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

Sponsor
Novartis (Industry)
Overall Status
Completed
CT.gov ID
NCT00145327
Collaborator
(none)
2,456
Enrollment
31
Locations
3
Arms
54
Duration (Months)
79.2
Patients Per Site
1.5
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Zoledronic Acid
  • Drug: Placebo
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
2456 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A 3-year, Double-blind Extension to CZOL446H2301 to Evaluate the Long-term Safety and Efficacy of Zoledronic Acid in the Treatment of Osteoporosis in Postmenopausal Women Taking Calcium and Vitamin D
Study Start Date :
May 1, 2005
Actual Primary Completion Date :
Nov 1, 2009
Actual Study Completion Date :
Nov 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: 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.

Drug: Zoledronic Acid
Zoledronic Acid 5 mg in 100 mL physiologic 0.9% normal saline for intravenous infusion.
Other Names:
  • Reclast, Aclasta

    		•
    Placebo Comparator: 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.

    Drug: Placebo
    100 mL physiologic 0.9% normal saline for intravenous infusion.
    Other Names:
  • Reclast, Aclasta

    		•
    Experimental: 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.

    Drug: Zoledronic Acid
    Zoledronic Acid 5 mg in 100 mL physiologic 0.9% normal saline for intravenous infusion.
    Other Names:
  • Reclast, Aclasta

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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 Outcome Measures

    1. 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.

    2. Bone Resorption and Formation Biochemical Markers at Year 6: P1NP [Year 6]

      The amount of serum P1NP as determined by the central laboratory

    3. 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).

    4. 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).

    5. 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).

    6. 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).

    7. 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).

    8. 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).

    9. 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.

    10. 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.

    11. 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).

    12. 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.

    13. 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.

    14. 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.

    15. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    68 Years to 90 Years
    Sexes Eligible for Study:
    Female
    Accepts 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/exclusion criteria may apply.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Southern Arizona VA Tucson Arizona United States 85723
    2 University of Arkansas for Medical Science Little Rock Arkansas United States 72205
    3 Osteoporosis Medical Center Beverly Hills California United States 90211
    4 Osteoporosis Prevention Center San Diego California United States 92103
    5 Diablo Clinical Research, Inc Walnut Creek California United States 94598
    6 Colorado Center for Bone Research Lakewood Colorado United States 80227
    7 CRIA Research Ft. Lauderdale Florida United States 33334
    8 Radiant Research Stuart Florida United States 34996
    9 Comprehensive Clinical Trials, LLC West Palm Beach Florida United States 33409
    10 United Osteoporosis Centers (UOC) Gainesville Georgia United States 30501
    11 Northwestern University Center for Clinical Research Chicago Illinois United States 60611
    12 School of Medicine Indianapolis Indiana United States 46202
    13 Medical Specialist Clinical Research Center Munster Indiana United States 46321
    14 Heartland Research Associates, LLC Wichita Kansas United States 67207
    15 Maine Center for Osteoporosis Research and Education Bangor Maine United States 04401
    16 Osteoporosis Clinical Trial Center Hagerstown Maryland United States 21740
    17 Clinical Pharmacology Study Groups Worcester Massachusetts United States 01610
    18 Washington University Center for Clinical Studies St. Louis Missouri United States 62110
    19 New Mexico Clinical Research and Osteoporosis Center Inc Albuquerque New Mexico United States 87106
    20 Winthrop U Hospital Mineola New York United States 11501
    21 Odyssey Research Services/CCRC Internal Medical Fargo North Dakota United States 58104
    22 University of Cincinnati Bone Health and Osteoporosis Center Cincinnati Ohio United States 45219
    23 Thomas Jefferson University Hospital Philadelphia Pennsylvania United States 19131
    24 University of Pittsburgh Pittsburgh Pennsylvania United States 15261
    25 Radiant Research Wyomissing Pennsylvania United States 19610
    26 Rhode Island Hospital, Endocrinology Clinical Research Unit Providence Rhode Island United States 02903
    27 University of Tennessee Health Science Memphis Tennessee United States 38105
    28 McGuire Veterans Affairs Medical Center Richmond Virginia United States 23249
    29 VA Commonwealth University Richmond Virginia United States 23298
    30 Puget Sound Osteoporosis Center Seattle Washington United States 98144
    31 Novartis Nuernberg Germany

