Study of AMG 162 in Subjects With Advanced Cancer Currently Being Treated With Intravenous (IV) Bisphosphonates: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of AMG 162 in Subjects With Advanced Cancer Currently Being Treated With Intravenous (IV) Bisphosphonates (NCT00104650), a randomized phase 2 study. The primary outcome is uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 13.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group Phase 2 study sponsored by Amgen. The registry reports an enrollment of 111 and a completed status. The recorded study dates are 2005-01 for study start and 2008-01 for primary completion. Masking was none, so the study was not blinded according to the registry.

The three treatment groups were intravenous bisphosphonate every 4 weeks, denosumab 180 mg subcutaneously every 12 weeks, and denosumab 180 mg subcutaneously every 4 weeks. The arm-level primary-outcome analysis counts were 35, 33, and 36, respectively. These are the counts attached to the posted primary outcome and are not interchangeable with the different safety denominators.

The trial focused on people with advanced cancer and bone metastases who were being treated with intravenous bisphosphonates. The registry conditions include bone metastases in men with hormone-refractory prostate cancer, bone metastases in subjects with advanced breast cancer, and bone metastases in subjects with advanced cancer or multiple myeloma. The primary endpoint timeframe was 13 weeks. The posted secondary outcomes include additional uNTx measures, serum CTX, time to first skeletal-related event, skeletal-related events, and hypercalcemia.

Although randomization is reported, the method used to generate the allocation sequence and whether allocation was concealed are not reported in the registry record. The registry record does not report the original sample-size justification, planned interim analyses, or the full statistical analysis plan. The arm descriptions mention a possible extension phase, but its participation and analysis details 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.

Treatment Period (25 Weeks)

Reasons for not completing this period:

Follow-up Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who are randomized to the treatment phase, receive at least one dose of treatment phase investigational product, and have treatment phase baseline measurements of uNTx and at least one treatment phase post-baseline measurement of uNTx.

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 uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 13, measured over 13 weeks.

The primary endpoint was the number of participants with urinary N-telopeptide corrected by creatinine (uNTx/Cr) below 50 nmol/mmol at week 13. uNTx is a marker of bone resorption; correcting it by creatinine accounts for urine concentration when expressing the measurement. The endpoint turns a continuous laboratory measurement into a binary outcome: each participant either met the threshold at the specified assessment or did not.

A threshold outcome can make the result easy to describe as the proportion of participants reaching a prespecified biomarker level. It also discards information about how far each participant’s result was above or below the threshold. Participants with measurements close to opposite sides of the cutoff are placed in different categories, while participants with different values on the same side are grouped together. These are general features of dichotomizing a continuous measurement.

The primary analysis population required randomization to the treatment phase, receipt of at least one dose of treatment-phase investigational product, a treatment-phase baseline uNTx measurement, and at least one treatment-phase post-baseline uNTx measurement. Thus, the endpoint description does not imply that every randomized participant contributed to this analysis. uNTx is a biomarker endpoint; by itself, a difference in threshold attainment does not establish a difference in symptoms, skeletal events, or other clinical outcomes.

7. Results Posted in the Registry

• Denosumab 180 mg Q12W: 63.6% (21/33) versus 28.6% (10/35) on control; risk difference 35.1 percentage points (95% CI 12.9 to 57.3), risk ratio 2.23 (1.24–3.99); unadjusted two-proportion z-test p = 0.004.
• Denosumab 180 mg Q4W: 77.8% (28/36) versus 28.6% (10/35) on control; risk difference 49.2 percentage points (95% CI 29.0 to 69.4), risk ratio 2.72 (1.57–4.73); unadjusted two-proportion z-test p = <0.001.

