Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Double-blind Extension of HORIZON Pivotal Fracture Trial (Zoledronic Acid in the Treatment of Postmenopausal Osteoporosis)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00145327
Recruitment Status : Completed
First Posted : September 5, 2005
Results First Posted : April 20, 2011
Last Update Posted : June 28, 2011
Sponsor:
Information provided by:
Novartis

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Osteoporosis
Interventions Drug: Zoledronic Acid
Drug: Placebo
Enrollment 2456
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.

Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description 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. 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. 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.
Period Title: Overall Study
Started 616 [1] 617 1223 [2]
Completed 474 493 975
Not Completed 142 124 248
Reason Not Completed
Withdrawal by Subject             77             72             164
Death             26             18             30
Adverse Event             14             11             22
Lost to Follow-up             9             14             14
Administrative problems             12             9             13
Protocol Violation             2             0             2
Abnormal laboratory value(s)             1             0             2
Missing - not stated             1             0             1
[1]
Group Z6 and Group Z3P3 have randomized participants.
[2]
Group P3Z3 have non-randomized participants
Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3 Total
Hide Arm/Group Description 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. 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 616 617 1223 2456
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 616 participants 617 participants 1223 participants 2456 participants
75.5  (4.88) 75.5  (4.89) 75.6  (4.95) 75.5  (4.92)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 616 participants 617 participants 1223 participants 2456 participants
Female
616
 100.0%
617
 100.0%
1223
 100.0%
2456
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 451 470 507
Mean (Standard Error)
Unit of Measure: Percentage Change in BMD
0.557  (0.2154) -0.493  (0.2249) 3.337  (0.2329)
2.Secondary Outcome
Title Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP
Hide Description The amount of serum n-terminal propeptide of type I collagen (P1NP) as determined by the central laboratory.
Time Frame Year 4.5
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 433 460 870
Mean (Standard Error)
Unit of Measure: ng/mL
18.842  (0.4325) 29.677  (0.6977) 17.256  (0.3743)
3.Secondary Outcome
Title Bone Resorption and Formation Biochemical Markers at Year 6: P1NP
Hide Description The amount of serum P1NP as determined by the central laboratory
Time Frame Year 6
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 392 414 426
Mean (Standard Error)
Unit of Measure: ng/mL
27.356  (0.6340) 30.344  (0.6050) 25.926  (0.7765)
4.Secondary Outcome
Title Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 101 102 195
Mean (Standard Error)
Unit of Measure: Percentage Change in BMD
2.618  (0.384) 1.196  (0.3510) 6.551  (0.3035)
5.Secondary Outcome
Title Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 100 84 128
Mean (Standard Error)
Unit of Measure: Percentage change in BMD
3.473  (0.4653) 1.606  (0.4550) 8.875  (0.5398)
6.Secondary Outcome
Title Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 100 99 188
Mean (Standard Error)
Unit of Measure: Percentage change in BMD
0.378  (0.3615) -0.924  (0.3158) 0.386  (0.3071)
7.Secondary Outcome
Title Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 96 82 125
Mean (Standard Error)
Unit of Measure: Percentage change in BMD
0.178  (0.3661) -0.567  (0.4025) 0.299  (0.3473)
8.Secondary Outcome
Title Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 525 544 1047
Mean (Standard Error)
Unit of Measure: Percentage change in BMD
Femoral Neck 0.738  (0.1874) 0.210  (0.2058) 2.697  (0.1516)
Total Hip 0.479  (0.1337) -0.070  (0.1354) 3.228  (0.1244)
Trochanter 0.813  (0.1919) 0.041  (0.1936) 4.611  (0.2050)
9.Secondary Outcome
Title Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 451 470 570
Mean (Standard Error)
Unit of Measure: Percentage change in BMD
Femoral Neck 0.577  (0.2154) -0.493  (0.2249) 3.337  (0.2329)
Total Hip 0.083  (0.1647) -1.151  (0.1817) 3.815  (0.1877)
Trochanter 0.628  (0.2275) -0.903  (0.2462) 6.072  (0.2894)
10.Secondary Outcome
Title Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 469 486 585
Measure Type: Number
Unit of Measure: Percentage of patients
New morphometric vertebral fracture 3.0 6.2 2.9
New/Worsening morphometric vertebral fracture 3.4 7.0 3.1
11.Secondary Outcome
Title Number of Participants With Incidence of Clinical Fracture
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 616 617 1223
Measure Type: Number
Unit of Measure: Participants
Clinical fracture 51 51 91
Clinical vertebral fractures 7 4 7
Non-vertebral fractures 45 47 85
Hip fracture 7 8 10
12.Secondary Outcome
Title Qualitative Bone Biopsy Parameters
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Bone Biopsy sub-population.
Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 3 2 0
Measure Type: Number
Unit of Measure: Participants
Osteomalacia 0 0
Woven bone 0 0
Cortical trabeculation 0 0
Marrow fibrosis 0 0
Normal mineralization and normal osteoid 3 2
Contained double labeling 3 2
13.Secondary Outcome
Title Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.
Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 613 616 1221
Mean (Standard Deviation)
Unit of Measure: μmol/L
1.96  (9.364) 1.28  (8.757) 0.21  (12.360)
14.Secondary Outcome
Title Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.
Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 613 616 1221
Mean (Standard Deviation)
Unit of Measure: μmol/L
3.35  (23.580) 2.23  (9.891) 2.47  (13.042)
15.Secondary Outcome
Title Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.
Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 613 616 1221
Mean (Standard Deviation)
Unit of Measure: μmol/L
3.46  (21.735) 0.71  (10.278) 1.04  (11.882)
16.Secondary Outcome
Title The Number of Participants With Clinically Significant Laboratory Parameters
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.
Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 612 615 1210
Measure Type: Number
Unit of Measure: Participants
Creatinine <18 μmol/L 1 0 1
Creatinine >221 μmol/L 3 0 2
Calcium <1.87 mmol/L 0 0 1
Calcium >2.89 mmol/L 4 0 4
Urea < 0.7 mmol/L 0 0 0
Urea >14.3 mmol/L 9 10 17
Time Frame Extension Baseline (Year 3; Month 36) to Year 6
Adverse Event Reporting Description Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
 
Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Hide Arm/Group Description 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. 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. 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.
All-Cause Mortality
Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   191/613 (31.16%)   168/616 (27.27%)   297/1221 (24.32%) 
Blood and lymphatic system disorders       
Anaemia  1  4/613 (0.65%)  1/616 (0.16%)  5/1221 (0.41%) 
Coagulopathy  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Iron deficiency anaemia  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Pancytopenia  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Cardiac disorders       
Acute coronary syndrome  1  1/613 (0.16%)  1/616 (0.16%)  2/1221 (0.16%) 
Acute myocardial infarction  1  2/613 (0.33%)  0/616 (0.00%)  4/1221 (0.33%) 
Angina pectoris  1  3/613 (0.49%)  1/616 (0.16%)  6/1221 (0.49%) 
Angina unstable  1  0/613 (0.00%)  2/616 (0.32%)  1/1221 (0.08%) 
Aortic valve disease  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Aortic valve incompetence  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Aortic valve stenosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Arrhythmia  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Atrial fibrillation  1  12/613 (1.96%)  7/616 (1.14%)  10/1221 (0.82%) 
Atrial tachycardia  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Atrioventricular block  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Atrioventricular block complete  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Atrioventricular block second degree  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Bradyarrhythmia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Bradycardia  1  2/613 (0.33%)  0/616 (0.00%)  4/1221 (0.33%) 
Bundle branch block left  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Cardiac arrest  1  2/613 (0.33%)  2/616 (0.32%)  2/1221 (0.16%) 
Cardiac disorder  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Cardiac failure  1  4/613 (0.65%)  1/616 (0.16%)  9/1221 (0.74%) 
Cardiac failure congestive  1  3/613 (0.49%)  2/616 (0.32%)  5/1221 (0.41%) 
Cardio-respiratory arrest  1  1/613 (0.16%)  1/616 (0.16%)  2/1221 (0.16%) 
Cardiogenic shock  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Cardiopulmonary failure  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Congestive cardiomyopathy  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Coronary artery disease  1  3/613 (0.49%)  2/616 (0.32%)  4/1221 (0.33%) 
Coronary artery occlusion  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Myocardial fibrosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Myocardial infarction  1  5/613 (0.82%)  4/616 (0.65%)  5/1221 (0.41%) 
Myocardial ischaemia  1  2/613 (0.33%)  0/616 (0.00%)  2/1221 (0.16%) 
Palpitations  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Pericarditis  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Sick sinus syndrome  1  0/613 (0.00%)  2/616 (0.32%)  3/1221 (0.25%) 
Supraventricular tachycardia  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Tachyarrhythmia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Tachycardia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Ventricular extrasystoles  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Congenital, familial and genetic disorders       
Dermoid cyst  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Ear and labyrinth disorders       
Deafness bilateral  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Meniere's disease  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Ototoxicity  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Tinnitus  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Vertigo  1  0/613 (0.00%)  3/616 (0.49%)  0/1221 (0.00%) 
Vertigo positional  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Endocrine disorders       
