Bone Metastases in Subjects With Advanced Breast Cancer, Breast Cancer, Metastases
Conditions
Keywords
Breast Cancer, Cancer
Brief summary
This study is to evaluate various doses and schedules for denosumab administration and characterize the safety profile in this indication.
Interventions
BIOLOGICALDenosumab
Denosumab administered by subcutaneous injection
DRUGIV Bisphosphonates
Commercially available intravenous (IV) bisphosphonates administered per package insert, included pamidronate, ibandronic acid, and zoledronic acid
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Histologically or cytologically confirmed breast adenocarcinoma * At least one bone metastasis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 13 in Creatinine-adjusted Urinary N-telopeptide (uNTx/Cr) | Baseline and Week 13 | Percent change from Baseline to Week 13 in Urinary N-telopeptide corrected by creatinine (uNTx/Cr) calculated using ((Week 13 value - Baseline value) / Baseline value ) x 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 25 in Urinary N-telopeptide (uNTx) | Baseline and Week 25 | Percent change from Baseline to Week 25 in Urinary N-telopeptide (uNTx) calculated using ((Week 25 value - Baseline value) / Baseline value) x 100. |
| Number of Participants Achieving 65% or More Reduction in Urinary N-telopeptide (uNTx) From Baseline at Week 13 | Baseline and Week 13 | The number of participants achieving a 65% reduction or more in uNTx from Baseline at Week 13. Calculation used is ((Week 13 value - Baseline value) / Baseline value ) x 100 and participants were considered having a 65% reduction or more if their value was ≤ -65%. |
| Number of Participants Achieving 65% or More Reduction in uNTX From Baseline at Week 25 | Baseline and Week 25 | The number of participants achieving a 65% reduction or more in uNTX from Baseline at Week 25. Calculation used is ((Week 25 value - Baseline value) / Baseline value) x 100 and participants were considered having a 65% reduction or more if their value was ≤ -65%. |
| Time to 65% or More Reduction in Urinary N-telopeptide (uNTX) From Baseline | Baseline to Week 57 | Kaplan-Meier estimate of the median time from enrollment to the first occurrence of a reduction of uNTx of ≥ 65% compared to Baseline. For participants whose uNTx did not fall below 65% of the Baseline value, the time was censored at time of last evaluation of uNTx. |
| Percent Change From Baseline to Week 13 in Serum C-Telopeptide (CTX) | Baseline and week 13 | Percent change from Baseline to Week 13 in type I serum C-telopeptide (CTX) calculated using ((Week 13 value - Baseline value) / Baseline value) x 100. |
| Percent Change From Baseline to Week 25 in Serum C-telopeptide (CTX) | Baseline and Week 25 | Percent change from Baseline to Week 25 in type I serum C-telopeptide calculated using ((Week 25 value - Baseline value) / Baseline value) x 100. |
| Percent Change From Baseline to Week 13 in Procollagen I N-terminal Peptide (P1NP) | Baseline and Week 13 | Percent change from Baseline to Week 13 in procollagen 1 N-terminal peptide calculated using ((Week 13 value - Baseline value) / Baseline value) x 100. |
| Percent Change From Baseline to Week 25 in P1NP | Baseline and Week 25 | Percent change from Baseline to Week 25 in procollagen 1 N-terminal peptide (P1NP) calculated using ((Week 25 value - Baseline value) / Baseline value ) x 100. |
| Percent Change From Baseline to Week 13 in Bone Specific Alkaline Phosphatase (BSAP) | Baseline and Week 13 | Percent change from Baseline to Week 13 in bone specific alkaline phosphatase (BSAP) calculated using ((Week 13 value - Baseline value) / Baseline value) x 100. |
