Osteoporosis
Conditions
Keywords
Osteoporosis, Zoledronic Acid
Brief summary
This extension study is designed to assess the long term safety and efficacy of zoledronic acid in postmenopausal women with osteoporosis who have participated in the CZOL446H2301 (NCT00049829): HORIZON Pivotal Fracture Trial. This extension study began after the 3-year core study ended. Baseline is the same as Year 3.
Interventions
DRUGZoledronic Acid
Zoledronic Acid 5 mg in 100 mL physiologic 0.9% normal saline for intravenous infusion.
DRUGPlacebo
100 mL physiologic 0.9% normal saline for intravenous infusion.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
68 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Patients who have received 3 infusions in the HORIZON-Pivotal Fracture (PFT) Study.
Exclusion criteria
* Poor kidney, eye, or liver health * Use of certain therapies for osteoporosis in the HORIZON-PFT study (other than the study medication) * Abnormal calcium levels in the blood Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3 | Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72; end of extension study) | The primary efficacy variable was the percentage change in BMD of the femoral neck as measured by dual x-ray absorptiometry (DXA) at Year 6 relative to Year 3. It was derived as 100 \*(femoral neck BMD at Year 6 - femoral neck BMD at Year 3) / (femoral neck BMD at Year 3). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bone Resorption and Formation Biochemical Markers at Year 6: P1NP | Year 6 | The amount of serum P1NP as determined by the central laboratory |
| Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3 | Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54) | The percentage change in BMD as measured by DXA at Year 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3). |
| Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3 | Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 | The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3). |
| Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3 | Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54) | The percentage change in BMD as measured by DXA at Year 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3). |
| Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3 | Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72) | The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3). |
| Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54) | The percentage change in BMD as measured by DXA at 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3). |
| Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72) | The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3). |
| Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP | Year 4.5 | The amount of serum n-terminal propeptide of type I collagen (P1NP) as determined by the central laboratory. |
| Number of Participants With Incidence of Clinical Fracture | Extension Baseline (Year 3; Month 36) to Year 6 | Clinical fracture excludes finger, toe, and facial bone fractures. Clinical vertebral fracture includes thoracic spine fracture and lumbar spine fracture. Non-vertebral fracture excludes clinical vertebral, finger, toe, and facial bone fractures. |
| Qualitative Bone Biopsy Parameters | End of Study Visit at Year 6 | Unpaired transiliac crest bone biopsy was performed for histomorphometry, which was obtained after double tetracycline labeling. No data were collected for Patients who received Placebo for the first 3 years of the study (Placebo 3 Zoledronic Acid 3). |
| Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion | Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 3 infusion | Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after study drug infusion in Z6 patients compared to Z3P3 patients and in P3Z3 patients. |
| Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion | Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 4 infusion | Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after Year 4 study drug infusion. |
| Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion | Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 5 infusion | Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after Year 5 study drug infusion. |
| The Number of Participants With Clinically Significant Laboratory Parameters | Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to Year 6 | Evaluate the laboratory key profile such as Calcium, Creatinine and Urea. The number of patients with clinically significant calcium, creatinine and urea were reported. |
| Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures | Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 | Lateral vertebral x-rays were performed at the final core study visit and at Year 6 and read by a central expert reader at a central imaging laboratory to assess for new or new/worsening morphometric vertebral fracture. The percentage of patients with new morphometric vertebral fractures (observed for the first time) and patients with either new or worsening morphometric vertebral fractures was calculated. |
Countries
Germany, United States
Participant flow
Recruitment details
This was an international, multicenter, randomized, double-blind 3-year extension study in postmenopausal women with osteoporosis who had completed participation in the CZOL446H2301 (NCT00049829) core study. The extension study started 17 May 2005 (First patient enrolled) and ended 24 Nov 2009 (Last patient completed).
