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    Clinical Trial Results:
    An Open Label, Single Arm, Extension Study to Evaluate the Long Term Safety and Sustained Efficacy of Denosumab (AMG162) in the Treatment of Postmenopausal Osteoporosis

    Summary
    EudraCT number
    2007-001041-17
    Trial protocol
    DK   SE   EE   DE   LV   GB   LT   HU   AT   FI   BE   MT   CZ   FR   ES   GR   IT   BG   SK  
    Global end of trial date
    29 Jul 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    01 Apr 2017
    First version publication date
    04 Aug 2016
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    add histomorphology endpoint data

    Trial information

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    Trial identification
    Sponsor protocol code
    20060289
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00523341
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen, inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to describe the safety and tolerability of up to 10 years or 7 years denosumab administration as measured by adverse event monitoring, immunogenicity and safety laboratory parameters in participants who previously received denosumab or placebo, respectively.
    Protection of trial subjects
    This study was conducted in accordance with the principles of the Food and Drug Administration (FDA) and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Aug 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 496
    Country: Number of subjects enrolled
    Denmark: 898
    Country: Number of subjects enrolled
    Czech Republic: 381
    Country: Number of subjects enrolled
    United Kingdom: 327
    Country: Number of subjects enrolled
    Estonia: 296
    Country: Number of subjects enrolled
    Brazil: 287
    Country: Number of subjects enrolled
    Argentina: 211
    Country: Number of subjects enrolled
    United States: 178
    Country: Number of subjects enrolled
    Spain: 165
    Country: Number of subjects enrolled
    Hungary: 132
    Country: Number of subjects enrolled
    Italy: 132
    Country: Number of subjects enrolled
    Germany: 116
    Country: Number of subjects enrolled
    Norway: 98
    Country: Number of subjects enrolled
    Austria: 86
    Country: Number of subjects enrolled
    Belgium: 84
    Country: Number of subjects enrolled
    France: 83
    Country: Number of subjects enrolled
    Sweden: 78
    Country: Number of subjects enrolled
    Latvia: 75
    Country: Number of subjects enrolled
    Mexico: 72
    Country: Number of subjects enrolled
    Canada: 66
    Country: Number of subjects enrolled
    Slovakia: 52
    Country: Number of subjects enrolled
    Lithuania: 45
    Country: Number of subjects enrolled
    Switzerland: 40
    Country: Number of subjects enrolled
    New Zealand: 33
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    Bulgaria: 25
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Malta: 15
    Country: Number of subjects enrolled
    Serbia: 15
    Country: Number of subjects enrolled
    Romania: 5
    Worldwide total number of subjects
    4550
    EEA total number of subjects
    3623
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    107
    From 65 to 84 years
    4304
    85 years and over
    139

    Subject disposition

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    Recruitment
    Recruitment details
    This was an extension study open to participants who had completed core study 20030216 (NCT00089791). The study was conducted at 178 centers in North America, South America, Europe, Australia, and New Zealand. Participants were enrolled from 7 August 2007 to 20 June 2008.

    Pre-assignment
    Screening details
    All participants received open-label denosumab during this study. Results are reported by the Study 20030216 randomized treatment groups (placebo versus denosumab).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo / Denosumab
    Arm description
    Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
    Arm type
    Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Prolia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 6 months.

    Arm title
    Denosumab / Denosumab
    Arm description
    Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
    Arm type
    Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Prolia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 6 months.

    Number of subjects in period 1
    Placebo / Denosumab Denosumab / Denosumab
    Started
    2207
    2343
    Received Treatment
    2206
    2343
    Completed
    1283
    1343
    Not completed
    924
    1000
         Ineligibility Determined
    3
    4
         Protocol Deviation
    6
    5
         Death
    101
    110
         Disease Progression
    1
    -
         Physician decision
    14
    13
         Other
    181
    198
         Non-compliance
    20
    13
         Adverse event, non-fatal
    122
    155
         Requirement for Alternative Therapy
    4
    14
         Consent withdrawn by subject
    399
    427
         Lost to follow-up
    73
    61

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo / Denosumab
    Reporting group description
    Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.

    Reporting group title
    Denosumab / Denosumab
    Reporting group description
    Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).