| Percent Change From Baseline to Week 25 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | Baseline and Week 25 | Percent change from Baseline to Week 25 in TRAP5b calculated using ((Week 25 value - Baseline value) / Baseline value) x 100. |
| Percent Change From Baseline to Week 25 in Bone Specific Alkaline Phosphatase (BSAP) | Baseline and Week 25 | Percent change from Baseline to Week 25 in BSAP calculated using ((Week 25 value - Baseline value) / Baseline value) x 100. |
| Percent Change From Baseline to Week 13 in Osteocalcin | Baseline and Week 13 | Percent change from Baseline to Week 13 in osteocalcin calculated using ((Week 13 value - Baseline value) / Baseline value ) x 100. |
| Percent Change From Baseline to Week 25 in Osteocalcin | Baseline and Week 25 | Percent change from Baseline to Week 25 in osteocalcin calculated using ((Week 25 value - Baseline value) / Baseline value) x 100. |
| Time to First Skeletal Related Event | Day 1 to Week 25 | Skeletal Related Event (SRE) defined as ≥ 1 of the following: pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone (including the use of radioisotopes). |
| Number of Participants With Skeletal Related Events | From Day 1 to Week 25 | Skeletal Related Events (SRE) are defined as ≥ 1 of the following: pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone (including the use of radioisotopes). |
| Number of Participants With Hypercalcemia | Day 1 to Week 57 | Occurrence of grade 3 or 4 hypercalcemia according to the Common Terminology Criteria for Adverse Events (CTCAE) v3. A summary of hypercalcemia events is reported under adverse events. |
| Percent Change From Baseline to Week 13 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | Baseline and Week 13 | Percent change from Baseline to Week 13 in tartrate-resistant acid phosphatase 5b calculated using ((Week 13 value - Baseline value) / Baseline value) x 100. |
Participant flow
Recruitment details
Participants were enrolled from 8 September 2004 through 9 May 2005
Participants by arm
| Arm | Count |
|---|---|
| Bisphosphonate IV Q4W Open label bisphosphonate every 4 weeks (Q4W) by intravenous infusion | 43 |
| Denosumab 30 mg Q4W Denosumab 30 mg by subcutaneous injection every 4 weeks (Q4W) | 42 |
| Denosumab 60 mg Q12W Denosumab 60 mg by subcutaneous injection every 12 weeks (Q12W) | 42 |
| Denosumab 180 mg Q12W Denosumab 180 mg by subcutaneous injection every 12 weeks (Q12W) | 43 |
| Denosumab 120 mg Q4W Denosumab 120 mg by subcutaneous injection every 4 weeks (Q4W) | 42 |
| Denosumab 180 mg Q4W Denosumab 180 mg by subcutaneous injection every 4 weeks (Q4W) | 43 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 3 | 0 |
| Overall Study | Death | 6 | 4 | 5 | 8 | 5 | 6 |
| Overall Study | Disease Progression | 2 | 0 | 0 | 1 | 1 | 2 |
| Overall Study | Ineligibility Determined | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 3 | 3 | 2 | 1 |
| Overall Study | Noncompliance | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 0 | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Total | Denosumab 180 mg Q4W | Bisphosphonate IV Q4W | Denosumab 120 mg Q4W | Denosumab 180 mg Q12W | Denosumab 60 mg Q12W | Denosumab 30 mg Q4W |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.8 Years STANDARD_DEVIATION 11.4 | 57.6 Years STANDARD_DEVIATION 13.9 | 52.0 Years STANDARD_DEVIATION 10.7 | 57.4 Years STANDARD_DEVIATION 11 | 58.2 Years STANDARD_DEVIATION 9.1 | 59.2 Years STANDARD_DEVIATION 12.3 | 56.5 Years STANDARD_DEVIATION 10.8 |
| BSAP | 50.75 U/L STANDARD_DEVIATION 55.04 | 48.82 U/L STANDARD_DEVIATION 35.13 | 54.84 U/L STANDARD_DEVIATION 51.69 | 47.89 U/L STANDARD_DEVIATION 30.46 | 62.39 U/L STANDARD_DEVIATION 109.18 | 45.62 U/L STANDARD_DEVIATION 26.02 | 44.33 U/L STANDARD_DEVIATION 26.06 |