Pre-assignment details
Patients who were receiving zoledronic acid in the core study were randomized in a 1:1 fashion to receive either zoledronic acid or placebo in the extension study. Patients who were receiving placebo in the core study were assigned to zoledronic acid in the extension study in order to retain the core study blind.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid 6 Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment. | 616 |
| Zoledronic Acid 3 Placebo 3 Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study. | 617 |
| Placebo 3 Zoledronic Acid 3 Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study. | 1,223 |
| Total | 2,456 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 1 | 0 | 2 |
| Overall Study | Administrative problems | 12 | 9 | 13 |
| Overall Study | Adverse Event | 14 | 11 | 22 |
| Overall Study | Death | 26 | 18 | 30 |
| Overall Study | Lost to Follow-up | 9 | 14 | 14 |
| Overall Study | Missing - not stated | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 77 | 72 | 164 |
Baseline characteristics
| Characteristic | Zoledronic Acid 6 | Zoledronic Acid 3 Placebo 3 | Placebo 3 Zoledronic Acid 3 | Total |
|---|---|---|---|---|
| Age Continuous | 75.5 Years STANDARD_DEVIATION 4.88 | 75.5 Years STANDARD_DEVIATION 4.89 | 75.6 Years STANDARD_DEVIATION 4.95 | 75.5 Years STANDARD_DEVIATION 4.92 |
| Sex: Female, Male Female | 616 Participants | 617 Participants | 1223 Participants | 2456 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 421 / 613 | 427 / 616 | 908 / 1,221 |
| serious Total, serious adverse events | 191 / 613 | 168 / 616 | 297 / 1,221 |
Outcome results
Primary
Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3
The primary efficacy variable was the percentage change in BMD of the femoral neck as measured by dual x-ray absorptiometry (DXA) at Year 6 relative to Year 3. It was derived as 100 \*(femoral neck BMD at Year 6 - femoral neck BMD at Year 3) / (femoral neck BMD at Year 3).
Time frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72; end of extension study)
Population: Modified intent-to-treat (MITT) population. The MITT population included all patients in the ITT population who had DXA measurements of the femoral neck at Year 3 and Year 6. This was the primary population for primary efficacy parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3 | 0.557 Percentage Change in BMD | Standard Error 0.2154 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3 | -0.493 Percentage Change in BMD | Standard Error 0.2249 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3 | 3.337 Percentage Change in BMD | Standard Error 0.2329 |
Secondary
Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP
The amount of serum n-terminal propeptide of type I collagen (P1NP) as determined by the central laboratory.
Time frame: Year 4.5
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 4.5 as determined by the analysis window.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP | 18.842 ng/mL | Standard Error 0.4325 |
| Zoledronic Acid 3 Placebo 3 | Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP | 29.677 ng/mL | Standard Error 0.6977 |
| Placebo 3 Zoledronic Acid 3 | Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP | 17.256 ng/mL | Standard Error 0.3743 |
Secondary
Bone Resorption and Formation Biochemical Markers at Year 6: P1NP
The amount of serum P1NP as determined by the central laboratory
Time frame: Year 6
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The Number of patients analyzed = the number of patients with measurements in Year 6 as determined by the analysis window.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Bone Resorption and Formation Biochemical Markers at Year 6: P1NP | 27.356 ng/mL | Standard Error 0.634 |
| Zoledronic Acid 3 Placebo 3 | Bone Resorption and Formation Biochemical Markers at Year 6: P1NP | 30.344 ng/mL | Standard Error 0.605 |
| Placebo 3 Zoledronic Acid 3 | Bone Resorption and Formation Biochemical Markers at Year 6: P1NP | 25.926 ng/mL | Standard Error 0.7765 |
Secondary
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion
Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after study drug infusion in Z6 patients compared to Z3P3 patients and in P3Z3 patients.
Time frame: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 3 infusion
Population: Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion | 1.96 μmol/L | Standard Deviation 9.364 |
| Zoledronic Acid 3 Placebo 3 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion | 1.28 μmol/L | Standard Deviation 8.757 |
| Placebo 3 Zoledronic Acid 3 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion | 0.21 μmol/L | Standard Deviation 12.36 |
Secondary
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion
Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after Year 4 study drug infusion.