Goitre  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Thyrotoxic crisis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Eye disorders       
Amaurosis fugax  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Cataract  1  4/613 (0.65%)  6/616 (0.97%)  13/1221 (1.06%) 
Eye disorder  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Eye inflammation  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Eye pain  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Hyalosis asteroid  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Retinal artery embolism  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Retinal detachment  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Sympathetic ophthalmia  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Trichiasis  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Uveitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Gastrointestinal disorders       
Abdominal distension  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Abdominal hernia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Abdominal pain  1  3/613 (0.49%)  1/616 (0.16%)  8/1221 (0.66%) 
Abdominal pain upper  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Abdominal strangulated hernia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Anal polyp  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Colitis  1  2/613 (0.33%)  0/616 (0.00%)  1/1221 (0.08%) 
Colitis ischaemic  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Colonic polyp  1  0/613 (0.00%)  1/616 (0.16%)  5/1221 (0.41%) 
Colonic stenosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Constipation  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Diarrhoea  1  0/613 (0.00%)  0/616 (0.00%)  4/1221 (0.33%) 
Diverticular perforation  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Diverticulum  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Diverticulum intestinal  1  0/613 (0.00%)  0/616 (0.00%)  3/1221 (0.25%) 
Diverticulum intestinal haemorrhagic  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Duodenal ulcer  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Duodenal ulcer haemorrhage  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Dyspepsia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Enteritis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Enterocolitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Femoral hernia, obstructive  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Flatulence  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Gastric ulcer  1  3/613 (0.49%)  1/616 (0.16%)  2/1221 (0.16%) 
Gastric ulcer haemorrhage  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Gastritis  1  1/613 (0.16%)  1/616 (0.16%)  1/1221 (0.08%) 
Gastritis erosive  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Gastritis haemorrhagic  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Gastrointestinal haemorrhage  1  1/613 (0.16%)  1/616 (0.16%)  2/1221 (0.16%) 
Gastrooesophageal reflux disease  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Gastrooesophagitis  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Haematochezia  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Hiatus hernia  1  0/613 (0.00%)  2/616 (0.32%)  0/1221 (0.00%) 
Ileal perforation  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Ileus  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Ileus paralytic  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Inguinal hernia  1  1/613 (0.16%)  2/616 (0.32%)  1/1221 (0.08%) 
Intestinal haemorrhage  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Intestinal ischaemia  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Intestinal obstruction  1  2/613 (0.33%)  3/616 (0.49%)  2/1221 (0.16%) 
Intestinal polyp  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Irritable bowel syndrome  1  0/613 (0.00%)  2/616 (0.32%)  0/1221 (0.00%) 
Large intestinal ulcer  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Mechanical ileus  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Melaena  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Nausea  1  1/613 (0.16%)  1/616 (0.16%)  1/1221 (0.08%) 
Oesophagitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Pancreatic duct dilatation  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Pancreatitis acute  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Proctalgia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Rectal haemorrhage  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Rectal prolapse  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Reflux oesophagitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Small intestinal obstruction  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Subileus  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Volvulus of small bowel  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Vomiting  1  3/613 (0.49%)  1/616 (0.16%)  3/1221 (0.25%) 
General disorders       
Accidental death  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Asthenia  1  1/613 (0.16%)  0/616 (0.00%)  3/1221 (0.25%) 
Chest pain  1  1/613 (0.16%)  1/616 (0.16%)  3/1221 (0.25%) 
Chills  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Death  1  0/613 (0.00%)  0/616 (0.00%)  3/1221 (0.25%) 
Fatigue  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Gait disturbance  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