| Osleocalcin | 9.20 ng/mL STANDARD_DEVIATION 4.93 | 9.31 ng/mL STANDARD_DEVIATION 4.06 | 9.42 ng/mL STANDARD_DEVIATION 5.89 | 8.09 ng/mL STANDARD_DEVIATION 3.36 | 8.96 ng/mL STANDARD_DEVIATION 5.03 | 10.04 ng/mL STANDARD_DEVIATION 5.7 | 9.25 ng/mL STANDARD_DEVIATION 4.98 |
| P1NP | 126.20 µg/L STANDARD_DEVIATION 284.81 | 139.01 µg/L STANDARD_DEVIATION 188.02 | 111.01 µg/L STANDARD_DEVIATION 97.21 | 98.47 µg/L STANDARD_DEVIATION 83.46 | 193.03 µg/L STANDARD_DEVIATION 641.13 | 114.29 µg/L STANDARD_DEVIATION 113.51 | 98.54 µg/L STANDARD_DEVIATION 72.69 |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 71 Participants | 10 Participants | 16 Participants | 10 Participants | 9 Participants | 13 Participants | 13 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White or Caucasian | 179 Participants | 33 Participants | 25 Participants | 30 Participants | 34 Participants | 29 Participants | 28 Participants |
| Serum CTx | 0.692 ng/mL STANDARD_DEVIATION 0.605 | 0.846 ng/mL STANDARD_DEVIATION 0.892 | 0.592 ng/mL STANDARD_DEVIATION 0.284 | 0.714 ng/mL STANDARD_DEVIATION 0.564 | 0.647 ng/mL STANDARD_DEVIATION 0.703 | 0.720 ng/mL STANDARD_DEVIATION 0.559 | 0.632 ng/mL STANDARD_DEVIATION 0.43 |
| Sex: Female, Male Female | 255 Participants | 43 Participants | 43 Participants | 42 Participants | 43 Participants | 42 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| TRAP 5b | 7.057 U/L STANDARD_DEVIATION 4.358 | 7.009 U/L STANDARD_DEVIATION 4.217 | 6.907 U/L STANDARD_DEVIATION 3.28 | 6.765 U/L STANDARD_DEVIATION 4.34 | 7.628 U/L STANDARD_DEVIATION 6.83 | 7.116 U/L STANDARD_DEVIATION 3.493 | 6.879 U/L STANDARD_DEVIATION 2.878 |
| uNTx/Cr | 85.78 nmol/mmol STANDARD_DEVIATION 111.94 | 98.22 nmol/mmol STANDARD_DEVIATION 168.42 | 83.16 nmol/mmol STANDARD_DEVIATION 94.37 | 102.06 nmol/mmol STANDARD_DEVIATION 129.12 | 75.92 nmol/mmol STANDARD_DEVIATION 91.03 | 89.41 nmol/mmol STANDARD_DEVIATION 98.58 | 66.44 nmol/mmol STANDARD_DEVIATION 61.17 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 36 / 43 | 33 / 42 | 37 / 41 | 36 / 43 | 37 / 42 | 35 / 43 |
| serious Total, serious adverse events | 15 / 43 | 11 / 42 | 19 / 41 | 16 / 43 | 14 / 42 | 15 / 43 |
Outcome results
Primary
Percent Change From Baseline to Week 13 in Creatinine-adjusted Urinary N-telopeptide (uNTx/Cr)
Percent change from Baseline to Week 13 in Urinary N-telopeptide corrected by creatinine (uNTx/Cr) calculated using ((Week 13 value - Baseline value) / Baseline value ) x 100.
Time frame: Baseline and Week 13
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 13 in Creatinine-adjusted Urinary N-telopeptide (uNTx/Cr) | -10.19 Percent change | Standard Deviation 208.84 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 13 in Creatinine-adjusted Urinary N-telopeptide (uNTx/Cr) | -52.87 Percent change | Standard Deviation 95.14 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 13 in Creatinine-adjusted Urinary N-telopeptide (uNTx/Cr) | -54.21 Percent change | Standard Deviation 61.34 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 13 in Creatinine-adjusted Urinary N-telopeptide (uNTx/Cr) | -57.36 Percent change | Standard Deviation 41.46 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 13 in Creatinine-adjusted Urinary N-telopeptide (uNTx/Cr) | -51.73 Percent change | Standard Deviation 60.85 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 13 in Creatinine-adjusted Urinary N-telopeptide (uNTx/Cr) | -18.46 Percent change | Standard Deviation 125.86 |
p-value: 0.245ANCOVA
Secondary
Number of Participants Achieving 65% or More Reduction in uNTX From Baseline at Week 25
The number of participants achieving a 65% reduction or more in uNTX from Baseline at Week 25. Calculation used is ((Week 25 value - Baseline value) / Baseline value) x 100 and participants were considered having a 65% reduction or more if their value was ≤ -65%.