Time frame: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 4 infusion
Population: Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion | 3.35 μmol/L | Standard Deviation 23.58 |
| Zoledronic Acid 3 Placebo 3 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion | 2.23 μmol/L | Standard Deviation 9.891 |
| Placebo 3 Zoledronic Acid 3 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion | 2.47 μmol/L | Standard Deviation 13.042 |
Secondary
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion
Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after Year 5 study drug infusion.
Time frame: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 5 infusion
Population: Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion | 3.46 μmol/L | Standard Deviation 21.735 |
| Zoledronic Acid 3 Placebo 3 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion | 0.71 μmol/L | Standard Deviation 10.278 |
| Placebo 3 Zoledronic Acid 3 | Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion | 1.04 μmol/L | Standard Deviation 11.882 |
Secondary
Number of Participants With Incidence of Clinical Fracture
Clinical fracture excludes finger, toe, and facial bone fractures. Clinical vertebral fracture includes thoracic spine fracture and lumbar spine fracture. Non-vertebral fracture excludes clinical vertebral, finger, toe, and facial bone fractures.
Time frame: Extension Baseline (Year 3; Month 36) to Year 6
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. n = the number of patients with measurements at Year 6 as determined by the analysis window.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 6 | Number of Participants With Incidence of Clinical Fracture | Clinical fracture | 51 Participants | 8.15 |
| Zoledronic Acid 6 | Number of Participants With Incidence of Clinical Fracture | Clinical vertebral fractures | 7 Participants | — |
| Zoledronic Acid 6 | Number of Participants With Incidence of Clinical Fracture | Non-vertebral fractures | 45 Participants | — |
| Zoledronic Acid 6 | Number of Participants With Incidence of Clinical Fracture | Hip fracture | 7 Participants | — |
| Zoledronic Acid 3 Placebo 3 | Number of Participants With Incidence of Clinical Fracture | Hip fracture | 8 Participants | — |
| Zoledronic Acid 3 Placebo 3 | Number of Participants With Incidence of Clinical Fracture | Clinical fracture | 51 Participants | 8.52 |
| Zoledronic Acid 3 Placebo 3 | Number of Participants With Incidence of Clinical Fracture | Non-vertebral fractures | 47 Participants | — |
| Zoledronic Acid 3 Placebo 3 | Number of Participants With Incidence of Clinical Fracture | Clinical vertebral fractures | 4 Participants | — |
| Placebo 3 Zoledronic Acid 3 | Number of Participants With Incidence of Clinical Fracture | Hip fracture | 10 Participants | — |
| Placebo 3 Zoledronic Acid 3 | Number of Participants With Incidence of Clinical Fracture | Clinical vertebral fractures | 7 Participants | — |
| Placebo 3 Zoledronic Acid 3 | Number of Participants With Incidence of Clinical Fracture | Non-vertebral fractures | 85 Participants | — |
| Placebo 3 Zoledronic Acid 3 | Number of Participants With Incidence of Clinical Fracture | Clinical fracture | 91 Participants | — |
Secondary
Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3
The percentage change in BMD as measured by DXA at Year 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).
Time frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 4.5 and Year 3 as determined by the analysis window.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3 | 0.378 Percentage change in BMD | Standard Error 0.3615 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3 | -0.924 Percentage change in BMD | Standard Error 0.3158 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3 | 0.386 Percentage change in BMD | Standard Error 0.3071 |
Secondary
Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3
The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3).
Time frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72)
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 6 and Year 3 as determined by the analysis window.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3 | 0.178 Percentage change in BMD | Standard Error 0.3661 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3 | -0.567 Percentage change in BMD | Standard Error 0.4025 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3 | 0.299 Percentage change in BMD | Standard Error 0.3473 |
Secondary
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3
The percentage change in BMD as measured by DXA at 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).