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.

uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 25

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Denosumab 180 mg Q12W: 63.6% (21/33) versus 37.1% (13/35) on control; risk difference 26.5 percentage points (95% CI 3.6 to 49.4), risk ratio 1.71 (1.04–2.83); unadjusted two-proportion z-test p = 0.029.
  • Denosumab 180 mg Q4W: 63.9% (23/36) versus 37.1% (13/35) on control; risk difference 26.7 percentage points (95% CI 4.3 to 49.2), risk ratio 1.72 (1.05–2.82); unadjusted two-proportion z-test p = 0.024.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Denosumab 180 mg Q12W than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Denosumab 180 mg Q4W than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percent Change of uNTx (Corrected by Creatinne) From Baseline to Week 25

• 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:
  • Denosumab 180 mg Q12W: mean -69.09 versus -32.91 on control; difference -36.18 (95% CI -65.57 to -6.79), standardized effect d = -0.72; z-test p = 0.016.
  • Denosumab 180 mg Q4W: mean -41.68 versus -32.91 on control; difference -8.77 (95% CI -61.63 to 44.09), standardized effect d = -0.09; z-test p = 0.745.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Denosumab 180 mg Q12W than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Denosumab 180 mg Q4W and the control. The interval gives the range of effects that remain compatible with the data.

Time to Reduction of uNTX (Corrected by Creatinine) to <50nmol/mmol

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Regression, Cox); it was not recalculated.
• Result:
  • Bisphosphonate IV Q4W vs Denosumab 180 mg Q4W: hazard ratio 3.79 (95% CI 2.01–7.15), reported p < 0.001 (as reported in the registry).
  • Bisphosphonate IV Q4W vs Denosumab 180 mg Q12W: hazard ratio 4.32 (95% CI 2.23–8.36), reported p < 0.001 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval excludes no difference (a ratio of 1), so the hazard of the event is statistically higher for Bisphosphonate IV Q4W vs Denosumab 180 mg Q4W than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference (a ratio of 1), so the hazard of the event is statistically higher for Bisphosphonate IV Q4W vs Denosumab 180 mg Q12W than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes cover several aspects of bone turnover and skeletal health: uNTx threshold attainment at a later assessment, change in uNTx, time to reaching the threshold, serum CTX change, time to first skeletal-related event, skeletal-related events, and hypercalcemia. The posted results span more than one outcome type and use different analysis populations and methods. They should not be treated as a single uniform body of evidence.

Broadly, the posted threshold and time-to-threshold results point in the same direction as the primary week-13 result, while the continuous uNTx-change analyses do not show a consistent pattern across the reported comparisons. This mixture matters: results for reaching a cutoff and for average change answer related but distinct questions, and a group difference on one measure does not require an equally clear difference on another. The secondary results do not independently establish clinical benefit.

The registry lists time to first skeletal-related event, skeletal-related events, and hypercalcemia among the outcomes, but their results are not reported in the registry record. Therefore, the biomarker findings cannot be used to infer those clinical outcomes from this record. Additional secondary endpoint values and analyses should be interpreted on their own terms rather than inferred from the primary endpoint.

There are multiple secondary outcomes and comparisons. When many tests are considered, some apparently notable findings can occur by chance. The registry record does not report a multiplicity adjustment strategy or identify which secondary hypotheses, if any, were intended to be confirmatory. For that reason, unadjusted secondary results carry less weight than a prespecified primary analysis and are best read as supportive or exploratory evidence. This caution does not erase the observed results; it limits how strongly they can support broad conclusions.

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

• uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 25
• Percent Change of uNTx (Corrected by Creatinne) From Baseline to Week 25
• Time to Reduction of uNTX (Corrected by Creatinine) to <50nmol/mmol
• Duration of Maintaining uNTX (Corrected by Creatinine) < 50nmol/mmol
• Percent Change of Serum CTX From Baseline to Week 25
• Time to First Skeletal Related Event
• Skeletal Related Events
• Hypercalcemia

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: participants are counted according to whether their uNTx/Cr result was below the stated cutoff at week 13. For a binary outcome, a proportion describes the share of an analysis group meeting the endpoint. The posted arm counts and percentages offer a direct descriptive comparison, while a comparative effect measure summarizes how the groups differ. General statistical interpretation should distinguish these descriptions from evidence about other outcomes.