Time frame: Baseline and Week 25
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | Number of Participants Achieving 65% or More Reduction in uNTX From Baseline at Week 25 | 19 Participants |
| Denosumab 30 mg Q4W | Number of Participants Achieving 65% or More Reduction in uNTX From Baseline at Week 25 | 25 Participants |
| Denosumab 120 mg Q4W | Number of Participants Achieving 65% or More Reduction in uNTX From Baseline at Week 25 | 23 Participants |
| Denosumab 180 mg Q4W | Number of Participants Achieving 65% or More Reduction in uNTX From Baseline at Week 25 | 25 Participants |
| Denosumab 60 mg Q12W | Number of Participants Achieving 65% or More Reduction in uNTX From Baseline at Week 25 | 21 Participants |
| Denosumab 180 mg Q12W | Number of Participants Achieving 65% or More Reduction in uNTX From Baseline at Week 25 | 15 Participants |
95% CI: [0.69, 4.79]
95% CI: [0.25, 1.76]
95% CI: [0.24, 1.77]
95% CI: [0.22, 1.58]
95% CI: [0.25, 1.92]
Secondary
Number of Participants Achieving 65% or More Reduction in Urinary N-telopeptide (uNTx) From Baseline at Week 13
The number of participants achieving a 65% reduction or more in uNTx from Baseline at Week 13. Calculation used is ((Week 13 value - Baseline value) / Baseline value ) x 100 and participants were considered having a 65% reduction or more if their value was ≤ -65%.
Time frame: Baseline and Week 13
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a Baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | Number of Participants Achieving 65% or More Reduction in Urinary N-telopeptide (uNTx) From Baseline at Week 13 | 25 Participants |
| Denosumab 30 mg Q4W | Number of Participants Achieving 65% or More Reduction in Urinary N-telopeptide (uNTx) From Baseline at Week 13 | 24 Participants |
| Denosumab 120 mg Q4W | Number of Participants Achieving 65% or More Reduction in Urinary N-telopeptide (uNTx) From Baseline at Week 13 | 26 Participants |
| Denosumab 180 mg Q4W | Number of Participants Achieving 65% or More Reduction in Urinary N-telopeptide (uNTx) From Baseline at Week 13 | 24 Participants |
| Denosumab 60 mg Q12W | Number of Participants Achieving 65% or More Reduction in Urinary N-telopeptide (uNTx) From Baseline at Week 13 | 20 Participants |
| Denosumab 180 mg Q12W | Number of Participants Achieving 65% or More Reduction in Urinary N-telopeptide (uNTx) From Baseline at Week 13 | 21 Participants |
95% CI: [0.68, 4.35]
95% CI: [0.51, 3.24]
95% CI: [0.34, 2.29]
95% CI: [0.51, 3.2]
95% CI: [0.7, 4.34]
Secondary
Number of Participants With Hypercalcemia
Occurrence of grade 3 or 4 hypercalcemia according to the Common Terminology Criteria for Adverse Events (CTCAE) v3. A summary of hypercalcemia events is reported under adverse events.
Time frame: Day 1 to Week 57
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | Number of Participants With Hypercalcemia | 0 Participants |
| Denosumab 30 mg Q4W | Number of Participants With Hypercalcemia | 0 Participants |
| Denosumab 120 mg Q4W | Number of Participants With Hypercalcemia | 0 Participants |
| Denosumab 180 mg Q4W | Number of Participants With Hypercalcemia | 0 Participants |
| Denosumab 60 mg Q12W | Number of Participants With Hypercalcemia | 0 Participants |
| Denosumab 180 mg Q12W | Number of Participants With Hypercalcemia | 0 Participants |
Secondary
Number of Participants With Skeletal Related Events
Skeletal Related Events (SRE) are defined as ≥ 1 of the following: pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone (including the use of radioisotopes).