Time frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 4.5 and Year 3 as determined by the analysis window.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 6 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Total Hip | 0.479 Percentage change in BMD | Standard Error 0.1337 |
| Zoledronic Acid 6 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Femoral Neck | 0.738 Percentage change in BMD | Standard Error 0.1874 |
| Zoledronic Acid 6 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Trochanter | 0.813 Percentage change in BMD | Standard Error 0.1919 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Total Hip | -0.070 Percentage change in BMD | Standard Error 0.1354 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Femoral Neck | 0.210 Percentage change in BMD | Standard Error 0.2058 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Trochanter | 0.041 Percentage change in BMD | Standard Error 0.1936 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Femoral Neck | 2.697 Percentage change in BMD | Standard Error 0.1516 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Trochanter | 4.611 Percentage change in BMD | Standard Error 0.205 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 | Total Hip | 3.228 Percentage change in BMD | Standard Error 0.1244 |
Secondary
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3
The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3).
Time frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72)
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 6 and Year 3 as determined by the analysis window.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 6 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Total Hip | 0.083 Percentage change in BMD | Standard Error 0.1647 |
| Zoledronic Acid 6 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Femoral Neck | 0.577 Percentage change in BMD | Standard Error 0.2154 |
| Zoledronic Acid 6 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Trochanter | 0.628 Percentage change in BMD | Standard Error 0.2275 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Total Hip | -1.151 Percentage change in BMD | Standard Error 0.1817 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Femoral Neck | -0.493 Percentage change in BMD | Standard Error 0.2249 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Trochanter | -0.903 Percentage change in BMD | Standard Error 0.2462 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Femoral Neck | 3.337 Percentage change in BMD | Standard Error 0.2329 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Trochanter | 6.072 Percentage change in BMD | Standard Error 0.2894 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 | Total Hip | 3.815 Percentage change in BMD | Standard Error 0.1877 |
Secondary
Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3
The percentage change in BMD as measured by DXA at Year 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).
Time frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 4.5 and Year 3 as determined by the analysis window.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3 | 2.618 Percentage Change in BMD | Standard Error 0.384 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3 | 1.196 Percentage Change in BMD | Standard Error 0.351 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3 | 6.551 Percentage Change in BMD | Standard Error 0.3035 |
Secondary
Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3
The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3).
Time frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 6 and Year 3 as determined by the analysis window.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 6 | Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3 | 3.473 Percentage change in BMD | Standard Error 0.4653 |
| Zoledronic Acid 3 Placebo 3 | Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3 | 1.606 Percentage change in BMD | Standard Error 0.455 |
| Placebo 3 Zoledronic Acid 3 | Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3 | 8.875 Percentage change in BMD | Standard Error 0.5398 |
Secondary
Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures
Lateral vertebral x-rays were performed at the final core study visit and at Year 6 and read by a central expert reader at a central imaging laboratory to assess for new or new/worsening morphometric vertebral fracture. The percentage of patients with new morphometric vertebral fractures (observed for the first time) and patients with either new or worsening morphometric vertebral fractures was calculated.
Time frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6
Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 6 as determined by the analysis window.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid 6 | Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures | New morphometric vertebral fracture | 3.0 Percentage of patients |
| Zoledronic Acid 6 | Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures | New/Worsening morphometric vertebral fracture | 3.4 Percentage of patients |
| Zoledronic Acid 3 Placebo 3 | Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures | New morphometric vertebral fracture | 6.2 Percentage of patients |
| Zoledronic Acid 3 Placebo 3 | Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures | New/Worsening morphometric vertebral fracture | 7.0 Percentage of patients |
| Placebo 3 Zoledronic Acid 3 | Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures | New morphometric vertebral fracture | 2.9 Percentage of patients |
| Placebo 3 Zoledronic Acid 3 | Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures | New/Worsening morphometric vertebral fracture | 3.1 Percentage of patients |
Secondary
Qualitative Bone Biopsy Parameters
Unpaired transiliac crest bone biopsy was performed for histomorphometry, which was obtained after double tetracycline labeling. No data were collected for Patients who received Placebo for the first 3 years of the study (Placebo 3 Zoledronic Acid 3).