    Sponsors and Collaborators

    • Novartis

    Investigators

    • Study Chair: Novartis Pharmaceuticals, Sponsor GmbH

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00145327
    Other Study ID Numbers:
    • CZOL446H2301E1
    First Posted:
    Sep 5, 2005
    Last Update Posted:
    Jun 28, 2011
    Last Verified:
    Jun 1, 2011
    Keywords provided by , ,
    Osteoporosis, Zoledronic Acid
    Additional relevant MeSH terms:
    Osteoporosis
    Zoledronic Acid

    Study Results

    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 Detail 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
    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 616 617 1223
    COMPLETED 474 493 975
    NOT COMPLETED 142 124 248

    Baseline Characteristics

    Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3 Total
    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 Participants 616 617 1223 2456
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    75.5
    (4.88)
    75.5
    (4.89)
    75.6
    (4.95)
    75.5
    (4.92)
    Sex: Female, Male (Count of Participants)
    Female
    616
    100%
    617
    100%
    1223
    100%
    2456
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3
    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)

    Outcome Measure Data

    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
    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.
    Measure Participants 451 470 507
    Mean (Standard Error) [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
    Description The amount of serum n-terminal propeptide of type I collagen (P1NP) as determined by the central laboratory.
    Time Frame Year 4.5

    Outcome Measure Data

    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
    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.
    Measure Participants 433 460 870
    Mean (Standard Error) [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
    Description The amount of serum P1NP as determined by the central laboratory
    Time Frame Year 6

    Outcome Measure Data

    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
    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.
    Measure Participants 392 414 426
    Mean (Standard Error) [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
    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)

    Outcome Measure Data

    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
    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.
    Measure Participants 101 102 195
    Mean (Standard Error) [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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 100 84 128
    Mean (Standard Error) [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
    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)

    Outcome Measure Data

    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
    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.
    Measure Participants 100 99 188
    Mean (Standard Error) [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
    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)

    Outcome Measure Data

    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
    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.
    Measure Participants 96 82 125
    Mean (Standard Error) [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
    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)

    Outcome Measure Data

    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
    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.
    Measure Participants 525 544 1047
    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
    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)

    Outcome Measure Data

    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
    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.
    Measure Participants 451 470 570
    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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 469 486 585
    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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 616 617 1223
    Clinical fracture
    51
    (8.15) 8.3%
    51
    (8.52) 8.3%
    91
    7.4%
    Clinical vertebral fractures
    7
    1.1%
    4
    0.6%
    7
    0.6%
    Non-vertebral fractures
    45
    7.3%
    47
    7.6%
    85
    7%
    Hip fracture
    7
    1.1%
    8
    1.3%
    10
    0.8%
    12. Secondary Outcome
    Title Qualitative Bone Biopsy Parameters
    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

    Outcome Measure Data

    Analysis Population Description
    Bone Biopsy sub-population.
    Arm/Group Title Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
    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.
    Measure Participants 3 2 0
    Osteomalacia
    0
    0%
    0
    0%
    Woven bone
    0
    0%
    0
    0%
    Cortical trabeculation
    0
    0%
    0
    0%
    Marrow fibrosis
    0
    0%
    0
    0%
    Normal mineralization and normal osteoid
    3
    0.5%
    2
    0.3%
    Contained double labeling
    3
    0.5%
    2
    0.3%
    13. Secondary Outcome
    Title Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 613 616 1221
    Mean (Standard Deviation) [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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 613 616 1221
    Mean (Standard Deviation) [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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 613 616 1221
    Mean (Standard Deviation) [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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 612 615 1210
    Creatinine <18 μmol/L
    1
    0.2%
    0
    0%
    1
    0.1%
    Creatinine >221 μmol/L
    3
    0.5%
    0
    0%
    2
    0.2%
    Calcium <1.87 mmol/L
    0
    0%
    0
    0%
    1
    0.1%
    Calcium >2.89 mmol/L
    4
    0.6%
    0
    0%
    4
    0.3%
    Urea < 0.7 mmol/L
    0
    0%
    0
    0%
    0
    0%
    Urea >14.3 mmol/L
    9
    1.5%
    10
    1.6%
    17
    1.4%