Time frame: From Day 1 to Week 25
Population: All participants who were exposed to investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | Number of Participants With Skeletal Related Events | 7 Participants |
| Denosumab 30 mg Q4W | Number of Participants With Skeletal Related Events | 4 Participants |
| Denosumab 120 mg Q4W | Number of Participants With Skeletal Related Events | 8 Participants |
| Denosumab 180 mg Q4W | Number of Participants With Skeletal Related Events | 6 Participants |
| Denosumab 60 mg Q12W | Number of Participants With Skeletal Related Events | 4 Participants |
| Denosumab 180 mg Q12W | Number of Participants With Skeletal Related Events | 4 Participants |
95% CI: [0.51, 7.17]
95% CI: [0.36, 3.97]
95% CI: [0.26, 2.52]
95% CI: [0.5, 7.05]
95% CI: [0.5, 7.05]
Secondary
Percent Change From Baseline to Week 13 in Bone Specific Alkaline Phosphatase (BSAP)
Percent change from Baseline to Week 13 in bone specific alkaline phosphatase (BSAP) calculated using ((Week 13 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and Week 13
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 13 in Bone Specific Alkaline Phosphatase (BSAP) | -40.01 Percent change | Standard Deviation 24.42 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 13 in Bone Specific Alkaline Phosphatase (BSAP) | 26.37 Percent change | Standard Deviation 406.79 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 13 in Bone Specific Alkaline Phosphatase (BSAP) | -40.23 Percent change | Standard Deviation 27.34 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 13 in Bone Specific Alkaline Phosphatase (BSAP) | -38.42 Percent change | Standard Deviation 25.44 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 13 in Bone Specific Alkaline Phosphatase (BSAP) | -37.11 Percent change | Standard Deviation 31.33 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 13 in Bone Specific Alkaline Phosphatase (BSAP) | -35.94 Percent change | Standard Deviation 25.49 |
Secondary
Percent Change From Baseline to Week 13 in Osteocalcin
Percent change from Baseline to Week 13 in osteocalcin calculated using ((Week 13 value - Baseline value) / Baseline value ) x 100.
Time frame: Baseline and Week 13
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 13 in Osteocalcin | 6.82 Percent change | Standard Deviation 49.78 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 13 in Osteocalcin | -19.35 Percent change | Standard Deviation 38.71 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 13 in Osteocalcin | -2.39 Percent change | Standard Deviation 47.96 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 13 in Osteocalcin | -6.23 Percent change | Standard Deviation 40.82 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 13 in Osteocalcin | -23.78 Percent change | Standard Deviation 35.46 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 13 in Osteocalcin | -5.96 Percent change | Standard Deviation 41.92 |
Secondary
Percent Change From Baseline to Week 13 in Procollagen I N-terminal Peptide (P1NP)
Percent change from Baseline to Week 13 in procollagen 1 N-terminal peptide calculated using ((Week 13 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and Week 13
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 13 in Procollagen I N-terminal Peptide (P1NP) | -50.75 Percent change | Standard Deviation 29.47 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 13 in Procollagen I N-terminal Peptide (P1NP) | -52.35 Percent change | Standard Deviation 36.9 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 13 in Procollagen I N-terminal Peptide (P1NP) | -48.23 Percent change | Standard Deviation 36.83 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 13 in Procollagen I N-terminal Peptide (P1NP) | -50.47 Percent change | Standard Deviation 54.67 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 13 in Procollagen I N-terminal Peptide (P1NP) | -43.94 Percent change | Standard Deviation 44.53 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 13 in Procollagen I N-terminal Peptide (P1NP) | -59.42 Percent change | Standard Deviation 18.6 |
Secondary
Percent Change From Baseline to Week 13 in Serum C-Telopeptide (CTX)
Percent change from Baseline to Week 13 in type I serum C-telopeptide (CTX) calculated using ((Week 13 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and week 13
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 13 in Serum C-Telopeptide (CTX) | -66.92 Percent change | Standard Deviation 44.05 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 13 in Serum C-Telopeptide (CTX) | -80.76 Percent change | Standard Deviation 12.66 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 13 in Serum C-Telopeptide (CTX) | -78.45 Percent change | Standard Deviation 28.89 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 13 in Serum C-Telopeptide (CTX) | -81.79 Percent change | Standard Deviation 13.29 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 13 in Serum C-Telopeptide (CTX) | -70.50 Percent change | Standard Deviation 41.76 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 13 in Serum C-Telopeptide (CTX) | -78.13 Percent change | Standard Deviation 16.66 |
Secondary
Percent Change From Baseline to Week 13 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b)
Percent change from Baseline to Week 13 in tartrate-resistant acid phosphatase 5b calculated using ((Week 13 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and Week 13
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 13 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -37.45 Percent change | Standard Deviation 19.87 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 13 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -56.07 Percent change | Standard Deviation 17.8 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 13 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -58.24 Percent change | Standard Deviation 15.07 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 13 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -53.12 Percent change | Standard Deviation 50 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 13 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -55.85 Percent change | Standard Deviation 27.22 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 13 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -55.91 Percent change | Standard Deviation 17.61 |
