Safety and Efficacy of Alendronate (Fosamax) in Children With Osteoporosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Alendronate (Fosamax) in Children With Osteoporosis (NCT00259857), a randomized phase 2 study. The primary outcome is Number of Participants With Improvement in Bone Mineral Density (BMD) of Spine After Therapy.

2. Clinical Question

The primary outcome is expressed as a count of participants with improvement, rather than as the size of each participant’s change in bone mineral density. The registry says lumbar-spine bone mineral density was assessed using a DXA scan at a visit 12 months after alendronate or placebo treatment. It does not report the threshold used to define improvement.

The registry describes the study as a Phase II randomized, double-blind, placebo-controlled, prospective crossover trial. The intervention descriptions include calcium and vitamin D with both alendronate and placebo. In a crossover design, participants receive different study conditions in sequence, so the comparison concerns treatment experiences within a study that also has sequence and time periods. The registry’s arm descriptions identify the sequences as alendronate followed by placebo and placebo followed by alendronate.

The outcome counts are reported by sequence group, and the record does not provide a treatment-effect estimate separating the alendronate and placebo periods. It also does not give participant-level changes, a comparison of changes, or uncertainty around a treatment contrast. Consequently, the counts alone do not answer how large or precise a difference between treatments may be.

3. Trial Design

This was a Phase II, randomized, double-blind, placebo-controlled, prospective crossover trial sponsored by the Medical University of South Carolina. The registry lists the study as completed. Its recorded start was 2003-10, and its primary completion was 2008-03. The stated enrollment was 22.

The arm descriptions identify two treatment sequences. One sequence is labeled alendronate in the first year followed by placebo, with calcium and vitamin D; the other is labeled placebo in the first year followed by alendronate, also with supplements. The descriptions state that participants crossed over in the second year. They do not give a complete account of the timing, administration, or analysis for every treatment period. One sequence description is incomplete in the registry record, so details beyond the stated crossover and labels should not be inferred.

Randomization assigns participants to a treatment sequence; it does not make the sequence groups interchangeable with independent treatment groups at each period. Blinding is intended to limit differences in behavior or assessment associated with knowing the assigned condition. The registry identifies double masking but does not report who was masked or how masking was maintained.

The primary outcome was the number of participants with improvement in spine bone mineral density after 12 months of therapy. The listed group counts are 10 and 9, associated with the two sequence labels. These outcome counts are not identical to the adverse-event risk counts, which are 11 in each sequence group. The registry does not explain this difference. The record lists six outcome measures and four secondary-outcome entries, including repeated descriptions of hip bone mineral density improvement and atraumatic fractures.

The trial description reports both per-protocol and intention-to-treat analysis populations. However, detailed analysis methods, participant flow, treatment-period results, and an adjusted crossover comparison are not reported in the registry record. The reported endpoint counts therefore have to be read as registry summaries, not as a complete account of the planned or conducted statistical analysis.

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.

12 Months Treatment

Reasons for not completing this period:

24 Months Treatment

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was done per protocol and intention to treat.

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 Number of Participants With Improvement in Bone Mineral Density (BMD) of Spine After Therapy, measured over 12 months therapy.

The primary endpoint counts participants classified as having improvement in lumbar-spine bone mineral density after 12 months of therapy. The registry says bone mineral density was assessed by DXA at a visit 12 months after alendronate or placebo treatment. It reports counts of 10 and 9 for the two sequence groups.

Bone mineral density is a measured characteristic of bone, and a change in that measure can be used as an endpoint in a study of osteoporosis. A count of participants with improvement reduces a continuous measurement to a binary classification: each participant is categorized as having improvement or not having improvement. This makes the outcome straightforward to express as a number of participants, but the count does not show the amount of change or how close a measurement was to any threshold.

The registry does not report the definition of improvement, the underlying bone mineral density values, the magnitude of change, or the uncertainty of those changes. It also does not report a treatment contrast for the primary outcome. Thus, the posted endpoint counts describe how many participants were classified as improved in each sequence group, but they cannot by themselves establish whether one treatment period had a different result from the other.

Because this was a crossover study, interpretation also depends on how measurements from the treatment periods were assigned and compared. The registry record does not describe that analysis in enough detail to identify a period-specific treatment estimate. The endpoint is clinically interpretable as a count, but its statistical interpretation is limited without the classification rule and comparison method.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s design and endpoint require care in interpreting the posted counts. The registry describes random allocation, double masking, placebo control, and a crossover model. The primary outcome is binary: a participant either met the study’s definition of improvement in spine bone mineral density or did not. The registry reports counts, not continuous measurements or an estimated treatment effect.

What does a crossover design compare?

In general, a crossover design assigns participants to sequences of treatments, with participants receiving more than one condition over time. This can allow comparisons that account for stable differences between participants, because each participant may contribute observations under more than one condition. The comparison nevertheless depends on which outcomes are collected in each period and how period and sequence are handled analytically. The registry describes two sequences and a second-year crossover, but does not provide a complete statistical description of the period-level analysis.