    Adverse Events

    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
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 191/613 (31.2%) 168/616 (27.3%) 297/1221 (24.3%)
    Blood and lymphatic system disorders
    Anaemia 4/613 (0.7%) 1/616 (0.2%) 5/1221 (0.4%)
    Coagulopathy 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Iron deficiency anaemia 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Pancytopenia 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Cardiac disorders
    Acute coronary syndrome 1/613 (0.2%) 1/616 (0.2%) 2/1221 (0.2%)
    Acute myocardial infarction 2/613 (0.3%) 0/616 (0%) 4/1221 (0.3%)
    Angina pectoris 3/613 (0.5%) 1/616 (0.2%) 6/1221 (0.5%)
    Angina unstable 0/613 (0%) 2/616 (0.3%) 1/1221 (0.1%)
    Aortic valve disease 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Aortic valve incompetence 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Aortic valve stenosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Arrhythmia 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Atrial fibrillation 12/613 (2%) 7/616 (1.1%) 10/1221 (0.8%)
    Atrial tachycardia 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Atrioventricular block 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Atrioventricular block complete 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Atrioventricular block second degree 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Bradyarrhythmia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Bradycardia 2/613 (0.3%) 0/616 (0%) 4/1221 (0.3%)
    Bundle branch block left 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Cardiac arrest 2/613 (0.3%) 2/616 (0.3%) 2/1221 (0.2%)
    Cardiac disorder 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Cardiac failure 4/613 (0.7%) 1/616 (0.2%) 9/1221 (0.7%)
    Cardiac failure congestive 3/613 (0.5%) 2/616 (0.3%) 5/1221 (0.4%)
    Cardio-respiratory arrest 1/613 (0.2%) 1/616 (0.2%) 2/1221 (0.2%)
    Cardiogenic shock 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Cardiopulmonary failure 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Congestive cardiomyopathy 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Coronary artery disease 3/613 (0.5%) 2/616 (0.3%) 4/1221 (0.3%)
    Coronary artery occlusion 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Myocardial fibrosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Myocardial infarction 5/613 (0.8%) 4/616 (0.6%) 5/1221 (0.4%)
    Myocardial ischaemia 2/613 (0.3%) 0/616 (0%) 2/1221 (0.2%)
    Palpitations 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Pericarditis 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Sick sinus syndrome 0/613 (0%) 2/616 (0.3%) 3/1221 (0.2%)
    Supraventricular tachycardia 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Tachyarrhythmia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Tachycardia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Ventricular extrasystoles 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Congenital, familial and genetic disorders
    Dermoid cyst 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Ear and labyrinth disorders
    Deafness bilateral 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Meniere's disease 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Ototoxicity 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Tinnitus 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Vertigo 0/613 (0%) 3/616 (0.5%) 0/1221 (0%)
    Vertigo positional 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Endocrine disorders
    Goitre 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Thyrotoxic crisis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Eye disorders
    Amaurosis fugax 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Cataract 4/613 (0.7%) 6/616 (1%) 13/1221 (1.1%)
    Eye disorder 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Eye inflammation 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Eye pain 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Hyalosis asteroid 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Retinal artery embolism 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Retinal detachment 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Sympathetic ophthalmia 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Trichiasis 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Uveitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Gastrointestinal disorders
    Abdominal distension 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Abdominal hernia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Abdominal pain 3/613 (0.5%) 1/616 (0.2%) 8/1221 (0.7%)
    Abdominal pain upper 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Abdominal strangulated hernia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Anal polyp 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Colitis 2/613 (0.3%) 0/616 (0%) 1/1221 (0.1%)
    Colitis ischaemic 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Colonic polyp 0/613 (0%) 1/616 (0.2%) 5/1221 (0.4%)
    Colonic stenosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Constipation 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Diarrhoea 0/613 (0%) 0/616 (0%) 4/1221 (0.3%)
    Diverticular perforation 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Diverticulum 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Diverticulum intestinal 0/613 (0%) 0/616 (0%) 3/1221 (0.2%)
    Diverticulum intestinal haemorrhagic 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Duodenal ulcer 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Duodenal ulcer haemorrhage 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Dyspepsia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Enteritis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Enterocolitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Femoral hernia, obstructive 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Flatulence 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Gastric ulcer 3/613 (0.5%) 1/616 (0.2%) 2/1221 (0.2%)