What does an odds ratio describe?

The registry reports comparative odds ratios using the Cochran-Mantel-Haenszel method. Odds are the count of participants with the endpoint relative to the count without it. An odds ratio compares those odds between groups. A value above 1 in the reported comparisons indicates higher odds of meeting the threshold in the denosumab group than in the bisphosphonate group, given the direction of the comparisons. The odds ratio is not a risk difference, and it is not the same as the ratio of the two percentages.

The Cochran-Mantel-Haenszel method is a standard way to combine comparisons across strata. It can account for stratification when the underlying analysis uses strata. The registry record names the method but does not state the stratification factors or give enough detail to describe how the analysis was implemented. No specific adjustment factors should therefore be inferred from the method name alone.

How do the re-calculations differ?

The unadjusted re-calculations use the posted participant counts to estimate risk differences and their confidence intervals. A risk difference is the difference between the proportions meeting the endpoint in two groups. It expresses an absolute difference in the observed proportions, whereas an odds ratio expresses a relative comparison of odds. The re-calculations do not reproduce the registry’s Cochran-Mantel-Haenszel analysis. Their p-values are unadjusted and should be interpreted as simple comparisons based on the posted summaries, not as a replacement for the sponsor’s analysis.

The registry does not identify a discrepancy between the posted counts and its reported analysis. The sponsor’s reported method and estimates are therefore the main registry-reported inferential results. The re-calculations are useful as a separate, transparent description of the unadjusted contrast, but they answer the question using a different effect measure and analysis approach.

What does a confidence interval convey?

A confidence interval gives a range of values compatible with the data and the statistical method, under its assumptions. It communicates uncertainty in the estimated effect; it is not a range containing a known true value with certainty. For the binary outcome, the registry reports 95% confidence intervals for the arm percentages and for the odds ratios. The re-calculated risk differences also have intervals. Their widths reflect that the estimates are based on finite groups, and the intervals allow readers to judge how precisely the effects have been estimated.

A p-value describes how unusual data at least as incompatible with a specified null hypothesis would be under the test’s assumptions. It does not give the probability that the null hypothesis is true, nor does it measure clinical importance. The registry’s reported p-values accompany the comparative analyses. The re-calculated p-values are explicitly unadjusted. Neither type of p-value resolves questions about other endpoints, analysis choices not described in the registry, or the relevance of the biomarker to clinical outcomes.

How should secondary analyses be viewed?

The registry lists multiple secondary outcomes, including binary threshold outcomes, continuous changes, and time-to-event outcomes. Each outcome type requires a different summary. A mean change describes an average continuous change; a median time describes the midpoint of observed event times; and a hazard ratio compares event rates over time under the assumptions of a time-to-event model. The registry reports an ANCOVA p-value for the continuous uNTx change outcome and Cox regression results for time to threshold reduction. The precise analysis details beyond those method labels are not reported in the registry record.

Multiple outcomes and comparisons create more opportunities for apparently notable results by chance. Unless a prespecified strategy controls the overall error from testing multiple hypotheses, individual secondary p-values should be treated as exploratory rather than as a set of confirmatory conclusions. The registry record does not report a multiplicity adjustment plan. This general concern applies even when individual results have small p-values; it is not a claim that a particular result is false.

General statistical principles also matter for the open-label design and the endpoint definition. A laboratory threshold is less directly subjective than a symptom rating, but open-label knowledge can still affect study conduct and other assessments. The primary analysis population’s measurement requirements mean that participants without the required baseline or follow-up measurement are not included in that defined group. How missing measurements were handled beyond this population definition is not reported in the registry record.