Secondary
Percent Change From Baseline to Week 25 in Bone Specific Alkaline Phosphatase (BSAP)
Percent change from Baseline to Week 25 in BSAP calculated using ((Week 25 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and Week 25
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 25 in Bone Specific Alkaline Phosphatase (BSAP) | -46.56 Percent change | Standard Deviation 26.02 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 25 in Bone Specific Alkaline Phosphatase (BSAP) | 15.88 Percent change | Standard Deviation 347.47 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 25 in Bone Specific Alkaline Phosphatase (BSAP) | -49.01 Percent change | Standard Deviation 21.24 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 25 in Bone Specific Alkaline Phosphatase (BSAP) | -52.60 Percent change | Standard Deviation 16.23 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 25 in Bone Specific Alkaline Phosphatase (BSAP) | -46.72 Percent change | Standard Deviation 23.25 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 25 in Bone Specific Alkaline Phosphatase (BSAP) | -48.24 Percent change | Standard Deviation 27.61 |
Secondary
Percent Change From Baseline to Week 25 in Osteocalcin
Percent change from Baseline to Week 25 in osteocalcin calculated using ((Week 25 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and Week 25
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 25 in Osteocalcin | -4.74 Percent change | Standard Deviation 86.98 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 25 in Osteocalcin | -30.78 Percent change | Standard Deviation 34.94 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 25 in Osteocalcin | -22.80 Percent change | Standard Deviation 46.36 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 25 in Osteocalcin | -26.95 Percent change | Standard Deviation 41.49 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 25 in Osteocalcin | -23.93 Percent change | Standard Deviation 43.99 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 25 in Osteocalcin | -22.69 Percent change | Standard Deviation 36.79 |
Secondary
Percent Change From Baseline to Week 25 in P1NP
Percent change from Baseline to Week 25 in procollagen 1 N-terminal peptide (P1NP) calculated using ((Week 25 value - Baseline value) / Baseline value ) x 100.
Time frame: Baseline and Week 25
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 25 in P1NP | -50.48 Percent change | Standard Deviation 41.22 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 25 in P1NP | -53.48 Percent change | Standard Deviation 54.79 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 25 in P1NP | -55.90 Percent change | Standard Deviation 30.66 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 25 in P1NP | -57.88 Percent change | Standard Deviation 51.97 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 25 in P1NP | -51.18 Percent change | Standard Deviation 40.41 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 25 in P1NP | -51.37 Percent change | Standard Deviation 47.53 |
Secondary
Percent Change From Baseline to Week 25 in Serum C-telopeptide (CTX)
Percent change from Baseline to Week 25 in type I serum C-telopeptide calculated using ((Week 25 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and Week 25
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 25 in Serum C-telopeptide (CTX) | -73.09 Percent change | Standard Deviation 22.42 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 25 in Serum C-telopeptide (CTX) | -82.70 Percent change | Standard Deviation 11.92 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 25 in Serum C-telopeptide (CTX) | -74.48 Percent change | Standard Deviation 30.26 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 25 in Serum C-telopeptide (CTX) | -80.07 Percent change | Standard Deviation 22.26 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 25 in Serum C-telopeptide (CTX) | -70.64 Percent change | Standard Deviation 36.94 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 25 in Serum C-telopeptide (CTX) | -78.31 Percent change | Standard Deviation 14 |
Secondary
Percent Change From Baseline to Week 25 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b)
Percent change from Baseline to Week 25 in TRAP5b calculated using ((Week 25 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and Week 25
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 25 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -38.59 Percent change | Standard Deviation 26.06 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 25 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -58.58 Percent change | Standard Deviation 18.93 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 25 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -52.39 Percent change | Standard Deviation 25.3 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 25 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -51.15 Percent change | Standard Deviation 44.49 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 25 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -56.25 Percent change | Standard Deviation 32.3 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 25 in Tartrate-resistant Acid Phosphatase 5b (TRAP5b) | -53.13 Percent change | Standard Deviation 22.23 |
Secondary
Percent Change From Baseline to Week 25 in Urinary N-telopeptide (uNTx)
Percent change from Baseline to Week 25 in Urinary N-telopeptide (uNTx) calculated using ((Week 25 value - Baseline value) / Baseline value) x 100.