    Gastric ulcer haemorrhage 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Gastritis 1/613 (0.2%) 1/616 (0.2%) 1/1221 (0.1%)
    Gastritis erosive 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Gastritis haemorrhagic 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Gastrointestinal haemorrhage 1/613 (0.2%) 1/616 (0.2%) 2/1221 (0.2%)
    Gastrooesophageal reflux disease 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Gastrooesophagitis 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Haematochezia 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Hiatus hernia 0/613 (0%) 2/616 (0.3%) 0/1221 (0%)
    Ileal perforation 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Ileus 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Ileus paralytic 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Inguinal hernia 1/613 (0.2%) 2/616 (0.3%) 1/1221 (0.1%)
    Intestinal haemorrhage 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Intestinal ischaemia 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Intestinal obstruction 2/613 (0.3%) 3/616 (0.5%) 2/1221 (0.2%)
    Intestinal polyp 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Irritable bowel syndrome 0/613 (0%) 2/616 (0.3%) 0/1221 (0%)
    Large intestinal ulcer 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Mechanical ileus 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Melaena 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Nausea 1/613 (0.2%) 1/616 (0.2%) 1/1221 (0.1%)
    Oesophagitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Pancreatic duct dilatation 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Pancreatitis acute 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Proctalgia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Rectal haemorrhage 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Rectal prolapse 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Reflux oesophagitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Small intestinal obstruction 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Subileus 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Volvulus of small bowel 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Vomiting 3/613 (0.5%) 1/616 (0.2%) 3/1221 (0.2%)
    General disorders
    Accidental death 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Asthenia 1/613 (0.2%) 0/616 (0%) 3/1221 (0.2%)
    Chest pain 1/613 (0.2%) 1/616 (0.2%) 3/1221 (0.2%)
    Chills 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Death 0/613 (0%) 0/616 (0%) 3/1221 (0.2%)
    Fatigue 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Gait disturbance 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    General physical health deterioration 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Impaired healing 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Malaise 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Multi-organ failure 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Necrosis 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Non-cardiac chest pain 1/613 (0.2%) 1/616 (0.2%) 5/1221 (0.4%)
    Oedema peripheral 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Pain 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Pyrexia 0/613 (0%) 1/616 (0.2%) 2/1221 (0.2%)
    Sudden death 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Systemic inflammatory response syndrome 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Hepatobiliary disorders
    Acute hepatic failure 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Bile duct stone 0/613 (0%) 3/616 (0.5%) 1/1221 (0.1%)
    Cholangitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Cholecystitis 1/613 (0.2%) 3/616 (0.5%) 2/1221 (0.2%)
    Cholecystitis acute 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Cholecystitis chronic 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Cholelithiasis 4/613 (0.7%) 6/616 (1%) 3/1221 (0.2%)
    Cholestasis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Hepatic failure 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Jaundice 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Immune system disorders
    Hypersensitivity 0/613 (0%) 1/616 (0.2%) 2/1221 (0.2%)
    Infections and infestations
    Abdominal abscess 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Acute sinusitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Appendicitis 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Appendicitis perforated 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Arthritis bacterial 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Bronchitis 2/613 (0.3%) 5/616 (0.8%) 1/1221 (0.1%)
    Bronchitis bacterial 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Bronchopneumonia 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Cellulitis 3/613 (0.5%) 2/616 (0.3%) 1/1221 (0.1%)
    Clostridial infection 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Cystitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Device related infection 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Diarrhoea infectious 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Diverticulitis 0/613 (0%) 0/616 (0%) 5/1221 (0.4%)
    Endocarditis bacterial 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Endometritis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Endophthalmitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Erysipelas 2/613 (0.3%) 0/616 (0%) 1/1221 (0.1%)
    Furuncle 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Gastroenteritis 1/613 (0.2%) 1/616 (0.2%) 1/1221 (0.1%)