Time frame: End of Study Visit at Year 6
Population: Bone Biopsy sub-population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid 6 | Qualitative Bone Biopsy Parameters | Osteomalacia | 0 Participants |
| Zoledronic Acid 6 | Qualitative Bone Biopsy Parameters | Woven bone | 0 Participants |
| Zoledronic Acid 6 | Qualitative Bone Biopsy Parameters | Cortical trabeculation | 0 Participants |
| Zoledronic Acid 6 | Qualitative Bone Biopsy Parameters | Marrow fibrosis | 0 Participants |
| Zoledronic Acid 6 | Qualitative Bone Biopsy Parameters | Normal mineralization and normal osteoid | 3 Participants |
| Zoledronic Acid 6 | Qualitative Bone Biopsy Parameters | Contained double labeling | 3 Participants |
| Zoledronic Acid 3 Placebo 3 | Qualitative Bone Biopsy Parameters | Normal mineralization and normal osteoid | 2 Participants |
| Zoledronic Acid 3 Placebo 3 | Qualitative Bone Biopsy Parameters | Osteomalacia | 0 Participants |
| Zoledronic Acid 3 Placebo 3 | Qualitative Bone Biopsy Parameters | Marrow fibrosis | 0 Participants |
| Zoledronic Acid 3 Placebo 3 | Qualitative Bone Biopsy Parameters | Woven bone | 0 Participants |
| Zoledronic Acid 3 Placebo 3 | Qualitative Bone Biopsy Parameters | Contained double labeling | 2 Participants |
| Zoledronic Acid 3 Placebo 3 | Qualitative Bone Biopsy Parameters | Cortical trabeculation | 0 Participants |
Secondary
The Number of Participants With Clinically Significant Laboratory Parameters
Evaluate the laboratory key profile such as Calcium, Creatinine and Urea. The number of patients with clinically significant calcium, creatinine and urea were reported.
Time frame: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to Year 6
Population: Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid 6 | The Number of Participants With Clinically Significant Laboratory Parameters | Creatinine <18 μmol/L | 1 Participants |
| Zoledronic Acid 6 | The Number of Participants With Clinically Significant Laboratory Parameters | Creatinine >221 μmol/L | 3 Participants |
| Zoledronic Acid 6 | The Number of Participants With Clinically Significant Laboratory Parameters | Calcium <1.87 mmol/L | 0 Participants |
| Zoledronic Acid 6 | The Number of Participants With Clinically Significant Laboratory Parameters | Calcium >2.89 mmol/L | 4 Participants |
| Zoledronic Acid 6 | The Number of Participants With Clinically Significant Laboratory Parameters | Urea < 0.7 mmol/L | 0 Participants |
| Zoledronic Acid 6 | The Number of Participants With Clinically Significant Laboratory Parameters | Urea >14.3 mmol/L | 9 Participants |
| Zoledronic Acid 3 Placebo 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Urea >14.3 mmol/L | 10 Participants |
| Zoledronic Acid 3 Placebo 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Creatinine <18 μmol/L | 0 Participants |
| Zoledronic Acid 3 Placebo 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Calcium >2.89 mmol/L | 0 Participants |
| Zoledronic Acid 3 Placebo 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Urea < 0.7 mmol/L | 0 Participants |
| Zoledronic Acid 3 Placebo 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Creatinine >221 μmol/L | 0 Participants |
| Zoledronic Acid 3 Placebo 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Calcium <1.87 mmol/L | 0 Participants |
| Placebo 3 Zoledronic Acid 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Creatinine >221 μmol/L | 2 Participants |
| Placebo 3 Zoledronic Acid 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Calcium <1.87 mmol/L | 1 Participants |
| Placebo 3 Zoledronic Acid 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Urea >14.3 mmol/L | 17 Participants |
| Placebo 3 Zoledronic Acid 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Calcium >2.89 mmol/L | 4 Participants |
| Placebo 3 Zoledronic Acid 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Creatinine <18 μmol/L | 1 Participants |
| Placebo 3 Zoledronic Acid 3 | The Number of Participants With Clinically Significant Laboratory Parameters | Urea < 0.7 mmol/L | 0 Participants |