    Reporting group values
    Placebo / Denosumab Denosumab / Denosumab Total
    Number of subjects
    2207 2343 4550
    Age, Customized
    Units: participants
        60 - 64 years
    58 49 107
        65 - 69 years
    326 320 646
        70 - 74 years
    672 716 1388
        ≥ 75 years
    1151 1258 2409
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    74.8 ± 5.1 74.9 ± 5 -
    Gender, Male/Female
    Units: participants
        Female
    2207 2343 4550
        Male
    0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    2063 2169 4232
        Black
    16 19 35
        Hispanic or Latino
    121 145 266
        Asian
    2 3 5
        Japanese
    3 5 8
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Other
    1 2 3
    Bone Mineral Density T-score | Lumbar spine
    The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old. Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.
    Units: T-score
        arithmetic mean (standard deviation)
    -2.81 ± 0.75 -2.14 ± 0.8 -
    Bone Mineral Density T-score | Total hip
    The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old. Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.
    Units: T-score
        arithmetic mean (standard deviation)
    -1.93 ± 0.8 -1.5 ± 0.79 -
    Bone Mineral Density T-score | Femoral neck
    The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old. Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.
    Units: T-score
        arithmetic mean (standard deviation)
    -2.17 ± 0.72 -1.83 ± 0.75 -
    Bone Mineral Density T-score at Study 20030216 Baseline | Lumbar spine
    Units: T-score
        arithmetic mean (standard deviation)
    -2.84 ± 0.68 -2.83 ± 0.67 -
    Bone Mineral Density T-score at Study 20030216 Baseline | Total hip
    Units: T-score
        arithmetic mean (standard deviation)
    -1.85 ± 0.79 -1.85 ± 0.79 -
    Bone Mineral Density T-score at Study 20030216 Baseline | Femoral neck
    Units: T-score
        arithmetic mean (standard deviation)
    -2.11 ± 0.71 -2.11 ± 0.71 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo / Denosumab
    Reporting group description
    Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.

    Reporting group title
    Denosumab / Denosumab
    Reporting group description
    Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).

    Primary: Number of participants with Adverse Events (AEs)

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    End point title
    Number of participants with Adverse Events (AEs) [1]
    End point description
    A serious adverse event (SAE) is defined as an AE that: • is fatal • is life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is other significant medical hazard. Treatment-related adverse events includes only events for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. The following were classified as adverse events of interest (events that are considered to be identified or potential risks of denosumab treatment): positively adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral fracture, hypocalcemia, adverse events potentially related to hypersensitivity, serious infection (including bacterial cellulitis), malignancy, cardiac disorders, vascular disorders, fracture healing complications, eczema, acute pancreatitis, and musculoskeletal pain.
    End point type
    Primary
    End point timeframe
    84 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical testing was performed.
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2206
    2343
    Units: participants
    number (not applicable)
        Any adverse event (AE)
    2070
    2173
        Serious adverse event
    945
    1014
        Fatal adverse event
    101
    108
        AE leading to study discontinuation
    145
    173
        AE leading to discontinuation of denosumab
    184
    216
        Treatment-related adverse events (TRAE)
    185
    188
        Serious treatment-related adverse events
    26
    28
        Fatal treatment-related adverse events
    1
    0
        TRAE leading to study discontinuation
    16
    9
        TRAE leading to discontinuation of denosumab
    30
    25
        Positively adjudicated osteonecrosis of the jaw
    6
    7
        Positively adjudicated atypical femoral fracture
    1
    1
        Hypocalcaemia
    10
    6
        AEs potentially related to hypersensitivity
    260
    280
        Serious infections
    161
    185
        Serious bacterial cellulitis
    7
    12
        Malignancy
    227
    237
        Cardiac disorders
    449
    492
        Vascular disorders
    693
    732
        Fracture healing complications
    0
    1
        Eczema
    99
    115
        Acute pancreatitis
    4
    8
        Musculoskeletal pain
    1125
    1206
    No statistical analyses for this end point

    Primary: Number of Participants with Laboratory Toxicities of Grade ≥ 3

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    End point title
    Number of Participants with Laboratory Toxicities of Grade ≥ 3 [2]
    End point description
    Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity.
    End point type
    Primary
    End point timeframe
    84 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical testing was performed.
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2206
    2343
    Units: participants
    number (not applicable)
        Low sodium - Grade 3
    28
    25
        Low sodium - Grade 4
    1
    0
        High potassium - Grade 3
    9
    11
        High potassium - Grade 4
    0
    3
        Low potassium - Grade 3
    7
    7
        Low magnesium - Grade 3
    1
    1
        Low magnesium - Grade 4
    0
    1
        High calcium - Grade 3
    2
    3
        High calcium - Grade 4
    0
    2
        High corrected calcium - Grade 3
    2
    3
        High corrected calcium - Grade 4
    0
    2
        Low phosphorus - Grade 3
    3
    1
        High Creatinine - Grade 3
    0
    1
        High aspartate amino transferase (AST) - Grade 3
    5
    11
        High aspartate amino transferase (AST) - Grade 4
    1
    0
        High alanine amino transferase (ALT) - Grade 3
    8
    10
        High alanine amino transferase (ALT) - Grade 4
    1
    0
        High total bilirubin - Grade 3
    2
    3
        Low albumin - Grade 3
    0
    1
        High glucose - Grade 3
    35
    37
        High glucose - Grade 4
    0
    1
        Low glucose - Grade 3
    4
    1
        Low glucose - Grade 4
    1
    1
        Low hemoglobin - Grade 3
    6
    4
        Low platelets - Grade 3
    3
    7
        Low platelets - Grade 4
    2
    4
        Low white blood cells - Grade 3
    5
    7
        Low white blood cells - Grade 4
    0
    1
        Low lymphocytes - Grade 3
    17
    16
        Low lymphocytes - Grade 4
    2
    1
    No statistical analyses for this end point