General physical health deterioration  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Impaired healing  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Malaise  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Multi-organ failure  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Necrosis  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Non-cardiac chest pain  1  1/613 (0.16%)  1/616 (0.16%)  5/1221 (0.41%) 
Oedema peripheral  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Pain  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Pyrexia  1  0/613 (0.00%)  1/616 (0.16%)  2/1221 (0.16%) 
Sudden death  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Systemic inflammatory response syndrome  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Hepatobiliary disorders       
Acute hepatic failure  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Bile duct stone  1  0/613 (0.00%)  3/616 (0.49%)  1/1221 (0.08%) 
Cholangitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Cholecystitis  1  1/613 (0.16%)  3/616 (0.49%)  2/1221 (0.16%) 
Cholecystitis acute  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Cholecystitis chronic  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Cholelithiasis  1  4/613 (0.65%)  6/616 (0.97%)  3/1221 (0.25%) 
Cholestasis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Hepatic failure  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Jaundice  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Immune system disorders       
Hypersensitivity  1  0/613 (0.00%)  1/616 (0.16%)  2/1221 (0.16%) 
Infections and infestations       
Abdominal abscess  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Acute sinusitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Appendicitis  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Appendicitis perforated  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Arthritis bacterial  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Bronchitis  1  2/613 (0.33%)  5/616 (0.81%)  1/1221 (0.08%) 
Bronchitis bacterial  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Bronchopneumonia  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Cellulitis  1  3/613 (0.49%)  2/616 (0.32%)  1/1221 (0.08%) 
Clostridial infection  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Cystitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Device related infection  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Diarrhoea infectious  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Diverticulitis  1  0/613 (0.00%)  0/616 (0.00%)  5/1221 (0.41%) 
Endocarditis bacterial  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Endometritis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Endophthalmitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Erysipelas  1  2/613 (0.33%)  0/616 (0.00%)  1/1221 (0.08%) 
Furuncle  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Gastroenteritis  1  1/613 (0.16%)  1/616 (0.16%)  1/1221 (0.08%) 
Influenza  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Intervertebral discitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Labyrinthitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Laryngitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Osteomyelitis  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Osteomyelitis chronic  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Otitis externa  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Pneumococcal sepsis  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Pneumonia  1  10/613 (1.63%)  5/616 (0.81%)  13/1221 (1.06%) 
Pneumonia influenzal  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Post procedural pneumonia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Pseudomembranous colitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Pyelonephritis  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Pyelonephritis acute  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Sepsis  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Staphylococcal infection  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Staphylococcal sepsis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Tinea cruris  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Tracheitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Tracheobronchitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Urinary tract infection  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Viral infection  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Wound infection  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Injury, poisoning and procedural complications       
Accidental overdose  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Ankle fracture  1  2/613 (0.33%)  2/616 (0.32%)  3/1221 (0.25%) 
Avulsion fracture  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Brain contusion  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Comminuted fracture  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Concussion  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Contrast media reaction  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Contusion  1  1/613 (0.16%)  2/616 (0.32%)  2/1221 (0.16%) 
Device breakage  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Device dislocation  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Excoriation  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Face injury  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Fall  1  3/613 (0.49%)  4/616 (0.65%)  7/1221 (0.57%) 
Femoral neck fracture  1  2/613 (0.33%)  1/616 (0.16%)  1/1221 (0.08%) 
Femur fracture  1  3/613 (0.49%)  2/616 (0.32%)  5/1221 (0.41%) 