    Influenza 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Intervertebral discitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Labyrinthitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Laryngitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Osteomyelitis 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Osteomyelitis chronic 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Otitis externa 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Pneumococcal sepsis 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Pneumonia 10/613 (1.6%) 5/616 (0.8%) 13/1221 (1.1%)
    Pneumonia influenzal 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Post procedural pneumonia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Pseudomembranous colitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Pyelonephritis 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Pyelonephritis acute 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Sepsis 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Staphylococcal infection 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Staphylococcal sepsis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Tinea cruris 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Tracheitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Tracheobronchitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Urinary tract infection 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Viral infection 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Wound infection 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Injury, poisoning and procedural complications
    Accidental overdose 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Ankle fracture 2/613 (0.3%) 2/616 (0.3%) 3/1221 (0.2%)
    Avulsion fracture 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Brain contusion 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Comminuted fracture 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Concussion 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Contrast media reaction 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Contusion 1/613 (0.2%) 2/616 (0.3%) 2/1221 (0.2%)
    Device breakage 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Device dislocation 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Excoriation 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Face injury 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Fall 3/613 (0.5%) 4/616 (0.6%) 7/1221 (0.6%)
    Femoral neck fracture 2/613 (0.3%) 1/616 (0.2%) 1/1221 (0.1%)
    Femur fracture 3/613 (0.5%) 2/616 (0.3%) 5/1221 (0.4%)
    Forearm fracture 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Fracture 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Fractured coccyx 0/613 (0%) 2/616 (0.3%) 0/1221 (0%)
    Fractured ischium 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Hand fracture 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Head injury 1/613 (0.2%) 2/616 (0.3%) 2/1221 (0.2%)
    Hip fracture 5/613 (0.8%) 7/616 (1.1%) 5/1221 (0.4%)
    Humerus fracture 3/613 (0.5%) 3/616 (0.5%) 5/1221 (0.4%)
    Jaw fracture 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Joint dislocation 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Joint injury 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Limb injury 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Lower limb fracture 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Lumbar vertebral fracture 1/613 (0.2%) 1/616 (0.2%) 1/1221 (0.1%)
    Meniscus lesion 1/613 (0.2%) 2/616 (0.3%) 2/1221 (0.2%)
    Mouth injury 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Patella fracture 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Pelvic fracture 5/613 (0.8%) 5/616 (0.8%) 2/1221 (0.2%)
    Post-traumatic pain 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Procedural pain 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Pubic rami fracture 2/613 (0.3%) 1/616 (0.2%) 1/1221 (0.1%)
    Radius fracture 1/613 (0.2%) 0/616 (0%) 5/1221 (0.4%)
    Rib fracture 2/613 (0.3%) 1/616 (0.2%) 4/1221 (0.3%)
    Road traffic accident 0/613 (0%) 2/616 (0.3%) 0/1221 (0%)
    Scapula fracture 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Skin laceration 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Spinal compression fracture 1/613 (0.2%) 2/616 (0.3%) 0/1221 (0%)
    Spinal fracture 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Sternal fracture 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Subdural haematoma 5/613 (0.8%) 0/616 (0%) 2/1221 (0.2%)
    Subdural haemorrhage 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Therapeutic agent toxicity 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Thoracic vertebral fracture 1/613 (0.2%) 1/616 (0.2%) 1/1221 (0.1%)
    Tibia fracture 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Ulna fracture 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Upper limb fracture 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Wound 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Wound secretion 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Wrist fracture 1/613 (0.2%) 4/616 (0.6%) 4/1221 (0.3%)
    Investigations
    Barium enema 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Blood glucose decreased 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Blood osmolarity decreased 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Blood pressure increased 0/613 (0%) 0/616 (0%) 3/1221 (0.2%)
    International normalised ratio decreased 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Intraocular pressure increased 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Weight decreased 0/613 (0%) 1/616 (0.2%) 2/1221 (0.2%)
    Metabolism and nutrition disorders
    Cachexia 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Decreased appetite 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Dehydration 2/613 (0.3%) 2/616 (0.3%) 4/1221 (0.3%)