    Primary: Number of Participants with Antibodies to Denosumab

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    End point title
    Number of Participants with Antibodies to Denosumab [3]
    End point description
    End point type
    Primary
    End point timeframe
    Every 12 months through Month 84
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical testing was performed.
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2206
    2343
    Units: participants
        number (not applicable)
    1
    0
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit

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    End point title
    Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit
    End point description
    Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2040, 2168)
    5.2 (5 to 5.3)
    2 (1.8 to 2.2)
        Month 24 (n = 1935, 2061)
    7.7 (7.5 to 7.9)
    3.5 (3.4 to 3.7)
        Month 36 (n = 1497, 1607)
    9.4 (9.1 to 9.6)
    4.9 (4.7 to 5.1)
        Month 60 (n = 1472, 1567)
    13 (12.7 to 13.3)
    7.9 (7.6 to 8.2)
        Month 84 (n = 1223, 1264)
    16.5 (16.1 to 16.9)
    10.8 (10.4 to 11.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total Hip Bone Mineral Density by Visit

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    End point title
    Percent Change From Baseline in Total Hip Bone Mineral Density by Visit
    End point description
    Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2029, 2160)
    3 (2.8 to 3.1)
    0.8 (0.7 to 0.9)
        Month 24 (n = 1918, 2045)
    4.1 (4 to 4.2)
    1.4 (1.3 to 1.5)
        Month 36 (n = 1475, 1591)
    4.9 (4.7 to 5)
    1.8 (1.7 to 2)
        Month 60 (n = 1439, 1538)
    6.2 (6 to 6.4)
    2.6 (2.4 to 2.8)
        Month 84 (n = 1200, 1232)
    7.4 (7.1 to 7.6)
    3.4 (3.2 to 3.7)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit

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    End point title
    Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit
    End point description
    Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2029, 2160)
    2.1 (1.9 to 2.3)
    0.8 (0.7 to 1)
        Month 24 (n = 1918, 2045)
    3.2 (3.1 to 3.4)
    1.2 (1 to 1.4)
        Month 36 (n = 1475, 1591)
    4 (3.8 to 4.3)
    1.7 (1.5 to 1.9)
        Month 60 (n = 1439, 1538)
    5.7 (5.4 to 5.9)
    2.8 (2.6 to 3.1)
        Month 84 (n = 1200, 1232)
    7.1 (6.8 to 7.4)
    3.8 (3.5 to 4.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit

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    End point title
    Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit
    End point description
    1/3 radius bone mineral density was measured in a subset of participants by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants in the DXA substudy with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    449
    467
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 114, 134)
    0.3 (-0.2 to 0.9)
    0.6 (0.1 to 1.2)
        Month 24 (n = 108, 127)
    0.2 (-0.4 to 0.9)
    0.2 (-0.4 to 0.8)
        Month 36 (n = 73, 93)
    1.3 (0.5 to 2)
    0.6 (-0.1 to 1.3)
        Month 60 (n = 59, 84)
    1.8 (0.9 to 2.7)
    1.4 (0.6 to 2.2)
        Month 84 (n = 39, 56)
    2.2 (0.9 to 3.6)
    1 (-0.1 to 2.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit

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    End point title
    Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit
    End point description
    Lumbar spine bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2030, 2148)
    5.9 (5.6 to 6.1)
    11.9 (11.7 to 12.2)
        Month 24 (n = 1924, 2041)
    8.4 (8.1 to 8.7)
    13.7 (13.4 to 13.9)
        Month 36 (n = 1487, 1589)
    10.1 (9.8 to 10.4)
    15.2 (14.9 to 15.5)
        Month 60 (n = 1464, 1551)
    13.8 (13.4 to 14.1)
    18.4 (18.1 to 18.8)
        Month 84 (n = 1216, 1251)
    17.3 (16.8 to 17.8)
    21.7 (21.2 to 22.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit

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    End point title
    Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit
    End point description
    Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. M Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2006, 2132)
    1.7 (1.6 to 1.9)
    6.4 (6.3 to 6.6)
        Month 24 (n = 1895, 2017)
    2.9 (2.7 to 3)
    7.1 (6.9 to 7.2)
        Month 36 (n = 1457, 1567)
    3.6 (3.4 to 3.8)
    7.5 (7.3 to 7.7)
        Month 60 (n = 1424, 1518)
    4.9 (4.7 to 5.2)
    8.4 (8.1 to 8.6)
        Month 84 (n = 1189, 1215)
    6.1 (5.8 to 6.4)
    9.2 (8.9 to 9.5)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit

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    End point title
    Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit
    End point description
    Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2006, 2132)
    1.4 (1.2 to 1.7)
    5.8 (5.6 to 6)
        Month 24 (n = 1895, 2017)
    2.6 (2.3 to 2.8)
    6.2 (6 to 6.5)
        Month 36 (n = 1457, 1567)
    3.4 (3.1 to 3.6)
    6.7 (6.5 to 7)
        Month 60 (n = 1424, 1518)
    5 (4.7 to 5.3)
    7.9 (7.6 to 8.2)
        Month 84 (n = 1189, 1215)
    6.4 (6 to 6.8)
    9 (8.6 to 9.4)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit

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    End point title
    Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit
    End point description
    1/3 radius BMD was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants in the DXA substudy with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    449
    467
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 113, 133)
    -1 (-1.7 to -0.3)
    2.6 (1.9 to 3.2)
        Month 24 (n = 107, 127)
    -1.2 (-1.9 to -0.4)
    2.1 (1.4 to 2.8)
        Month 36 (n = 73, 92)
    -0.2 (-1.1 to 0.7)
    2.4 (1.6 to 3.2)
        Month 60 (n = 59, 83)
    0.3 (-0.7 to 1.3)
    3.3 (2.4 to 4.2)
        Month 84 (n = 39, 56)
    0.6 (-0.8 to 2.1)
    2.8 (1.6 to 4.1)
    No statistical analyses for this end point

    Secondary: Number of Participants With New Vertebral Fractures

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    End point title
    Number of Participants With New Vertebral Fractures
    End point description
    A new vertebral fracture, assessed by lateral spine X-ray using Genant semiquantitative scoring method, was identified as an ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4, excluding any fracture associated with high trauma severity or a pathologic fracture. Analysis includes all participants enrolled in the extension study who have vertebral X-ray assessment at the extension baseline and at least 1 post-extension baseline visit.
    End point type
    Secondary
    End point timeframe
    84 months
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    1991
    2116
    Units: participants
        number (not applicable)
    145
    149
    No statistical analyses for this end point

    Secondary: Number of Participants With Non-Vertebral Fractures

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    End point title
    Number of Participants With Non-Vertebral Fractures
    End point description
    Non-vertebral fractures (osteoporotic) were defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging (MRI) confirming the fracture, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. Analysis includes all enrolled participants.
    End point type
    Secondary
    End point timeframe
    84 months
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2207
    2343
    Units: participants
        number (not applicable)
    219
    172
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit

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    End point title
    Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit
    End point description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    318
    342
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Day 10 (n = 26, 47)
    -90 (-93 to -85)
    -72 (-86 to -47)
        Month 6 (n = 30, 56)
    -85 (-91 to -73)
    -26 (-63 to 1)
        Month 12 (n = 27, 56)
    -75 (-90 to -54)
    -13 (-37 to 24)
        Month 24 (n = 27, 47)
    -67 (-84 to -29)
    10 (-27 to 55)
        Month 36 (n = 68, 81)
    -59 (-84 to -28)
    2 (-32 to 68)
        Month 48 (n = 62, 75)
    -58 (-84 to -12)
    0 (-46 to 56)
        Month 60 (n = 59, 70)
    -65 (-90 to -19)
    0 (-47 to 83)
        Month 72 (n = 56, 62)
    -60 (-85 to -16)
    -1 (-47 to 76)
        Month 84 (n = 41, 41)
    -64 (-86 to -28)
    -6 (-26 to 68)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit

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    End point title
    Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit
    End point description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    318
    342
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Day 10 (n = 30, 51)
    6 (-5 to 30)
    14 (-1 to 25)
        Month 6 (n = 30, 53)
    -71 (-78 to -62)
    -23 (-50 to -2)
        Month 12 (n = 26, 56)
    -67 (-76 to -57)
    7 (-15 to 30)
        Month 24 (n = 27, 47)
    -63 (-77 to -41)
    11 (-17 to 42)
        Month 36 (n = 69, 83)
    -57 (-67 to -29)
    29 (-6 to 91)
        Month 48 (n = 61, 73)
    -60 (-70 to -41)
    8 (-21 to 49)
        Month 60 (n = 61, 71)
    -54 (-72 to -35)
    30 (-6 to 67)
        Month 72 (n = 55, 64)
    -50 (-60 to -36)
    44 (3 to 103)
        Month 84 (n = 48, 50)
    -59 (-73 to -40)
    32 (-4 to 75)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in CTX-1 by Visit