11. Confidence Intervals and Precision

The registry reports 95% confidence intervals for the primary group percentages: 14.6 to 46.3 for bisphosphonate, 45.1 to 79.6 for denosumab every 12 weeks, and 60.8 to 89.9 for denosumab every 4 weeks. These intervals show that the estimated proportions are not exact; a range of values is compatible with the observed data under the methods used. The group intervals overlap to some extent, but overlap between separate group intervals is not itself a formal test of the difference between groups.

For the reported comparative odds ratios, the 95% confidence interval is 3.35 to 45.03 for every-4-weeks denosumab versus bisphosphonate and 1.74 to 16.36 for every-12-weeks denosumab versus bisphosphonate. Both intervals are wide, particularly the first, so the data are more informative about the direction of the reported contrast than about its exact magnitude. The intervals include values representing a range of possible effect sizes; a point estimate alone would conceal this uncertainty.

The unadjusted risk-difference intervals are 0.29 to 0.694 for every-4-weeks denosumab and 0.129 to 0.573 for every-12-weeks denosumab. The interval estimates are based on the posted counts and a simple unadjusted method. They should be distinguished from the sponsor’s reported odds-ratio intervals because the scales and analyses differ.

These intervals describe precision for the stated outcome and analysis population, not precision for clinical benefit or for the trial’s other outcomes. The registry does not report confidence intervals for every secondary result. A lack of an interval in the record does not mean an estimate is precise; it means that precision cannot be assessed from a reported interval for that result.

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 observed effects, not the trial’s original design calculations. For the binary and continuous-outcome comparisons, the displayed counts are participants per arm. For the time-to-event comparisons, the figures are total events, not participants per arm. They should not be read as the actual enrollment or as the number of participants who experienced an event.

The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The assumed effect to detect is the stated fraction of the observed effect. The time-to-event illustrations use the Schoenfeld method. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

The 80% power column represents the planned number of participants per arm, or total events for time-to-event calculations, under which a study would have an 80% probability of detecting the specified effect if that effect and the assumptions were correct. The 90% column uses a higher probability of detection and therefore generally calls for more information. These are planning quantities, not a guarantee that a future study will obtain a significant result.

Rows based on smaller fractions of the observed effect require more participants per arm or more total events than rows based on the full observed effect. This is a general feature of power planning: smaller effects are harder to distinguish from random variation. Because the observed effect may itself be imprecise, especially in a modest trial, using it directly can yield optimistic planning illustrations. These values are not observed power.

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 = 0.286; treatment proportion p₁ = 0.636; average p̄ = 0.461.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7050 = 1.3817.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6599 = 0.5554.
4. n = (1.3817 + 0.5554)² / (0.3506)² = 30.5, rounded up to 31 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 <- 0.285714285714286                          # control proportion
p1 <- 0.636363636363636                          # 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(104650)
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 = 31 (80% power), 41 (90% power)
 75% of observed effect: n per arm = 54 (80% power), 72 (90% power)
 50% of observed effect: n per arm = 119 (80% power), 158 (90% power)
power.prop.test: 30.5 
Simulated power at n = 31 per arm: 0.824 (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. Analyses Reported by the Sponsor

The registry’s own primary comparative analyses use the Cochran-Mantel-Haenszel method and report odds ratios. They give an odds ratio of 12.28 for every-4-weeks denosumab versus intravenous bisphosphonate and 5.33 for every-12-weeks denosumab versus intravenous bisphosphonate, with their respective 95% confidence intervals and p-values. The registry also reports a percentage and confidence interval for each group.

The unadjusted re-calculation instead uses the posted counts to express the group contrast as a risk difference. It is a simple comparison of proportions, not a reconstruction of the sponsor’s odds-ratio analysis. Odds ratios and risk differences use different scales, so their numerical estimates should not be compared as if they were the same quantity. The reported p-values also arise from different analyses.