    Diabetes mellitus 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Failure to thrive 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Gout 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Hypercalcaemia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Hypercholesterolaemia 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Hyperglycaemia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Hyperkalaemia 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Hyponatraemia 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Lipomatosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Vitamin D deficiency 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/613 (0.2%) 3/616 (0.5%) 8/1221 (0.7%)
    Arthritis 1/613 (0.2%) 1/616 (0.2%) 3/1221 (0.2%)
    Arthrofibrosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Back pain 7/613 (1.1%) 4/616 (0.6%) 3/1221 (0.2%)
    Cervical spinal stenosis 1/613 (0.2%) 2/616 (0.3%) 0/1221 (0%)
    Flank pain 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Foot deformity 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Fracture delayed union 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Intervertebral disc degeneration 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Intervertebral disc protrusion 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Joint swelling 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Knee deformity 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Lumbar spinal stenosis 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Muscle haemorrhage 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Muscular weakness 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Musculoskeletal pain 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Myalgia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Myopathy 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Osteitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Osteoarthritis 6/613 (1%) 4/616 (0.6%) 13/1221 (1.1%)
    Osteonecrosis 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Pain in extremity 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Periarthritis 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Polymyalgia rheumatica 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Rotator cuff syndrome 0/613 (0%) 2/616 (0.3%) 1/1221 (0.1%)
    Spinal column stenosis 3/613 (0.5%) 0/616 (0%) 2/1221 (0.2%)
    Spinal osteoarthritis 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Spondylolisthesis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal neoplasm 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Anal cancer 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    B-cell lymphoma 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    B-cell lymphoma stage IV 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Basal cell carcinoma 4/613 (0.7%) 4/616 (0.6%) 1/1221 (0.1%)
    Benign gastric neoplasm 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Bowen's disease 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Brain cancer metastatic 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Brain neoplasm 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Breast cancer 7/613 (1.1%) 2/616 (0.3%) 6/1221 (0.5%)
    Carcinoma in situ 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Chronic lymphocytic leukaemia 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Chronic myeloid leukaemia 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Colon adenoma 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Colon cancer 3/613 (0.5%) 4/616 (0.6%) 3/1221 (0.2%)
    Colon neoplasm 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Gastric cancer 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Gastric neoplasm 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Gastrointestinal carcinoma 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Gastrointestinal neoplasm 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Gastrointestinal tract adenoma 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Haemangioma 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Hodgkin's disease 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Intestinal adenocarcinoma 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Lipoma 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Lung neoplasm malignant 3/613 (0.5%) 2/616 (0.3%) 1/1221 (0.1%)
    Lung squamous cell carcinoma stage unspecified 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Lymphoma 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Malignant melanoma 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Meningioma 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Metastases to bone 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Metastases to chest wall 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Metastases to liver 0/613 (0%) 2/616 (0.3%) 0/1221 (0%)
    Metastasis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Metastatic neoplasm 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Morton's neuroma 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Mucoepidermoid carcinoma 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Multiple myeloma 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Myelodysplastic syndrome 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Myeloproliferative disorder 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Nasal cavity cancer 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Neoplasm skin 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Ovarian cancer metastatic 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Pancreatic carcinoma 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Pancreatic neoplasm 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Rectal cancer stage I 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Rectal neoplasm 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Renal cancer 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Salivary gland neoplasm 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Seborrhoeic keratosis 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Skin cancer 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Spinal cord neoplasm 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Squamous cell carcinoma 3/613 (0.5%) 0/616 (0%) 2/1221 (0.2%)