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    End point title
    Percent Change From Study 20030216 Baseline in CTX-1 by Visit
    End point description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    End point type
    Secondary
    End point timeframe
    Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    318
    342
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Day 10 (n = 26, 56)
    -90 (-91 to -78)
    -91 (-93 to -86)
        Month 6 (n = 32, 72)
    -83 (-90 to -72)
    -77 (-87 to -49)
        Month 12 (n = 27, 65)
    -77 (-91 to -45)
    -63 (-87 to -11)
        Month 24 (n = 28, 60)
    -65 (-80 to -24)
    -53 (-82 to 0)
        Month 36 (n = 289, 313)
    -71 (-88 to -40)
    -52 (-86 to -4)
        Month 48 (n = 274, 290)
    -70 (-88 to -36)
    -61 (-85 to -24)
        Month 60 (n = 268, 276)
    -67 (-88 to -25)
    -53 (-86 to -18)
        Month 72 (n = 243, 248)
    -69 (-88 to -32)
    -59 (-86 to -21)
        Month 84 (n = 217, 216)
    -63 (-88 to -19)
    -53 (-84 to -12)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in P1NP by Visit

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    End point title
    Percent Change From Study 20030216 Baseline in P1NP by Visit
    End point description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    End point type
    Secondary
    End point timeframe
    Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    318
    342
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Day 10 (n = 30, 51)
    9 (-14 to 34)
    -59 (-74 to -22)
        Month 6 (n = 32, 57)
    -74 (-80 to -67)
    -75 (-80 to -55)
        Month 12 (n = 26, 56)
    -74 (-79 to -51)
    -63 (-76 to -36)
        Month 24 (n = 28, 51)
    -67 (-75 to -51)
    -56 (-72 to -30)
        Month 36 (n = 70, 83)
    -59 (-75 to -37)
    -60 (-71 to -40)
        Month 48 (n = 61, 73)
    -67 (-75 to -46)
    -63 (-77 to -42)
        Month 60 (n = 61, 71)
    -62 (-75 to -42)
    -55 (-74 to -30)
        Month 72 (n = 56, 67)
    -62 (-71 to -35)
    -55 (-70 to -27)
        Month 84 (n =49, 53)
    -68 (-78 to -56)
    -57 (-74 to -38)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10

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    End point title
    Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
    End point description
    Analysis includes participants who had a calcium corrected by albumin measurement within the Day 10 visit window up to May 31, 2008.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and day 10
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2027
    2154
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -3.1 (-6.1 to 0)
    -2 (-5.1 to 1.1)
    No statistical analyses for this end point

    Secondary: Serum Denosumab Concentration

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    End point title
    Serum Denosumab Concentration
    End point description
    Serum concentrations of denosumab were measured by a validated conventional sandwich enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 0.8 ng/mL. Values of 0 in the table below indicate data below the lower limit of quantification. Analysis includes participants who participated in the Study 20030216 PK substudy, for whom dosing information was not missing and for whom sampling was within 14 days of specified sampling times.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    97
    113
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n = 97, 113)
    0 ± 0
    113 ± 107
        Day 10 (n = 92, 106)
    5890 ± 2010
    6010 ± 2530
        Month 3 (n = 81, 92)
    1000 ± 560
    1190 ± 690
        Month 4 (n = 87, 104)
    429 ± 378
    554 ± 480
        Month 6 (n = 87, 103)
    20.8 ± 61.7
    66 ± 147.2
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Cancellous Bone Volume

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    End point title
    Bone Histomorphometry: Cancellous Bone Volume
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by quantitative histomorphometry. The analysis incudes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cancellous bone volume data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of total bone tissue volume
    arithmetic mean (standard deviation)
        Month 24 (n=13, 25)
    15.253 ± 6.065
    14.64 ± 6.979
        Month 84 (n=0, 19)
    99999 ± 99999
    16.358 ± 4.438
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Trabecular Number

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    End point title
    Bone Histomorphometry: Trabecular Number
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular number is the number of trabeculae present per lineal mm and is calculated as trabecular bone volume/trabecular thickness. Trabecular number is a measure of trabecular connectivity and decreases with bone loss. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    1.005 ± 0.242
    0.904 ± 0.243
        Month 84 (n = 0, 19)
    99999 ± 99999
    1.235 ± 0.254
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Trabecular Separation

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    End point title
    Bone Histomorphometry: Trabecular Separation
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular separation is the mean distance between trabeculae (measured by integrated computer graphics). Trabecular separation increases with trabecular bone loss. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular separation data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    919.693 ± 358.238
    1033.416 ± 352.259
        Month 84 (n = 0, 19)
    99999 ± 99999
    708.669 ± 171.782
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Trabecular Thickness

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    End point title
    Bone Histomorphometry: Trabecular Thickness
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Mean trabecular thickness is a measure of trabecular structure and is calculated as the reciprocal of total bone (trabecular) surfaces. Trabecular thickness is reduced by aging and osteoporosis. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular thickness data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    153.878 ± 51.859
    156.335 ± 48.567
        Month 84 (n = 0, 19)
    99999 ± 99999
    132.965 ± 28.064
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Cortical Width

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    End point title
    Bone Histomorphometry: Cortical Width
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cortical width is the average width of both inner and outer cortices. Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cortical width data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    45
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 28)
    622.22 ± 246.7
    707.69 ± 237.97
        Month 84 (n = 0, 21)
    99999 ± 99999
    786.19 ± 279.81
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry

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    End point title
    Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by tartrate-resistant acid phosphatase (TRAP) staining histomorphometry. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cancellous bone volume data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of total bone tissue volume
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    16.678 ± 7.27
    15.606 ± 6.986
        Month 84 (n = 0, 19)
    99999 ± 99999
    17.631 ± 4.387
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Surface Density

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    End point title
    Bone Histomorphometry: Surface Density
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Surface density is calculated by total bone (trabecular) surfaces / total tissue volume. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available surface density data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: mm² /mm³
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    2.009 ± 0.486
    1.807 ± 0.486
        Month 84 (n = 0, 19)
    99999 ± 99999
    2.472 ± 0.506
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoblast - Osteoid Interface

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    End point title
    Bone Histomorphometry: Osteoblast - Osteoid Interface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface * 100. Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoblast - osteoid interface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of osteoid surface
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    22.124 ± 34.879
    17.813 ± 28.381
        Month 84 (n = 0, 19)
    99999 ± 99999
    5.951 ± 15.223
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoid Surface

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    End point title
    Bone Histomorphometry: Osteoid Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid surface is the percent of bone surface covered in osteoid. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of total bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.915 ± 1.382
    0.982 ± 2.489
        Month 84 (n = 0, 19)
    99999 ± 99999
    0.421 ± 1.068
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoid Thickness

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    End point title
    Bone Histomorphometry: Osteoid Thickness
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid thickness (width) is the mean thickness of osteoid seams on cancellous surfaces. Osteoid thickness is normally <12.5 µm. Increased osteoid thickness suggests abnormal mineralization (osteomalacia). The analysis included participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid thickness data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    5.139 ± 3.261
    4.548 ± 4.973
        Month 84 (n = 0, 19)
    99999 ± 99999
    4.108 ± 3.476
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Wall Thickness

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    End point title
    Bone Histomorphometry: Wall Thickness
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Wall thickness is the average thickness of trabecular bone structural units (BSU) and is used to assess the overall balance between resorption and formation. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available wall thickness data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    43.11 ± 6.08
    49.74 ± 10.51
        Month 84 (n = 0, 19)
    99999 ± 99999
    39.59 ± 7.49
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Eroded Surface/Bone Surface

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    End point title
    Bone Histomorphometry: Eroded Surface/Bone Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Eroded surface/bone surface is the percentage of bone surface occupied by eroded (resorption) cavities (Howships lacunae), with or without osteoclasts. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available eroded surface/bone surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.414 ± 0.701
    0.328 ± 0.613
        Month 84 (n = 0, 19)
    99999 ± 99999
    0.511 ± 0.579
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoclast Number - Length Based

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    End point title
    Bone Histomorphometry: Osteoclast Number - Length Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per mm of bone. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.086 ± 0.119
    0.107 ± 0.198
        Month 84 (n = 0, 19)
    99999 ± 99999
    0.074 ± 0.101
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoclast Number - Surface Based

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    End point title
    Bone Histomorphometry: Osteoclast Number - Surface Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per 100 mm of bone surface. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/100 mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    8.6 ± 11.9
    10.7 ± 19.8
        Month 84 (n = 0, 19)
    99999 ± 99999
    7.4 ± 10.1
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoclast Number by TRAP - Length Based

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    End point title
    Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per mm of bone. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.096 ± 0.134
    0.11 ± 0.185
        Month 84 (n = 0, 19)
    99999 ± 99999
    0.077 ± 0.107
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based

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    End point title
    Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per 100 mm of bone surface. The analysis included participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/100 mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    9.6 ± 13.4
    11 ± 18.5
        Month 84 (n = 0, 19)
    99999 ± 99999
    7.7 ± 10.7
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Single-label Surface

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    End point title
    Bone Histomorphometry: Single-label Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. A single label is deposited if formation either started or ended during the interval between the uses of the two courses of tetracycline administration. Single-label surface is expressed as a percentage of total bone surface. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available single-label surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: percentage of bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.304 ± 0.302
    0.643 ± 0.661
        Month 84 (n = 0, 10)
    99999 ± 99999
    0.611 ± 0.726
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Double-label Surface

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    End point title
    Bone Histomorphometry: Double-label Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The presence of double labels indicates that normal bone mineralization was actively occurring over the entire labeling interval. Double-label surface is expressed as a percentage of total bone surface. The analysis includes Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available double-label surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: percentage of bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.258 ± 0.207
    0.356 ± 0.295
        Month 84 (n = 0, 10)
    99999 ± 99999
    0.106 ± 0.237
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Mineralizing Surface

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    End point title
    Bone Histomorphometry: Mineralizing Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Total mineralizing surfaces (MS) include all double and half of single-labeled surfaces. MS is expressed as a percentage of total bone surface. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineralizing surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: percentage of bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.406 ± 0.323
    0.681 ± 0.453
        Month 84 (n = 0, 10)
    99999 ± 99999
    0.412 ± 0.458
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Mineral Apposition Rate