The registry record does not flag a discrepancy between the reported results and the posted counts. The sponsor’s own analysis is therefore the relevant registry-reported comparative analysis; the re-calculation adds an unadjusted way to describe the absolute contrast. Neither analysis, on its own, establishes effects on outcomes beyond the specified biomarker endpoint.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary endpoint and lists multiple secondary outcomes, with multiple analyses recorded. However, a plan for controlling the chance of false-positive findings across the family of outcome tests is not reported in the registry record. It is therefore not possible to determine from the record whether the secondary p-values were adjusted, which comparisons were prioritized, or how the overall testing sequence was intended to work. Individual unadjusted secondary p-values should be read with that uncertainty in mind.

The primary analysis population is defined as participants randomized to the treatment phase who received at least one dose of treatment-phase investigational product and had both baseline and at least one post-baseline uNTx measurement. This is an important detail for interpreting the endpoint: the population is not described simply as everyone randomized. The registry record does not report a separate missing-data method, such as an imputation procedure, or explain how participants lacking the required measurements were handled in analyses beyond the stated population definition.

Randomization and open-label allocation are reported, but the sequence-generation and concealment procedures are not reported in the registry record. The registry does not report the original sample-size justification, interim analyses, or a complete statistical analysis plan. Those omissions limit the ability to assess whether all analysis decisions were prespecified and whether the posted comparisons reflect a planned testing strategy.

The presence of several outcome types also complicates interpretation. Binary endpoints, continuous changes, and time-to-event outcomes have different estimands and rely on different assumptions. The reported method names identify some procedures, but details such as stratification variables and missing-data handling are not reported in the registry record. These gaps call for cautious interpretation, not an assumption that a particular unreported method was used.

16. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anaemia (11.4%), general physical health deterioration (8.6%), bone pain (8.6%), metastases to central nervous system (8.6%), thrombocytopenia (7.9%).

The registry reports serious adverse events for safety groups of 35 participants receiving intravenous bisphosphonate, 35 receiving denosumab every 12 weeks, and 38 receiving denosumab every 4 weeks. The corresponding numbers affected by at least one serious adverse event were 19, 16, and 21. These are group counts, not the primary-endpoint analysis counts, and should be read using the safety denominators stated for this outcome.

The registry also lists serious-event terms and percentages, including anaemia at 11.4%, general physical health deterioration at 8.6%, bone pain at 8.6%, metastases to central nervous system at 8.6%, thrombocytopenia at 7.9%, and prostate cancer at 7.9%. These entries describe reported serious-event terms; they do not by themselves establish that treatment caused an event. The record does not report death counts in the safety summary.

Counts of participants with serious adverse events do not give a complete account of safety. The registry record does not provide enough information to compare event timing, duration, severity distributions, exposure, or causal attribution. These figures should therefore be interpreted as descriptive safety reporting, not as a standalone comparative safety conclusion.

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

The primary result describes the proportion of participants meeting a laboratory threshold at week 13 in the defined analysis population. The posted proportions were higher in each denosumab group than in the intravenous bisphosphonate group, and the registry reports comparative odds ratios with confidence intervals that exclude 1. The unadjusted re-calculations likewise estimate positive risk differences. These findings characterize the biomarker outcome as reported; they do not answer every question about treatment or health outcomes.

uNTx/Cr is a biomarker, and threshold attainment is not the same as a demonstrated reduction in skeletal-related events, improvement in symptoms, or change in survival. The registry lists some such outcomes, but results for certain listed outcomes are not reported in the registry record. A conclusion about clinical outcomes cannot be inferred from the primary biomarker comparison alone.

The effect estimates also have uncertainty. The confidence intervals are broad, so the exact size of the group differences is not tightly pinned down. The study is open label, and the endpoint analysis population requires dosing and uNTx measurements. The record does not fully describe missing-data procedures, multiplicity control, or the original sample-size plan. These points affect how broadly and confidently the findings should be interpreted.

The results apply to the trial’s studied setting and population as described in the registry, including people with advanced cancer and bone metastases who were being treated with intravenous bisphosphonates. They do not automatically generalize to people outside that setting, other dosing schedules, or other outcomes. No medical decision should be based on this statistical summary alone.