Forearm fracture  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Fracture  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Fractured coccyx  1  0/613 (0.00%)  2/616 (0.32%)  0/1221 (0.00%) 
Fractured ischium  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Hand fracture  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Head injury  1  1/613 (0.16%)  2/616 (0.32%)  2/1221 (0.16%) 
Hip fracture  1  5/613 (0.82%)  7/616 (1.14%)  5/1221 (0.41%) 
Humerus fracture  1  3/613 (0.49%)  3/616 (0.49%)  5/1221 (0.41%) 
Jaw fracture  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Joint dislocation  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Joint injury  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Limb injury  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Lower limb fracture  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Lumbar vertebral fracture  1  1/613 (0.16%)  1/616 (0.16%)  1/1221 (0.08%) 
Meniscus lesion  1  1/613 (0.16%)  2/616 (0.32%)  2/1221 (0.16%) 
Mouth injury  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Patella fracture  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Pelvic fracture  1  5/613 (0.82%)  5/616 (0.81%)  2/1221 (0.16%) 
Post-traumatic pain  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Procedural pain  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Pubic rami fracture  1  2/613 (0.33%)  1/616 (0.16%)  1/1221 (0.08%) 
Radius fracture  1  1/613 (0.16%)  0/616 (0.00%)  5/1221 (0.41%) 
Rib fracture  1  2/613 (0.33%)  1/616 (0.16%)  4/1221 (0.33%) 
Road traffic accident  1  0/613 (0.00%)  2/616 (0.32%)  0/1221 (0.00%) 
Scapula fracture  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Skin laceration  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Spinal compression fracture  1  1/613 (0.16%)  2/616 (0.32%)  0/1221 (0.00%) 
Spinal fracture  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Sternal fracture  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Subdural haematoma  1  5/613 (0.82%)  0/616 (0.00%)  2/1221 (0.16%) 
Subdural haemorrhage  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Therapeutic agent toxicity  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Thoracic vertebral fracture  1  1/613 (0.16%)  1/616 (0.16%)  1/1221 (0.08%) 
Tibia fracture  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Ulna fracture  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Upper limb fracture  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Wound  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Wound secretion  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Wrist fracture  1  1/613 (0.16%)  4/616 (0.65%)  4/1221 (0.33%) 
Investigations       
Barium enema  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Blood glucose decreased  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Blood osmolarity decreased  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Blood pressure increased  1  0/613 (0.00%)  0/616 (0.00%)  3/1221 (0.25%) 
International normalised ratio decreased  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Intraocular pressure increased  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Weight decreased  1  0/613 (0.00%)  1/616 (0.16%)  2/1221 (0.16%) 
Metabolism and nutrition disorders       
Cachexia  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Decreased appetite  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Dehydration  1  2/613 (0.33%)  2/616 (0.32%)  4/1221 (0.33%) 
Diabetes mellitus  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Failure to thrive  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Gout  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Hypercalcaemia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Hypercholesterolaemia  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Hyperglycaemia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Hyperkalaemia  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Hyponatraemia  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Lipomatosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Vitamin D deficiency  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia  1  1/613 (0.16%)  3/616 (0.49%)  8/1221 (0.66%) 
Arthritis  1  1/613 (0.16%)  1/616 (0.16%)  3/1221 (0.25%) 
Arthrofibrosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Back pain  1  7/613 (1.14%)  4/616 (0.65%)  3/1221 (0.25%) 
Cervical spinal stenosis  1  1/613 (0.16%)  2/616 (0.32%)  0/1221 (0.00%) 
Flank pain  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Foot deformity  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Fracture delayed union  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Intervertebral disc degeneration  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Intervertebral disc protrusion  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Joint swelling  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Knee deformity  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Lumbar spinal stenosis  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Muscle haemorrhage  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Muscular weakness  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Musculoskeletal pain  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Myalgia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Myopathy  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Osteitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Osteoarthritis  1  6/613 (0.98%)  4/616 (0.65%)  13/1221 (1.06%) 