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    End point title
    Bone Histomorphometry: Mineral Apposition Rate
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the avarage rate at which new bone mineral is being added on any actively forming surface. MAR is calculated as the average distance between visible labels, divided by the labeling interval. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineral apposition rate data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: μm/day
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.616 ± 0.219
    0.722 ± 0.573
        Month 84 (n = 0, 10)
    99999 ± 99999
    0.394 ± 0.233
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Adjusted Apposition Rate

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    End point title
    Bone Histomorphometry: Adjusted Apposition Rate
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. MAR is the average rate at which new bone mineral is being added on any actively forming surface. Adjusted MAR is calculated as: (average distance between visible labels / labeling interval) * (total mineralizing surface/total bone surface). Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or 84 and with available adjusted apposition rate data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    19
    Units: μm/day
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 9)
    0.394 ± 0.471
    0.517 ± 0.537
        Month 84 (n = 0, 10)
    99999 ± 99999
    0.818 ± 1.207
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Bone Formation Rate - Surface Based

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    End point title
    Bone Histomorphometry: Bone Formation Rate - Surface Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - surface based is the calculated rate at which cancellous bone surface is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone surface). The analysis included participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available bone formation rate data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: μm³/μm²/year
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.898 ± 0.706
    2.153 ± 2.468
        Month 84 (n = 0, 10)
    99999 ± 99999
    0.691 ± 0.868
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Bone Formation Rate - Volume Based

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    End point title
    Bone Histomorphometry: Bone Formation Rate - Volume Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - volume based is the calculated rate at which cancellous bone volume is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone volume). The analyses includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available bone formation rate data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: percent of bone volume per year
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    1.454 ± 1.265
    3.162 ± 3.773
        Month 84 (n = 0, 10)
    99999 ± 99999
    1.071 ± 1.308
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Activation Frequency

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    End point title
    Bone Histomorphometry: Activation Frequency
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The average time that it takes for a new remodeling cycle to begin on any point on a cancellous surface is called the activation frequency. Activation frequency is calculated as the bone formation rate / wall width. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available activation frequency data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: /year
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.022 ± 0.019
    0.045 ± 0.049
        Month 84 (n = 0, 10)
    99999 ± 99999
    0.014 ± 0.024
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Formation Period

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    End point title
    Bone Histomorphometry: Formation Period
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Formation period (FP) is the mean time required to rebuild a new bone structural unit or osteon from the cement line back to the bone surface at a single location, and is given by wall width / adjusted apposition rate. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available formation period data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: days
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    593.5 ± 996.8
    287.3 ± 391.5
        Month 84 (n = 0, 10)
    99999 ± 99999
    229.7 ± 512
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoid Volume

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    End point title
    Bone Histomorphometry: Osteoid Volume
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid volume is the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid). The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid volume data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of total bone tissue
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.108 ± 0.193
    0.146 ± 0.382
        Month 84 (n = 0, 19)
    99999 ± 99999
    0.048 ± 0.133
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Mineralization Lag Time

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    End point title
    Bone Histomorphometry: Mineralization Lag Time
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Mineralization lag time is the average time interval between osteoid formation and its subsequent mineralization and is calculated by dividing the osteoid width by the apposition rate. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineralization lag time data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: days
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    84.9 ± 136.8
    54.3 ± 76.1
        Month 84 (n = 0, 10)
    99999 ± 99999
    52.3 ± 114.5
    No statistical analyses for this end point

    Secondary: Bone Histology at Month 24

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    End point title
    Bone Histology at Month 24
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone. Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, and had at least 1 evaluable bone biopsy at extension month 24.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    28
    Units: biopsies
        Normal lamellar bone
    13
    28
        Normal mineralization
    13
    28
        Osteoid
    13
    23
        Osteomalacia
    0
    0
        Marrow fibrosis
    0
    0
        Woven bone
    0
    0
    No statistical analyses for this end point

    Secondary: Bone Histology at Month 84

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    End point title
    Bone Histology at Month 84
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone. Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, and had at least 1 evaluable bone biopsy at extension month 84.
    End point type
    Secondary
    End point timeframe
    Month 84
    End point values
    Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    0 [4]
    22
    Units: biopsies
        Normal lamellar bone
    22
        Normal mineralization
    22
        Osteoid
    18
        Osteomalacia
    0
        Marrow fibrosis
    0
        Woven bone
    0
    Notes
    [4] - No participants had biopsies collected at month 84
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    84 Months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo/Denosumab 60 mg Q6M
    Reporting group description
    Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.

    Reporting group title
    Denosumab/Denosumab 60 mg Q6M
    Reporting group description
    Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).