18. Why This Trial Matters Statistically

This trial is statistically informative because it compares two denosumab schedules with an active intravenous bisphosphonate comparator in a randomized parallel-group design. It reports both arm-level biomarker proportions and comparative analyses, allowing readers to distinguish the observed frequencies from the estimated between-group effects. The two denosumab schedules also make schedule-specific comparisons possible within the posted results.

The example illustrates why effect measures matter. Odds ratios describe relative odds, whereas risk differences describe absolute differences in proportions. They summarize the same binary outcome from different perspectives and have different numerical scales. Reporting the measure and its interval is necessary for a meaningful interpretation; a p-value alone does not communicate effect magnitude or precision.

It also demonstrates the limits of a statistically distinct biomarker finding. The primary endpoint is a threshold on uNTx/Cr, not a clinical event. Secondary outcomes include clinical events, but their results are not all reported in the registry record. This distinction is central when evaluating what a trial establishes: an analysis can be informative about its prespecified endpoint without resolving the broader clinical question.

Finally, the registry record shows why study design and reporting details matter alongside estimates. Open-label conduct, a defined measurement-based analysis population, multiple secondary outcomes, and unreported details of multiplicity and missing-data handling all affect the strength and scope of interpretation. Statistical significance is only one part of assessing the evidence.

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.

This trial has limitations specific to its design and registry reporting. It was open label with no masking, so participants and study personnel knew the assigned treatment. The primary endpoint is an objective laboratory threshold, but open-label conduct can still affect study management and outcomes that involve clinical assessment. The registry record does not describe allocation concealment or sequence generation.

The trial includes several cancer settings listed in the registry, including prostate cancer, breast cancer, advanced cancer, and multiple myeloma. The record does not provide outcome estimates by cancer group, so the degree to which results may differ across these populations cannot be assessed from the posted primary result. The primary endpoint is a uNTx/Cr threshold at week 13, which gives a limited view of a biomarker at a particular time rather than a full assessment of clinical outcomes or longer-term effects.

The registry defines the primary analysis population using treatment receipt and availability of baseline and post-baseline uNTx measurements. The record does not report additional missing-data methods, reasons for missing measurements, or analyses of the impact of missing data. The registry lists several secondary outcomes, but results for some listed clinical outcomes are not reported. It also does not report the multiplicity strategy, the original sample-size rationale, or interim analyses.

The reported comparative analysis uses the Cochran-Mantel-Haenszel method, but the registry record does not give the stratification details. The unadjusted re-calculations are based on posted summaries and do not reproduce the sponsor’s analysis. Finally, the arm descriptions mention an extension phase, but extension-phase participation and results are not reported in the registry record. These limitations constrain interpretation of the available estimates.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study of AMG 162 in Subjects With Advanced Cancer Currently Being Treated With Intravenous (IV) Bisphosphonates — NCT00104650.
• Registry record last updated 2011-01-24; status last verified 2011-01.
• Results first posted 2011-01-07.
• 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

NCT00104650 was a completed randomized, open-label, parallel-group Phase 2 study sponsored by Amgen, with enrollment of 111. It compared intravenous bisphosphonate every 4 weeks with denosumab 180 mg subcutaneously every 12 weeks or every 4 weeks in people with advanced cancer and bone metastases who were being treated with intravenous bisphosphonates.

The primary outcome was the number of participants with uNTx/Cr below 50 nmol/mmol at week 13. The registry reported higher threshold attainment proportions in both denosumab groups than in the bisphosphonate group, with Cochran-Mantel-Haenszel odds ratios for the two comparisons. Unadjusted risk-difference re-calculations give an additional absolute-scale description, but use a different analysis.

The outcome is a biomarker measure, and the registry record does not report results for every listed secondary clinical outcome. Details on multiplicity, missing-data methods, and the original sample-size justification are not reported in the registry record. The findings should be interpreted within the endpoint, analysis population, and trial setting recorded.