Impact of Chemotherapy Followed by Aromatase Inhibitors on Bone Health of Women With ER-positive Early Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Impact of Chemotherapy Followed by Aromatase Inhibitors on Bone Health of Women With ER-positive Early Breast Cancer (NCT01298362), a registered phase not stated study. The primary outcome is Mean Percentage Change in Lumbar Spine Bone Mineral Density From Baseline (Before Chemotherapy Commencement) to Month 12 of AI Therapy.

2. Clinical Question

The study also describes bone mineral density measurements at the hip and lumbar spine at several treatment stages, as well as bone fracture rate. These outcomes address different aspects of bone health and use different time intervals. They do not replace the primary question, which focuses on lumbar-spine change across the chemotherapy and aromatase inhibitor treatment sequence in the chemotherapy cohort.

The record reports enrollment of 290, but the primary outcome population is defined by having measurements at both specified times. The number of participants meeting that requirement is not reported in the registry record. The posted information therefore defines the question and measurement schedule, but does not establish the size of the analyzed primary outcome population or the amount of bone mineral density change observed.

3. Trial Design

This is a completed study registered as NCT01298362, sponsored by the Hellenic Breast Surgeons Society. The registry record gives a start date of 2011-03 and a primary completion date of 2013-12. Its stated setting is real-world clinical practice in Greece. The record lists breast cancer and other disorders of bone density and structure among the conditions studied.

The arm descriptions distinguish patients treated with aromatase inhibitors as first-line therapy from patients who received aromatase inhibitors as maintenance therapy after chemotherapy. Both descriptions concern postmenopausal patients with estrogen receptor-positive early breast cancer. Aromatase inhibitor treatment is described as lasting 12 months. For the post-chemotherapy cohort, initial chemotherapy is described as anthracycline- and/or taxane-based, with a treatment duration of 1-6 months.

The record does not state how participants were allocated to these treatment sequences. It explicitly warns that the comparison is not randomized, that allocation is not stated, and that the arms are not a like-for-like control comparison. Consequently, differences between cohorts, if estimated, could reflect differences between the patients or treatment circumstances as well as the treatment sequence. The registry record does not describe methods to address such differences.

The primary outcome description places the main comparison within the chemotherapy cohort: mean percentage change in lumbar-spine bone mineral density from before chemotherapy to the measurement after 12 months of aromatase inhibitor therapy. The hormone-therapy cohort is described as a control group. The relationship between that label and the arm descriptions is not explained further in the registry record.

The record lists seven outcome measures and gives the primary outcome timeframe as baseline and month 13-18, corresponding to 1-6 months of chemotherapy plus 12 months of aromatase inhibitor therapy. It reports enrollment of 290, but participant flow by cohort, outcome, or analysis population is not reported in the registry record. The number of analyses is recorded as zero; no inferential analysis result is posted.

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:

Analysis population for the primary outcome, as defined in the registry: Patients with LS BMd measurements both at baseline and at 12 months of AI therapy.

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.

Population: This analysis is based on the 209 patients having full data (i.e. BMD measurements at baseline and at 12 months) however, their profile is similar to the profile of the whole sample of 290 patients originally enrolled.

6. Primary Endpoint

The registry lists the primary outcome as Mean Percentage Change in Lumbar Spine Bone Mineral Density From Baseline (Before Chemotherapy Commencement) to Month 12 of AI Therapy, measured over Baseline and month 13-18 (1-6 months of chemotherapy + 12 months of AI therapy).

The primary endpoint is the mean percentage change in lumbar-spine bone mineral density from baseline before chemotherapy commencement to the measurement after 12 months of aromatase inhibitor therapy. The primary outcome description specifies that the comparison applies to the chemotherapy cohort. The unit is percentage of change, and the stated summary measure is a mean with a 95% confidence interval.

Bone mineral density is a continuous measurement. A mean percentage change summarizes the average relative change across the participants whose measurements contribute to the endpoint. It does not, by itself, describe how widely individual participant changes varied. The confidence interval is intended to express uncertainty around the estimated mean; its width depends on the data and the analysis. The endpoint estimate and confidence interval are not reported in the registry record, so their direction, magnitude, and precision cannot be described.