    Serious adverse events
    Placebo/Denosumab 60 mg Q6M Denosumab/Denosumab 60 mg Q6M
    Total subjects affected by serious adverse events
         subjects affected / exposed
    945 / 2206 (42.84%)
    1014 / 2343 (43.28%)
         number of deaths (all causes)
    101
    108
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone fissure
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cartilage injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract traumatic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    7 / 2206 (0.32%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery restenosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 2206 (0.00%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye penetration
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    16 / 2206 (0.73%)
    15 / 2343 (0.64%)
         occurrences causally related to treatment / all
    1 / 16
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    13 / 2206 (0.59%)
    16 / 2343 (0.68%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    14 / 2206 (0.63%)
    11 / 2343 (0.47%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    16 / 2206 (0.73%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    4 / 2206 (0.18%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    13 / 2206 (0.59%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury corneal
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    7 / 2206 (0.32%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    5 / 2206 (0.23%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    4 / 2206 (0.18%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    5 / 2206 (0.23%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative hernia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    3 / 2206 (0.14%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation mucositis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    7 / 2206 (0.32%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Radius fracture
         subjects affected / exposed
    25 / 2206 (1.13%)
    22 / 2343 (0.94%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scar
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    5 / 2206 (0.23%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skeletal injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin abrasion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    8 / 2206 (0.36%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    17 / 2206 (0.77%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant dysfunction
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ulna fracture
         subjects affected / exposed
    9 / 2206 (0.41%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulnar nerve injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antinuclear antibody positive
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoembryonic antigen increased
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure orthostatic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occult blood positive
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigation
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein total decreased
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    8 / 2206 (0.36%)
    18 / 2343 (0.77%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 19
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Acute coronary syndrome
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    7 / 2206 (0.32%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    17 / 2206 (0.77%)
    19 / 2343 (0.81%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adams-Stokes syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    4 / 2206 (0.18%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    3 / 2206 (0.14%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    50 / 2206 (2.27%)
    40 / 2343 (1.71%)
         occurrences causally related to treatment / all
    4 / 69
    0 / 47
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 2206 (0.00%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    5 / 2206 (0.23%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 2206 (0.18%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Bundle branch block left
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    15 / 2206 (0.68%)
    21 / 2343 (0.90%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 24
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    Cardiac failure acute
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    10 / 2206 (0.45%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 9
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Cardiac fibrillation
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve sclerosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiomyopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Chronic right ventricular failure
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    9 / 2206 (0.41%)
    17 / 2343 (0.73%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery insufficiency
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Heart valve calcification
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart valve incompetence
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left atrial dilatation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mitral valve disease
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease mixed
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    21 / 2206 (0.95%)
    24 / 2343 (1.02%)
         occurrences causally related to treatment / all
    0 / 26
    1 / 27
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    4 / 2206 (0.18%)
    13 / 2343 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    6 / 2206 (0.27%)
    10 / 2343 (0.43%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia induced cardiomyopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tricuspid valve disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital ureteric anomaly
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer gene carrier
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal dystrophy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular dystrophy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 2206 (0.50%)
    11 / 2343 (0.47%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow oedema
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Acoustic neuritis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Akinesia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery thrombosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral artery embolism
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral arteriosclerosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral atrophy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    5 / 2206 (0.23%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Cerebral infarction
         subjects affected / exposed
    5 / 2206 (0.23%)
    17 / 2343 (0.73%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral thrombosis
         subjects affected / exposed
    8 / 2206 (0.36%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    6 / 2206 (0.27%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral microangiopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    22 / 2206 (1.00%)
    29 / 2343 (1.24%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 30
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicogenic headache
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cubital tunnel syndrome
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic hyperosmolar coma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    2 / 2206 (0.09%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dysaesthesia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    5 / 2206 (0.23%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Facial paresis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Headache
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    11 / 2206 (0.50%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lacunar infarction
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor neurone disease
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mononeuropathy multiplex
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudoradicular syndrome
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    6 / 2206 (0.27%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Senile dementia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sensory disturbance
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tarsal tunnel syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    18 / 2206 (0.82%)
    20 / 2343 (0.85%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    21 / 2206 (0.95%)
    19 / 2343 (0.81%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular headache
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blepharochalasis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blindness unilateral
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    17 / 2206 (0.77%)
    15 / 2343 (0.64%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract diabetic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Detachment of macular retinal pigment epithelium
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectropion
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular fibrosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maculopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Open angle glaucoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vascular thrombosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoacusis
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    14 / 2206 (0.63%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 18
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otosclerosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia obstructive
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    10 / 2206 (0.45%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal rigidity
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acquired oesophageal web
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anal prolapse
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal sphincter atony
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 2206 (0.14%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coeliac disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    8 / 2206 (0.36%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    9 / 2206 (0.41%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 2206 (0.05%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum oesophageal
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecal incontinence
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epigastric discomfort
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    6 / 2206 (0.27%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    4 / 2206 (0.18%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    6 / 2206 (0.27%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal mucosal disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stenosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 2206 (0.14%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    2 / 2206 (0.09%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    7 / 2206 (0.32%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0