In this trial, the posted primary outcome counts are attached to sequence groups. They are not counts separately reported for the alendronate and placebo periods. A sequence-group count cannot be interpreted as a treatment-specific count unless the outcome definition and analysis establish that mapping. The registry does not report a direct within-participant contrast, a model for repeated measurements, or a treatment estimate adjusted for sequence or period.

What does a binary count leave out?

For a binary endpoint, the number classified as improved does not convey the magnitude of the measured change. General statistical practice distinguishes such a count from a continuous endpoint, which would retain the amount of change in bone mineral density. Categorizing a continuous measure can make results easier to summarize, but interpretation depends on the cutoff or rule that defines improvement. That rule is not reported in the registry record.

The posted outcome counts also do not include an interval estimate or a test of a treatment contrast. In general, an interval estimate communicates uncertainty around an estimated effect, and a hypothesis test evaluates compatibility with a specified null comparison under assumptions. Neither can be reconstructed from the listed counts alone in a crossover design without the participant-level pairing, period-level outcomes, and analysis details. No confidence interval or p-value for the primary comparison is reported.

How should planning calculations be read?

In general, sample-size planning asks how many participants per arm might be needed under selected assumptions to detect a specified effect with a chosen significance level and power. Such calculations are prospective illustrations, not evidence that a study had a particular probability of finding a result after completion. The registry describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect.

Those assumptions do not establish the trial’s original design rationale. The registry does not report the original sample-size justification or enough detail to evaluate how the observed effect for planning was obtained. Any planning values should be treated as illustrations, not as observed power or as a substitute for the trial’s actual estimate and uncertainty. The record’s enrollment and endpoint counts do not independently establish whether the study was adequately powered.

Why does over-dispersion matter in general?

General statistical models make assumptions about how variable observations are. Over-dispersion occurs when the observed variability is greater than a model assumes. If it is ignored, uncertainty can be understated and inferences can appear more precise than warranted. The registry reports a binary count endpoint and does not report a model or an over-dispersion assessment. It would therefore be inappropriate to claim that over-dispersion was present or that a particular adjustment was used.

What information is needed for a fuller analysis?

A fuller statistical interpretation would require the definition of improvement, participant-level or period-specific outcome data, the treatment contrast, and an account of the analysis populations and missing observations. For a crossover comparison, it would also be useful to know how treatment sequence and period were addressed and whether any carryover assessment was planned or performed. These details are not reported in the registry record. The registry’s statement that analyses were done per protocol and intention to treat identifies intended analysis populations, but does not supply the procedures or results needed to reproduce or assess those analyses.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Gr-1:Yr-1/Yr-2: Alendronate/Pbo, Calcium, Vitamin ", "Gr-2:Yr-1/Yr-2: Pbo/Alendronate, Calcium and Vitam")
n      <- c(10, 9)
events <- c(10, 9)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Gr-1:Yr-1/Yr-2: Alendronate/Pbo, Calcium, Vitamin   10  10  100.0  69.2  100.0  72.2  100.0  71.5  99.8
ARM  Gr-2:Yr-1/Yr-2: Pbo/Alendronate, Calcium and Vitam  9  9  100.0  66.4  100.0  70.1  100.0  69.2  99.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and four secondary-outcome entries. The secondary entries include hip bone mineral density improvement and atraumatic fractures, with each description appearing twice. The record does not explain whether these repeated entries represent separate measures, time points, or duplicate listings. It also does not report a multiplicity adjustment or a hierarchy for interpreting multiple outcomes.

Multiplicity is a general statistical concern when several outcomes or comparisons are examined: the chance of at least one apparently notable result can increase as the number of tests increases. Without the analysis plan or results for the secondary outcomes, the role of multiplicity in this study cannot be assessed. The registry records zero analyses in its analysis listing, and no outcome-specific statistical test results are posted in the registry record for interpretation.

The primary outcome description says that analysis was done per protocol and intention to treat. These terms refer, in general, to different analysis populations: an intention-to-treat analysis generally retains participants according to randomized assignment, while a per-protocol analysis generally focuses on those meeting specified protocol criteria. The registry does not define either population, report separate estimates, or explain how crossover periods were handled for those analyses.

Missing-data methods, reasons for missing observations, and the number of participants with missing primary endpoint measurements are not reported in the registry record. The difference between the primary outcome group counts and the adverse-event risk counts is also unexplained. Without a participant-flow account or analysis denominators, the effect of missing or excluded data cannot be evaluated.

12. 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 lists zero serious adverse events in each of the two sequence groups, with 11 participants at risk in each group. It also lists zero other adverse events in each group, with 11 at risk in each. No serious adverse-event terms are listed. These are the counts recorded in the registry; they should not be read as proof that risk was absent.

The record reports safety results by sequence group, not separately by treatment period. Because the study crossed participants between alendronate and placebo, these group-level figures do not identify which events, if any, occurred during a particular treatment. The registry does not report event timing, exposure-specific denominators, follow-up completeness, or an explanation for why the safety risk counts differ from the primary outcome counts.