The measurement schedule includes assessment before chemotherapy, before aromatase inhibitor therapy, and at the end of the 12 month follow-up while patients were receiving aromatase inhibitor treatment. The primary endpoint uses the pre-chemotherapy and later measurement, thereby covering the treatment sequence rather than isolating change during aromatase inhibitor therapy alone. The registry record also lists outcomes using other starting points, including before aromatase inhibitor commencement. Those are distinct questions and should not be conflated with the primary endpoint.

For measurement, the record describes dual-energy X-ray absorptiometry at the lumbar spine and hip. It states that measurements were performed with the Explorer absorptiometer produced by Hologic, with the same model and identical software used at two centres in other cities. The primary population requires measurements at both baseline and 12 months of aromatase inhibitor therapy. The number with paired measurements and the handling of missing measurements are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a continuous outcome: mean percentage change in lumbar-spine bone mineral density. A continuous outcome can take a range of measured values rather than placing participants into categories. A mean gives a measure of the average observed change among the participants included in an analysis. It does not imply that every participant had a change equal to that mean, and it does not describe the spread of individual values unless a separate measure of dispersion is reported.

What does a confidence interval communicate?

The registry record specifies a 95% confidence interval for the primary mean. In general, a confidence interval expresses uncertainty about an estimated quantity using the observed data and the method used to construct the interval. A narrower interval indicates greater precision under that method; a wider interval indicates less precision. It is not a range containing every participant’s change, and it does not resolve biases created by the way cohorts were formed. No endpoint estimate or confidence interval bounds are reported in the registry record, so the precision of the primary outcome cannot be assessed.

What does the measurement schedule mean?

The primary outcome compares lumbar-spine measurements before chemotherapy with measurements after 12 months of aromatase inhibitor therapy. The stated timeframe is baseline and month 13-18, reflecting 1-6 months of chemotherapy followed by 12 months of aromatase inhibitor therapy. This is a change across the described sequence. It is not a measurement of chemotherapy alone, nor is it limited to change during aromatase inhibitor therapy. Other listed outcomes use different starting points, including before aromatase inhibitor commencement, and should be interpreted as separate endpoints.

Measurements were made at the lumbar spine and hip using dual-energy X-ray absorptiometry. The registry record describes an Explorer absorptiometer and states that two centres in other cities used the same model with identical software. Consistent equipment and software can support comparability of measurements across sites, but they do not establish that all measurement or analysis procedures were identical. Further details of quality control, calibration, and measurement reliability are not reported in the registry record.

Why does the cohort comparison limit causal interpretation?

The arms represent different treatment sequences, and allocation is not stated. The record explicitly says the comparison is not randomized and that the arms are not a like-for-like control comparison. In general, random allocation can help balance measured and unmeasured characteristics between groups. Without it, the groups may differ for reasons related to clinical choices or participant characteristics. A difference in outcomes between such groups would therefore be an association, not automatically an effect caused by the treatment sequence.

Statistical adjustment can sometimes account for measured differences, but it cannot guarantee control of unmeasured differences. The registry record does not report an adjusted model, the covariates used, or any other method for addressing confounding. It also does not report whether any group comparison was performed. The posted record therefore supports describing the design limitation, but not claiming that it was resolved analytically.

What can the sample-size assumptions tell readers?

The planning illustration is described as a calculation based on the observed effect, using a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It considers the effect to detect as a stated fraction of the observed effect. Such calculations can illustrate the number of participants per arm needed for a specified planning target under stated assumptions. They are not the trial’s own sample-size justification, and they are not observed power. The registry record does not report the protocol’s sample-size rationale.

Planning results depend on the assumed effect and statistical model. If an assumed effect is smaller, more participants may generally be needed to distinguish it from random variation under the same design assumptions; this is a general statistical principle, not a finding about this study. A planning calculation cannot show whether the enrolled study had adequate power for the endpoint unless its assumptions, actual analysis population, and analysis method are suitable and known. The primary endpoint result and the number analyzed are not reported in the registry record.

Why can over-dispersion matter?

In general, over-dispersion means that observed variability is greater than a statistical model assumes. If a model understates variability, uncertainty intervals can be too narrow and significance tests can be too optimistic. The primary outcome is a continuous measure, and the registry record does not describe an over-dispersion analysis or a statistical model for the primary endpoint. This concept is therefore general context rather than a description of a method used in this study.

What does a significance level mean?

