow-up of participants who are not represented in a given result.

The analysis population is not reported in the registry record. It is therefore not possible to determine from the posted information whether the displayed outcome results follow an intention-to-treat approach, a per-protocol approach, or another defined population. Nor does the record explain whether participants were analyzed according to assigned group regardless of treatment received. This is a key distinction when interpreting randomized trial results.

Subgroup analysis plans and treatment-by-subgroup interaction tests are also not reported. The trial description includes participants receiving chemotherapy and/or hormonal therapy or no therapy, but the posted results do not establish separate effects within those background-treatment categories. Without reported subgroup definitions, sample sizes, and analysis methods, group-level results should not be extended to specific treatment combinations.

Finally, the registry record does not report interim analyses, monitoring boundaries, stopping criteria, or the trial’s original statistical plan. These details cannot be inferred from completion status or from the final posted summaries. Their absence from the registry record should be understood as a reporting limitation, rather than evidence for or against any particular procedure.

15. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutrophil count decreased (6.6%), white blood cell decreased (4.1%), thromboembolic event (1.8%), diarrhea (1.8%), infections and infestations - other, specify (1.7%).

The adverse-event record lists serious adverse events for groups with 1612 participants at risk in the clodronate group and 1623 at risk in the placebo group. It records 340 and 350 participants with a serious adverse event, respectively. For other adverse events, the corresponding numbers at risk are also 1612 and 1623, with 73 and 107 participants affected. The record lists 5 deaths for clodronate and 12 for placebo.

These are counts and denominators as recorded, not a complete safety comparison. The registry record does not report a statistical comparison, confidence intervals, adjustment for exposure time, or details about how events were attributed to treatment. The serious-event terms listed most often include neutrophil count decreased at 6.6%, white blood cell decreased at 4.1%, thromboembolic event at 1.8%, diarrhea at 1.8%, infections and infestations - Other, specify at 1.7%, and wound infection at 1.1%.

Adverse-event categories and event-term frequencies should be read as descriptive registry entries. They do not, on their own, establish whether an event was caused by study treatment or whether the groups differed statistically.

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

The primary posted result describes disease-free status at 8 years in the randomized clodronate and placebo groups. The clodronate group’s reported percentage is 81.0 and the placebo group’s is 79.6. The unadjusted re-calculated risk difference is 0.014, with a 95% confidence interval from -0.013 to 0.042. This is a group-level estimate with uncertainty, not a direct prediction for any individual participant.

The confidence interval includes zero, and the unadjusted p-value is 0.298. These features mean the posted summary does not provide a clear statistical distinction between the groups under the simple comparison reported. They do not prove that the groups are identical, nor do they prove that an effect is absent. The interval remains compatible with effects in either direction, and the registry record does not provide a prespecified equivalence margin or an equivalence analysis.

The outcome is a composite: recurrence, a second primary cancer, or death. Consequently, the overall percentage does not show which of those events contributed to the group summaries. It also does not describe the detailed timing of events or the handling of participants with incomplete follow-up. The registry record does not report those components or methods.

The secondary results offer additional descriptive information about survival and metastasis outcomes, but should not be treated as independent confirmation of the primary result. They are unadjusted comparisons, and multiplicity handling is not reported. Results for the listed incidence of non-skeletal metastasis outcome are not reported in the registry record.

These findings do not establish a benefit or lack of benefit for every subgroup or background-treatment context described in the trial title. The record does not give separate comparisons for chemotherapy or hormonal therapy categories. Nor should the posted group results be translated into individual medical decisions. The appropriate statistical conclusion is limited to the stated outcome, at the stated follow-up point, and to the randomized groups as represented in the registry record.

17. Why This Trial Matters Statistically

This trial is statistically informative because it combines random assignment, a placebo comparator, masking, and a large recorded enrollment with a long-term fixed-time outcome. Randomization is a design feature intended to support a comparison between groups, while masking can reduce the influence of expectations on trial conduct and outcome assessment. The registry record describes quadruple masking, but does not detail how it was implemented.

The result also illustrates why a point estimate and its uncertainty must be read together. The primary point estimate favors a higher disease-free percentage in the clodronate group, but the confidence interval spans zero. A single direction or p-value cannot replace consideration of the interval, the endpoint definition, and the analysis method. The reported comparison is an unadjusted re-calculation, rather than a documented reconstruction of the trial’s planned analysis.

The trial’s several survival and metastasis outcomes illustrate the challenge of interpreting a family of related endpoints. Consistent direction across estimates can be descriptively relevant, yet it does not remove the need to consider multiple testing, outcome definitions, and the dependence among measures. The record does not report multiplicity procedures or full analysis specifications.

Finally, the sample-size illustrations show how planning targets depend on the assumed effect size and power goal. They are distinct from the trial’s own design rationale, which is not reported in the registry record. Keeping planning calculations separate from observed results prevents a retrospective calculation from being mistaken for an original protocol decision or evidence of achieved power.

18. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record provides only limited detail about how the posted survival percentages were estimated. Although the primary endpoint is described as time to first event, the posted result is a percentage at 8 years. The record does not report the statistical estimator, the handling of censoring, follow-up completeness, or whether the percentage is based on a time-to-event analysis or another approach.

Outcome definitions are not fully specified. The primary event includes recurrence, a second primary cancer, or death, but the registry does not provide further operational definitions or component counts. The secondary outcome labels likewise do not provide complete event rules. This restricts comparison of the posted measures with differently defined outcomes in other settings.

The record does not report the trial’s analysis population, participant flow, missing-data methods, original statistical plan, or subgroup analyses. Although the description includes chemotherapy and/or hormonal therapy or no therapy, the reported results do not separate these contexts. The posted group comparison therefore cannot answer whether results differed across those treatment circumstances.

Several statistical details are also unavailable: the original sample-size justification, any interim analysis or stopping rules, the approach to multiplicity, and the planned model. The simple unadjusted re-calculations from posted summary statistics do not resolve these gaps. In addition, incidence of non-skeletal metastasis is listed as a secondary outcome, but its result is not reported in the registry record.

These limitations concern the information available in the registry record and do not establish that particular procedures were absent from the trial. They do mean that the posted results are not sufficient to evaluate every aspect of trial conduct, analysis, or outcome reporting.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Clodronate With or Without Chemotherapy and/or Hormonal Therapy in Treating Women With Stage I or Stage II Breast Cancer — NCT00009945.
• Registry record last updated 2017-12-13; status last verified 2017-11.
• Results first posted 2017-11-20.
• 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.

22. Record Summary

The registry describes a completed randomized phase III, parallel-group, quadruple-masked trial sponsored by NSABP Foundation Inc. It enrolled 3323 women with stage I or stage II breast cancer and compared clodronate with placebo; both arm descriptions specify 2 tablets once daily for 3 years.

The primary endpoint is disease-free survival at 8 years, defined by recurrence, a second primary cancer, or death. The posted percentages are 81.0 for clodronate and 79.6 for placebo. The unadjusted re-calculated risk difference is 0.014, with a 95% confidence interval from -0.013 to 0.042 and p = 0.298.

Secondary survival results are also posted, while the result for incidence of non-skeletal metastasis is not reported in the registry record. The registry does not report the original statistical analysis plan, missing-data methods, multiplicity procedures, or subgroup results.