Osteonecrosis  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Pain in extremity  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Periarthritis  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Polymyalgia rheumatica  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Rotator cuff syndrome  1  0/613 (0.00%)  2/616 (0.32%)  1/1221 (0.08%) 
Spinal column stenosis  1  3/613 (0.49%)  0/616 (0.00%)  2/1221 (0.16%) 
Spinal osteoarthritis  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Spondylolisthesis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Abdominal neoplasm  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Anal cancer  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
B-cell lymphoma  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
B-cell lymphoma stage IV  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Basal cell carcinoma  1  4/613 (0.65%)  4/616 (0.65%)  1/1221 (0.08%) 
Benign gastric neoplasm  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Bowen's disease  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Brain cancer metastatic  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Brain neoplasm  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Breast cancer  1  7/613 (1.14%)  2/616 (0.32%)  6/1221 (0.49%) 
Carcinoma in situ  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Chronic lymphocytic leukaemia  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Chronic myeloid leukaemia  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Colon adenoma  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Colon cancer  1  3/613 (0.49%)  4/616 (0.65%)  3/1221 (0.25%) 
Colon neoplasm  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Gastric cancer  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Gastric neoplasm  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Gastrointestinal carcinoma  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Gastrointestinal neoplasm  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Gastrointestinal tract adenoma  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Haemangioma  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Hodgkin's disease  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Intestinal adenocarcinoma  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Lipoma  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Lung neoplasm malignant  1  3/613 (0.49%)  2/616 (0.32%)  1/1221 (0.08%) 
Lung squamous cell carcinoma stage unspecified  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Lymphoma  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Malignant melanoma  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Meningioma  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Metastases to bone  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Metastases to chest wall  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Metastases to liver  1  0/613 (0.00%)  2/616 (0.32%)  0/1221 (0.00%) 
Metastasis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Metastatic neoplasm  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Morton's neuroma  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Mucoepidermoid carcinoma  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Multiple myeloma  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Myelodysplastic syndrome  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Myeloproliferative disorder  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Nasal cavity cancer  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Neoplasm skin  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Ovarian cancer metastatic  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Pancreatic carcinoma  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Pancreatic neoplasm  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Rectal cancer stage I  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Rectal neoplasm  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Renal cancer  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Salivary gland neoplasm  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Seborrhoeic keratosis  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Skin cancer  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Spinal cord neoplasm  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Squamous cell carcinoma  1  3/613 (0.49%)  0/616 (0.00%)  2/1221 (0.16%) 
Squamous cell carcinoma of skin  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Urinary bladder adenoma  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Nervous system disorders       
Amnesia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Anoxic encephalopathy  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Aphasia  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Basal ganglia infarction  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Brain injury  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Brain stem haemorrhage  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Cerebral artery embolism  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Cerebral artery occlusion  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Cerebral haemorrhage  1  2/613 (0.33%)  0/616 (0.00%)  2/1221 (0.16%) 
Cerebral infarction  1  0/613 (0.00%)  2/616 (0.32%)  4/1221 (0.33%) 
Cerebral ischaemia  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Cerebrosclerosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Cerebrovascular accident  1  6/613 (0.98%)  3/616 (0.49%)  8/1221 (0.66%) 