In general, a significance level is a threshold chosen for a statistical test that limits the probability of a specified type of false-positive result under the test’s assumptions. The 0.05 level appears in the planning illustration, but the inferential analysis plan for the trial is not reported in the registry record. It should not be assumed that this planning assumption was the analysis threshold used for the study’s results.

The registry record lists seven outcome measures and zero analysis entries. It does not report tests, model specifications, adjustment procedures, confidence interval methods, or estimates. Statistical methods should therefore be distinguished from the measurement plan: the record describes what was measured and when, but does not provide enough information to reconstruct how the primary outcome was analyzed.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists seven outcome measures, including the primary lumbar-spine measure, hip and lumbar-spine percentage changes over other intervals, and bone fracture rate. Considering multiple outcomes can raise a multiplicity issue: in general, the more statistical tests conducted, the greater the chance of at least one apparently unusual result occurring by chance if no adjustment or hierarchy is used. The record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or which analyses were prespecified.

The record lists zero analysis entries. It does not report primary or secondary outcome estimates, p-values, confidence intervals, or an analysis plan. Whether the investigators adjusted for multiple comparisons, selected a primary analysis in advance, or conducted additional analyses is not reported in the registry record. No claim about the handling of multiplicity can therefore be made.

The primary outcome population is defined as patients with lumbar-spine measurements at baseline and 12 months of aromatase inhibitor therapy. This makes paired measurements central to inclusion in that outcome. The number of participants with both measurements, the number missing either measurement, and reasons for missingness are not reported in the registry record. Methods for handling missing measurements, such as excluding incomplete pairs or imputing values, are also not reported.

The enrollment figure of 290 does not establish how many participants contributed to any particular outcome. The registry record does not provide participant flow, analysis-population definitions beyond the primary endpoint’s measurement requirement, or whether all enrolled participants were included in each outcome analysis. It also does not report an intention-to-treat or per-protocol analysis population. These omissions limit assessment of potential selection bias and the representativeness of any analyzed group.

11. Safety Results

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

Other (non-serious) adverse events

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

The adverse-event record presents a CT Cohort and an HT Cohort. For the CT Cohort, 86 participants are listed as at risk for serious adverse events and 0 as affected; 86 are listed as at risk for other adverse events and 0 as affected. For the HT Cohort, the corresponding counts are 123 at risk and 0 affected for serious adverse events, and 123 at risk and 0 affected for other adverse events.

These are the counts recorded in the adverse-event listing, not a detailed description of event monitoring or adjudication. The record does not list serious adverse-event terms. Death counts are not reported in the registry record. The adverse-event population counts are not identified as the same as the primary outcome population, which requires paired lumbar-spine measurements.

Zero recorded affected participants in these entries should be read narrowly: the registry listing reports no affected participants for the displayed categories. It does not establish that no events occurred outside the recorded categories or observation period, and it does not resolve differences in follow-up or ascertainment. The registry record does not describe safety-monitoring procedures, reporting thresholds, or the completeness of adverse-event collection. These entries also do not support a causal comparison between the nonrandomized cohorts.

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

The record establishes the study’s intended clinical measurement question, its cohort descriptions, and its measurement schedule. It does not report the primary lumbar-spine bone mineral density estimate, its confidence interval, or analyses of the listed secondary outcomes. As a result, the posted information does not show the direction or magnitude of bone mineral density change, nor how precisely any mean change was estimated.

The study is not described as randomized, allocation is not stated, and the record cautions that the arms are not a like-for-like comparison. Even if a numerical contrast were posted, differences between the cohorts would not by themselves establish that the treatment sequence caused the difference. The cohorts may differ for other reasons, and the record does not report an adjusted analysis that would address those differences.

The primary outcome spans before chemotherapy to after 12 months of aromatase inhibitor therapy in the chemotherapy cohort. It therefore concerns change across a treatment sequence. It should not be interpreted as an estimate of the effect of chemotherapy alone or aromatase inhibitor therapy alone. Other listed outcomes use different time intervals or measurement sites, and their results are not reported in the registry record.

The adverse-event entries record zero affected participants in the listed serious and other adverse-event categories for the displayed cohorts. Those counts do not establish the absence of all adverse events, and they do not provide a comparative estimate of safety. Death counts and detailed event terms are not reported in the registry record.