Deaths are recorded as not reported in the registry record. A missing death count is not equivalent to a reported count of zero. More generally, a zero event count is a descriptive observation over the recorded follow-up and population; it does not establish that an event could never occur, nor does it quantify uncertainty about event risk. The registry record does not provide an interval estimate for the safety counts.

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

The posted primary outcome provides a descriptive count: 10 participants were recorded as having improvement in spine bone mineral density in one sequence group, and 9 in the other. The outcome was assessed after 12 months of alendronate or placebo therapy according to the registry description. The available counts do not show how much bone mineral density changed or give a treatment-specific comparison.

These values should not be interpreted as a randomized comparison of alendronate against placebo based solely on sequence-group membership. In a crossover study, each sequence receives different treatments over time. A direct treatment contrast would require period-level data and a suitable analysis. Neither a treatment-effect estimate nor its uncertainty is reported in the registry record.

The record also does not report a definition of improvement, missing-data handling, or separate results for the per-protocol and intention-to-treat populations mentioned in the endpoint description. The counts therefore leave unresolved how participants were classified and which observations contributed to each result. The difference between endpoint and safety denominators is unexplained as well.

Statistically, the result can be described as the number of participants classified as improved in each sequence group. It cannot establish the magnitude, direction, or precision of a treatment effect from these counts alone. Nor does the absence of a reported inferential comparison mean that the treatments are equivalent. An equivalence conclusion would require an appropriate design, margin, and analysis, none of which are reported in the registry record.

The safety listing reports zero serious and zero other adverse events in both groups, but it does not establish zero risk. The record provides no event timing by treatment and no death count. The trial results should therefore be read as limited registry summaries of an endpoint and adverse-event counts, rather than as a complete account of treatment effects or safety.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines a crossover design with an endpoint reported as a binary participant count. Crossover designs generate observations across treatment periods, while the posted primary outcome is reported by sequence group. That distinction matters: a sequence label is not itself a treatment-period estimate. A clear account of the treatment contrast and analysis is needed to connect the reported counts to the comparative question.

The endpoint also illustrates the trade-off involved in reducing a measured quantity to a category. A count of participants classified as improved is easy to state, but it does not convey the size of change in bone mineral density. The registry does not report the threshold used to define improvement or the continuous measurements. As a result, the count is less informative about measurement-level change than a reported continuous estimate would be.

The record mentions both per-protocol and intention-to-treat analysis populations, but supplies no separate results or definitions. This highlights why analysis-population labels alone are not enough to assess a study. Readers also need to know which participants and periods contributed to an estimate, how missing observations were handled, and how the crossover structure was modeled.

Finally, the record lists secondary outcomes and planning assumptions without posting a full analysis or uncertainty estimates for the primary comparison. Planning calculations can help describe assumptions for future research, but they do not establish observed power or replace a treatment-effect estimate. This trial therefore offers a useful example of why statistical interpretation depends not only on outcome counts, but also on the design-specific analysis and transparent reporting of uncertainty.

15. Limitations

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

The primary endpoint is reported as a binary count, while the registry does not give the definition of improvement, the underlying bone mineral density measurements, or the magnitude of change. This prevents assessment of how the classification relates to the measured endpoint and limits interpretation of the counts.

The crossover design is described in broad terms, but the registry does not report a period-specific comparison or explain how treatment sequence, period, or possible carryover were handled. The outcome counts are attached to sequence groups, so they do not provide a direct treatment-specific result. One arm description is incomplete, and the registry does not fully detail the treatment-period schedule or analysis.

The endpoint counts are 10 and 9, while the adverse-event risk counts are 11 in each group. The registry record does not explain the difference or provide participant flow, endpoint denominators, or reasons for missing observations. Although the endpoint description mentions per-protocol and intention-to-treat analyses, their populations and results are not separately reported.

No treatment-effect estimate, confidence interval, or p-value is reported for the primary outcome. The registry also does not provide a statistical analysis plan, a sample-size justification, or details of multiplicity control. The secondary-outcome list repeats descriptions, without clarifying their status. Safety results are not allocated by treatment period, and deaths are not reported in the registry record. These limitations mean that the posted results are descriptive and do not support a precise comparative estimate.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Alendronate (Fosamax) in Children With Osteoporosis — NCT00259857.
• Registry record last updated 2011-01-19; status last verified 2010-12.
• Results first posted 2011-01-19.
• 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.

19. Record Summary

NCT00259857 is a completed Phase II randomized, double-blind, placebo-controlled prospective crossover trial sponsored by the Medical University of South Carolina. The registry lists 22 as the enrollment and records a start of 2003-10 and primary completion of 2008-03.

The trial studied alendronate with calcium and vitamin D, compared with placebo and the same supplements, using two crossover sequences. Its primary outcome was the number of participants with improvement in lumbar-spine bone mineral density after 12 months of therapy, assessed by DXA. The reported sequence-group counts are 10 and 9.

The registry describes analysis by per-protocol and intention-to-treat populations but does not report a treatment-effect estimate or uncertainty for the primary comparison. The improvement definition, missing-data methods, period-specific results, and explanation of differing outcome and safety denominators are not reported in the registry record. Safety listings show zero serious and zero other adverse events in each group; deaths are not reported.