Cerebrovascular disorder  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Convulsion  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Dementia  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Diabetic coma  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Dizziness  1  4/613 (0.65%)  0/616 (0.00%)  1/1221 (0.08%) 
Embolic stroke  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Encephalitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Encephalomyelitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Headache  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Hemiparesis  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Hemiplegia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Hydrocephalus  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Ischaemic stroke  1  0/613 (0.00%)  1/616 (0.16%)  2/1221 (0.16%) 
Lacunar infarction  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Loss of consciousness  1  2/613 (0.33%)  0/616 (0.00%)  1/1221 (0.08%) 
Memory impairment  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Monoparesis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Myelopathy  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Nerve compression  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Nerve root compression  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Neurodegenerative disorder  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Parkinson's disease  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Parkinsonism  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Post herpetic neuralgia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Presyncope  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Progressive bulbar palsy  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Sciatica  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Somnolence  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Spinal claudication  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Subarachnoid haemorrhage  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Syncope  1  1/613 (0.16%)  0/616 (0.00%)  5/1221 (0.41%) 
Temporal lobe epilepsy  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Thalamic infarction  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Transient ischaemic attack  1  7/613 (1.14%)  2/616 (0.32%)  3/1221 (0.25%) 
Trigeminal neuralgia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Vascular dementia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Vertebrobasilar insufficiency  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Psychiatric disorders       
Anxiety  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Anxiety disorder due to a general medical condition  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Confusional state  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Delirium  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Depression  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Insomnia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Major depression  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Mental disorder  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Suicide attempt  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Renal and urinary disorders       
Bladder prolapse  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Calculus urinary  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Glomerulonephritis chronic  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Haematuria  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Nephrolithiasis  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Proteinuria  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Renal cyst  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Renal failure  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Renal failure acute  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Urinary incontinence  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Reproductive system and breast disorders       
Bartholin's cyst  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Breast fibrosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Breast mass  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Cystocele  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Genital prolapse  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Ovarian cyst  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Pelvic prolapse  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Rectocele  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Urogenital prolapse  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Uterine polyp  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Uterine prolapse  1  0/613 (0.00%)  1/616 (0.16%)  2/1221 (0.16%) 
Uterovaginal prolapse  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Vaginal haemorrhage  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Vaginal prolapse  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Acute pulmonary oedema  1  0/613 (0.00%)  2/616 (0.32%)  1/1221 (0.08%) 
Acute respiratory failure  1  0/613 (0.00%)  2/616 (0.32%)  2/1221 (0.16%) 
Asthma  1  2/613 (0.33%)  0/616 (0.00%)  0/1221 (0.00%) 
Asthmatic crisis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Bronchospasm  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Chronic obstructive pulmonary disease  1  4/613 (0.65%)  5/616 (0.81%)  3/1221 (0.25%) 
Diaphragmatic hernia  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Dyspnoea  1  1/613 (0.16%)  0/616 (0.00%)  2/1221 (0.16%) 