In general, a well-defined endpoint and a measurement schedule help specify what a study set out to evaluate. They cannot substitute for posted results, participant counts for each analysis, or details of statistical methods. The enrollment of 290 does not reveal the number with complete measurements or the number included in any analysis. The record therefore supports an account of the research question and design limitations, but not a conclusion about the observed bone mineral density outcome or a treatment effect.

13. Why This Trial Matters Statistically

This study illustrates why the treatment sequence and endpoint timeframe need to be read together. The primary outcome begins before chemotherapy and ends after 12 months of aromatase inhibitor therapy. That interval captures the combined course described for the chemotherapy cohort; it does not isolate the contribution of any one treatment stage. A measurement collected at a different starting point answers a different question.

It also illustrates the difference between an outcome definition and an outcome result. The registry record specifies a continuous measure, a mean summary, a confidence interval, measurement sites, and a follow-up schedule. Those details clarify what an estimate would represent. But because the estimate and interval are not reported, neither the amount of change nor its precision can be evaluated from the posted record.

The comparison structure is another important statistical feature. The record does not state allocation and explicitly warns that the cohorts are not like-for-like controls. This limits causal interpretation even if outcomes were available. Describing a cohort as a control group does not by itself make it exchangeable with the other cohort; that depends on study design and the adequacy of methods addressing differences.

Finally, the record lists several outcome measures while providing no analysis entries. This makes multiplicity, missing data, and analysis-population questions especially relevant. The primary endpoint requires paired measurements, but the number of participants with those measurements is not reported. The record thus demonstrates why enrollment, endpoint definition, and analyzed sample size are distinct pieces of information, and why registry completion alone does not indicate that interpretable results are posted.

14. 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 central limitation for interpretation is that the primary outcome result is not reported in the registry record. Without the mean percentage change and its 95% confidence interval, neither the observed change nor its precision can be assessed. Results for the listed secondary outcomes are also not reported, so the record does not permit a broader comparison across bone sites, treatment intervals, or fracture outcomes.

The record describes a nonrandomized comparison and states that allocation is not stated and the arms are not a like-for-like control comparison. This makes causal interpretation limited. The registry record does not report participant characteristics by cohort, methods for adjustment, or the handling of possible confounding. It is therefore not possible to assess whether cohort differences were measured or addressed.

Although enrollment is reported as 290, the number of participants contributing to the primary endpoint is not reported. The endpoint requires lumbar-spine measurements at baseline and 12 months of aromatase inhibitor therapy, but completeness of those measurements, participant flow, and reasons for missing data are not reported in the registry record. The extent to which the outcome population represents all enrolled participants cannot be assessed.

The record lists seven outcomes but no analysis entries. Statistical models, hypothesis tests, covariate adjustment, multiplicity handling, and analysis-population definitions are not reported. Nor does the record provide the study’s own sample-size justification or a description of interim analyses. These details should not be inferred from the planning illustration.

For safety, the displayed adverse-event counts are limited to the categories recorded, and serious-event terms are not listed. Death counts are not reported in the registry record. Monitoring procedures, event definitions, and the completeness of safety reporting are also not described. These omissions constrain interpretation of the zero affected counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Impact of Chemotherapy Followed by Aromatase Inhibitors on Bone Health of Women With ER-positive Early Breast Cancer — NCT01298362.
• Registry record last updated 2016-09-20; status last verified 2016-07.
• Results first posted 2016-09-20.
• 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.

18. Record Summary

NCT01298362 is a completed study sponsored by the Hellenic Breast Surgeons Society, with enrollment of 290 and a stated real-world setting in Greece. It concerns postmenopausal patients with estrogen receptor-positive early breast cancer receiving aromatase inhibitors either as first-line therapy or after chemotherapy. The primary endpoint is mean percentage change in lumbar-spine bone mineral density from before chemotherapy to after 12 months of aromatase inhibitor therapy in the chemotherapy cohort.

The registry record describes dual-energy X-ray absorptiometry measurements at the lumbar spine and hip, lists seven outcome measures, and specifies a primary outcome population requiring measurements at both time points. It also states that allocation is not stated and that the cohort comparison is not like-for-like. The primary endpoint result, confidence interval, participant count for that analysis, and statistical analysis are not reported in the registry record.