Time frame: Baseline and Week 25
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change From Baseline to Week 25 in Urinary N-telopeptide (uNTx) | -39.52 Percent change | Standard Deviation 74.16 |
| Denosumab 30 mg Q4W | Percent Change From Baseline to Week 25 in Urinary N-telopeptide (uNTx) | -53.46 Percent change | Standard Deviation 100.77 |
| Denosumab 120 mg Q4W | Percent Change From Baseline to Week 25 in Urinary N-telopeptide (uNTx) | -43.16 Percent change | Standard Deviation 101.08 |
| Denosumab 180 mg Q4W | Percent Change From Baseline to Week 25 in Urinary N-telopeptide (uNTx) | -59.41 Percent change | Standard Deviation 43.31 |
| Denosumab 60 mg Q12W | Percent Change From Baseline to Week 25 in Urinary N-telopeptide (uNTx) | -41.79 Percent change | Standard Deviation 72.61 |
| Denosumab 180 mg Q12W | Percent Change From Baseline to Week 25 in Urinary N-telopeptide (uNTx) | -39.96 Percent change | Standard Deviation 65.85 |
p-value: 0.848ANCOVA
Secondary
Time to 65% or More Reduction in Urinary N-telopeptide (uNTX) From Baseline
Kaplan-Meier estimate of the median time from enrollment to the first occurrence of a reduction of uNTx of ≥ 65% compared to Baseline. For participants whose uNTx did not fall below 65% of the Baseline value, the time was censored at time of last evaluation of uNTx.
Time frame: Baseline to Week 57
Population: Primary Efficacy Subset, composed of all participants who were randomized, received at least one dose of denosumab or bisphosphonate, and had both a baseline and at least one postbaseline measurement of Urinary N-telopeptide corrected by creatinine (uNTx/Cr). Analysis was by Intention-to-Treat (ITT).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bisphosphonate IV Q4W | Time to 65% or More Reduction in Urinary N-telopeptide (uNTX) From Baseline | 10 Days |
| Denosumab 30 mg Q4W | Time to 65% or More Reduction in Urinary N-telopeptide (uNTX) From Baseline | 13 Days |
| Denosumab 120 mg Q4W | Time to 65% or More Reduction in Urinary N-telopeptide (uNTX) From Baseline | 11 Days |
| Denosumab 180 mg Q4W | Time to 65% or More Reduction in Urinary N-telopeptide (uNTX) From Baseline | 10 Days |
| Denosumab 60 mg Q12W | Time to 65% or More Reduction in Urinary N-telopeptide (uNTX) From Baseline | 9 Days |
| Denosumab 180 mg Q12W | Time to 65% or More Reduction in Urinary N-telopeptide (uNTX) From Baseline | 30 Days |
95% CI: [0.51, 1.31]
95% CI: [0.64, 1.65]
95% CI: [0.68, 1.74]
95% CI: [0.68, 1.74]
95% CI: [0.71, 1.83]
Secondary
Time to First Skeletal Related Event
Skeletal Related Event (SRE) defined as ≥ 1 of the following: pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone (including the use of radioisotopes).
Time frame: Day 1 to Week 25
Population: All participants who were exposed to investigational product.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bisphosphonate IV Q4W | Time to First Skeletal Related Event | NA Days |
| Denosumab 30 mg Q4W | Time to First Skeletal Related Event | NA Days |
| Denosumab 120 mg Q4W | Time to First Skeletal Related Event | NA Days |
| Denosumab 180 mg Q4W | Time to First Skeletal Related Event | NA Days |
| Denosumab 60 mg Q12W | Time to First Skeletal Related Event | NA Days |
| Denosumab 180 mg Q12W | Time to First Skeletal Related Event | NA Days |
95% CI: [0.159, 1.856]
95% CI: [0.159, 1.859]
95% CI: [0.266, 2.355]
95% CI: [0.389, 2.963]
95% CI: [0.158, 1.847]