    Squamous cell carcinoma of skin 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Urinary bladder adenoma 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Nervous system disorders
    Amnesia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Anoxic encephalopathy 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Aphasia 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Basal ganglia infarction 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Brain injury 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Brain stem haemorrhage 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Cerebral artery embolism 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Cerebral artery occlusion 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Cerebral haemorrhage 2/613 (0.3%) 0/616 (0%) 2/1221 (0.2%)
    Cerebral infarction 0/613 (0%) 2/616 (0.3%) 4/1221 (0.3%)
    Cerebral ischaemia 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Cerebrosclerosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Cerebrovascular accident 6/613 (1%) 3/616 (0.5%) 8/1221 (0.7%)
    Cerebrovascular disorder 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Convulsion 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Dementia 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Diabetic coma 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Dizziness 4/613 (0.7%) 0/616 (0%) 1/1221 (0.1%)
    Embolic stroke 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Encephalitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Encephalomyelitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Headache 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Hemiparesis 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Hemiplegia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Hydrocephalus 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Ischaemic stroke 0/613 (0%) 1/616 (0.2%) 2/1221 (0.2%)
    Lacunar infarction 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Loss of consciousness 2/613 (0.3%) 0/616 (0%) 1/1221 (0.1%)
    Memory impairment 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Monoparesis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Myelopathy 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Nerve compression 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Nerve root compression 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Neurodegenerative disorder 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Parkinson's disease 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Parkinsonism 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Post herpetic neuralgia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Presyncope 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Progressive bulbar palsy 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Sciatica 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Somnolence 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Spinal claudication 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Subarachnoid haemorrhage 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Syncope 1/613 (0.2%) 0/616 (0%) 5/1221 (0.4%)
    Temporal lobe epilepsy 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Thalamic infarction 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Transient ischaemic attack 7/613 (1.1%) 2/616 (0.3%) 3/1221 (0.2%)
    Trigeminal neuralgia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Vascular dementia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Vertebrobasilar insufficiency 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Psychiatric disorders
    Anxiety 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Anxiety disorder due to a general medical condition 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Confusional state 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Delirium 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Depression 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Insomnia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Major depression 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Mental disorder 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Suicide attempt 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Renal and urinary disorders
    Bladder prolapse 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Calculus urinary 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Glomerulonephritis chronic 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Haematuria 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Nephrolithiasis 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Proteinuria 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Renal cyst 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Renal failure 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Renal failure acute 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Urinary incontinence 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Reproductive system and breast disorders
    Bartholin's cyst 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Breast fibrosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Breast mass 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Cystocele 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Genital prolapse 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Ovarian cyst 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Pelvic prolapse 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Rectocele 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Urogenital prolapse 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Uterine polyp 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Uterine prolapse 0/613 (0%) 1/616 (0.2%) 2/1221 (0.2%)