Emphysema  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Epistaxis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Laryngeal oedema  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Lung disorder  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Mediastinal haemorrhage  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Nasal polyps  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Obstructive airways disorder  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Orthopnoea  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Pleural effusion  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Pneumonia aspiration  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Pneumonitis  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Pulmonary artery stenosis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Pulmonary embolism  1  1/613 (0.16%)  3/616 (0.49%)  5/1221 (0.41%) 
Pulmonary hypertension  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Pulmonary oedema  1  2/613 (0.33%)  0/616 (0.00%)  1/1221 (0.08%) 
Pulmonary thrombosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Respiratory arrest  1  1/613 (0.16%)  1/616 (0.16%)  0/1221 (0.00%) 
Respiratory failure  1  2/613 (0.33%)  2/616 (0.32%)  0/1221 (0.00%) 
Skin and subcutaneous tissue disorders       
Acrodermatitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Decubitus ulcer  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Dermatitis allergic  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Skin ulcer  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Social circumstances       
Immobile  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Social problem  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Vascular disorders       
Aortic dissection  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Aortic stenosis  1  2/613 (0.33%)  1/616 (0.16%)  0/1221 (0.00%) 
Arterial disorder  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Arterial stenosis limb  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Arteriosclerosis  1  1/613 (0.16%)  0/616 (0.00%)  3/1221 (0.25%) 
Deep vein thrombosis  1  3/613 (0.49%)  1/616 (0.16%)  2/1221 (0.16%) 
Embolism  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Femoral arterial stenosis  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Femoral artery occlusion  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Haematoma  1  0/613 (0.00%)  0/616 (0.00%)  2/1221 (0.16%) 
Hypertension  1  2/613 (0.33%)  1/616 (0.16%)  4/1221 (0.33%) 
Hypertensive crisis  1  2/613 (0.33%)  2/616 (0.32%)  3/1221 (0.25%) 
Hypotension  1  1/613 (0.16%)  0/616 (0.00%)  5/1221 (0.41%) 
Orthostatic hypotension  1  1/613 (0.16%)  0/616 (0.00%)  1/1221 (0.08%) 
Peripheral arterial occlusive disease  1  1/613 (0.16%)  0/616 (0.00%)  0/1221 (0.00%) 
Phlebitis  1  0/613 (0.00%)  1/616 (0.16%)  0/1221 (0.00%) 
Shock  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Thrombophlebitis  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Thrombosis  1  0/613 (0.00%)  1/616 (0.16%)  2/1221 (0.16%) 
Varicose vein  1  2/613 (0.33%)  1/616 (0.16%)  1/1221 (0.08%) 
Vasculitis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Vasoconstriction  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Venous insufficiency  1  0/613 (0.00%)  1/616 (0.16%)  1/1221 (0.08%) 
Venous thrombosis  1  0/613 (0.00%)  0/616 (0.00%)  1/1221 (0.08%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   421/613 (68.68%)   427/616 (69.32%)   908/1221 (74.37%) 
Eye disorders       
Cataract  1  35/613 (5.71%)  43/616 (6.98%)  72/1221 (5.90%) 
Gastrointestinal disorders       
Diarrhoea  1  31/613 (5.06%)  32/616 (5.19%)  57/1221 (4.67%) 
Nausea  1  20/613 (3.26%)  26/616 (4.22%)  94/1221 (7.70%) 
General disorders       
Fatigue  1  24/613 (3.92%)  20/616 (3.25%)  64/1221 (5.24%) 
Pyrexia  1  30/613 (4.89%)  19/616 (3.08%)  181/1221 (14.82%) 
Infections and infestations       
Bronchitis  1  48/613 (7.83%)  49/616 (7.95%)  80/1221 (6.55%) 
Influenza  1  32/613 (5.22%)  31/616 (5.03%)  63/1221 (5.16%) 
Nasopharyngitis  1  61/613 (9.95%)  61/616 (9.90%)  95/1221 (7.78%) 
Urinary tract infection  1  77/613 (12.56%)  94/616 (15.26%)  143/1221 (11.71%) 
Injury, poisoning and procedural complications       
Fall  1  50/613 (8.16%)  60/616 (9.74%)  110/1221 (9.01%) 
Musculoskeletal and connective tissue disorders       
Arthralgia  1  119/613 (19.41%)  106/616 (17.21%)  253/1221 (20.72%) 
Back pain  1  113/613 (18.43%)  111/616 (18.02%)  206/1221 (16.87%) 
Bone pain  1  30/613 (4.89%)  16/616 (2.60%)  88/1221 (7.21%) 
Musculoskeletal pain  1  34/613 (5.55%)  31/616 (5.03%)  76/1221 (6.22%) 
Myalgia  1  28/613 (4.57%)  25/616 (4.06%)  147/1221 (12.04%) 
Osteoarthritis  1  55/613 (8.97%)  49/616 (7.95%)  87/1221 (7.13%) 
Pain in extremity  1  51/613 (8.32%)  54/616 (8.77%)  121/1221 (9.91%) 
Nervous system disorders       
Dizziness  1  26/613 (4.24%)  31/616 (5.03%)  69/1221 (5.65%) 
Headache  1  37/613 (6.04%)  40/616 (6.49%)  125/1221 (10.24%) 
Vascular disorders       
Hypertension  1  46/613 (7.50%)  92/616 (14.94%)  136/1221 (11.14%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Layout table for additonal information
Responsible Party: External Affairs, Novartis
ClinicalTrials.gov Identifier: NCT00145327    
Other Study ID Numbers: CZOL446H2301E1
First Submitted: September 1, 2005
First Posted: September 5, 2005
Results First Submitted: January 21, 2011
Results First Posted: April 20, 2011
Last Update Posted: June 28, 2011