    Uterovaginal prolapse 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Vaginal haemorrhage 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Vaginal prolapse 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema 0/613 (0%) 2/616 (0.3%) 1/1221 (0.1%)
    Acute respiratory failure 0/613 (0%) 2/616 (0.3%) 2/1221 (0.2%)
    Asthma 2/613 (0.3%) 0/616 (0%) 0/1221 (0%)
    Asthmatic crisis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Bronchospasm 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Chronic obstructive pulmonary disease 4/613 (0.7%) 5/616 (0.8%) 3/1221 (0.2%)
    Diaphragmatic hernia 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Dyspnoea 1/613 (0.2%) 0/616 (0%) 2/1221 (0.2%)
    Emphysema 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Epistaxis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Laryngeal oedema 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Lung disorder 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Mediastinal haemorrhage 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Nasal polyps 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Obstructive airways disorder 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Orthopnoea 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Pleural effusion 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Pneumonia aspiration 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Pneumonitis 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Pulmonary artery stenosis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Pulmonary embolism 1/613 (0.2%) 3/616 (0.5%) 5/1221 (0.4%)
    Pulmonary hypertension 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Pulmonary oedema 2/613 (0.3%) 0/616 (0%) 1/1221 (0.1%)
    Pulmonary thrombosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Respiratory arrest 1/613 (0.2%) 1/616 (0.2%) 0/1221 (0%)
    Respiratory failure 2/613 (0.3%) 2/616 (0.3%) 0/1221 (0%)
    Skin and subcutaneous tissue disorders
    Acrodermatitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Decubitus ulcer 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Dermatitis allergic 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Skin ulcer 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Social circumstances
    Immobile 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Social problem 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Vascular disorders
    Aortic dissection 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Aortic stenosis 2/613 (0.3%) 1/616 (0.2%) 0/1221 (0%)
    Arterial disorder 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Arterial stenosis limb 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Arteriosclerosis 1/613 (0.2%) 0/616 (0%) 3/1221 (0.2%)
    Deep vein thrombosis 3/613 (0.5%) 1/616 (0.2%) 2/1221 (0.2%)
    Embolism 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Femoral arterial stenosis 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Femoral artery occlusion 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Haematoma 0/613 (0%) 0/616 (0%) 2/1221 (0.2%)
    Hypertension 2/613 (0.3%) 1/616 (0.2%) 4/1221 (0.3%)
    Hypertensive crisis 2/613 (0.3%) 2/616 (0.3%) 3/1221 (0.2%)
    Hypotension 1/613 (0.2%) 0/616 (0%) 5/1221 (0.4%)
    Orthostatic hypotension 1/613 (0.2%) 0/616 (0%) 1/1221 (0.1%)
    Peripheral arterial occlusive disease 1/613 (0.2%) 0/616 (0%) 0/1221 (0%)
    Phlebitis 0/613 (0%) 1/616 (0.2%) 0/1221 (0%)
    Shock 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Thrombophlebitis 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Thrombosis 0/613 (0%) 1/616 (0.2%) 2/1221 (0.2%)
    Varicose vein 2/613 (0.3%) 1/616 (0.2%) 1/1221 (0.1%)
    Vasculitis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Vasoconstriction 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Venous insufficiency 0/613 (0%) 1/616 (0.2%) 1/1221 (0.1%)
    Venous thrombosis 0/613 (0%) 0/616 (0%) 1/1221 (0.1%)
    Other (Not Including Serious) Adverse Events
    Zoledronic Acid 6 Zoledronic Acid 3 Placebo 3 Placebo 3 Zoledronic Acid 3
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 421/613 (68.7%) 427/616 (69.3%) 908/1221 (74.4%)
    Eye disorders
    Cataract 35/613 (5.7%) 43/616 (7%) 72/1221 (5.9%)
    Gastrointestinal disorders
    Diarrhoea 31/613 (5.1%) 32/616 (5.2%) 57/1221 (4.7%)
    Nausea 20/613 (3.3%) 26/616 (4.2%) 94/1221 (7.7%)
    General disorders
    Fatigue 24/613 (3.9%) 20/616 (3.2%) 64/1221 (5.2%)
    Pyrexia 30/613 (4.9%) 19/616 (3.1%) 181/1221 (14.8%)
    Infections and infestations
    Bronchitis 48/613 (7.8%) 49/616 (8%) 80/1221 (6.6%)
    Influenza 32/613 (5.2%) 31/616 (5%) 63/1221 (5.2%)
    Nasopharyngitis 61/613 (10%) 61/616 (9.9%) 95/1221 (7.8%)
    Urinary tract infection 77/613 (12.6%) 94/616 (15.3%) 143/1221 (11.7%)
    Injury, poisoning and procedural complications
    Fall 50/613 (8.2%) 60/616 (9.7%) 110/1221 (9%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 119/613 (19.4%) 106/616 (17.2%) 253/1221 (20.7%)
    Back pain 113/613 (18.4%) 111/616 (18%) 206/1221 (16.9%)
    Bone pain 30/613 (4.9%) 16/616 (2.6%) 88/1221 (7.2%)
    Musculoskeletal pain 34/613 (5.5%) 31/616 (5%) 76/1221 (6.2%)
    Myalgia 28/613 (4.6%) 25/616 (4.1%) 147/1221 (12%)
    Osteoarthritis 55/613 (9%) 49/616 (8%) 87/1221 (7.1%)
    Pain in extremity 51/613 (8.3%) 54/616 (8.8%) 121/1221 (9.9%)
    Nervous system disorders
    Dizziness 26/613 (4.2%) 31/616 (5%) 69/1221 (5.7%)
    Headache 37/613 (6%) 40/616 (6.5%) 125/1221 (10.2%)
    Vascular disorders
    Hypertension 46/613 (7.5%) 92/616 (14.9%) 136/1221 (11.1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    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

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862-778-8300
    Email
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00145327
    Other Study ID Numbers:
    • CZOL446H2301E1
    First Posted:
    Sep 5, 2005
    Last Update Posted:
    Jun 28, 2011
    Last Verified:
    Jun 1, 2011