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    Clinical Trial Results:
    Randomized, Double-blind, Active-controlled Study to Evaluate the Efficacy and Safety of Denosumab Compared With Risedronate in Glucocorticoid-treated Individuals

    Summary
    EudraCT number
    		 2010-024393-19
    Trial protocol
    		 BE   HU   NL   CZ   ES   PL   DE   DK   FR  
    Global end of trial date
    29 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2018
    First version publication date
    29 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20101217
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01575873
    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 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective in the glucocorticoid-continuing (GC-C) subpopulation treated with chronic glucocorticoid therapy (≥ 7.5 mg daily prednisone or its equivalent for ≥ 3 months and planning to continue treatment for a total of at least 6 months) is to demonstrate that treatment with denosumab 60 mg subcutaneously (SC) every 6 months (Q6M) is not inferior to treatment with oral risedronate 5 mg every day (QD) with respect to the percent change from baseline in lumbar spine BMD by dual X-ray absorptiometry (DXA) at 12 months. The primary objective in the glucocorticoid-initiating (GC-I) subpopulation treated with glucocorticoid therapy (≥ 7.5 mg daily prednisone or its equivalent for < 3 months and planning to continue treatment for a total of at least 6 months) is to demonstrate that treatment with denosumab 60 mg SC Q6M is not inferior to treatment with oral risedronate 5 mg QD with respect to the percent change from baseline in lumbar spine BMD by DXA at 12 months.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The protocol, proposed informed consent form, other written subject information, and any proposed advertising material was submitted to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for written approval. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 141
    Country: Number of subjects enrolled
    Poland: 96
    Country: Number of subjects enrolled
    Russian Federation: 75
    Country: Number of subjects enrolled
    Belgium: 59
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    Hungary: 37
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Denmark: 25
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Argentina: 74
    Country: Number of subjects enrolled
    Mexico: 32
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    United States: 76
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    Korea, Republic of: 33
    Worldwide total number of subjects
    795
    EEA total number of subjects
    456
    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)
    440
    From 65 to 84 years
    344
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 79 centers in Europe, North America, Latin America, and Korea from 28 March 2012 to 30 June 2015. Participants who had been taking glucocorticoids for at least 3 months were classed as glucocorticoid continuing; those who were taking glucocorticoids for less than 3 months were classed as glucocorticoid initiating.

    Pre-assignment
    Screening details
    		 Eligible patients were randomly assigned in a 1:1 ratio to receive 60 mg denosumab every 6 months or 5 mg oral risedronate daily for 24 months within each subpopulation. Randomization was stratified by sex within each subpopulation.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Risedronate: Glucocorticoid-initiating
    Arm description
    		 Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo for denosumab
    Investigational medicinal product code
    Other name
    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

    Investigational medicinal product name
    Risendronate
    Investigational medicinal product code
    Other name
    Actonel, Atelvia
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Arm title
    		 Denosumab: Glucocorticoid-initiating
    Arm description
    		 Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months.
    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

    Investigational medicinal product name
    Placebo for risendronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Arm title
    		 Risedronate: Glucocorticoid-continuing
    Arm description
    		 Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Risendronate
    Investigational medicinal product code
    Other name
    Actonel, Atelvia
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Investigational medicinal product name
    Placebo for denosumab
    Investigational medicinal product code
    Other name
    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: Glucocorticoid-continuing
    Arm description
    		 Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months.
    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

    Investigational medicinal product name
    Placebo for risendronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Number of subjects in period 1
    		Risedronate: Glucocorticoid-initiating Denosumab: Glucocorticoid-initiating Risedronate: Glucocorticoid-continuing Denosumab: Glucocorticoid-continuing
    Started
    145
    145
    252
    253
    Received Study Drug
    140
    142
    246
    251
    Completed
    117
    109
    178
    186
    Not completed
    28
    36
    74
    67
         Consent withdrawn by subject
    15
    20
    34
    34
         Adverse Event
    7
    7
    9
    12
         Administrative decision
    1
    1
    1
    -
         Death
    3
    2
    8
    9
         Other
    -
    -
    4
    2
         Protocol deviation
    -
    1
    -
    1
         Lost to follow-up
    1
    3
    13
    5
         Requirement for Alternative Therapy
    -
    -
    1
    1
         Noncompliance
    1
    2
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Risedronate: Glucocorticoid-initiating
    Reporting group description
    		 Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18.

    Reporting group title
    Denosumab: Glucocorticoid-initiating
    Reporting group description
    		 Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months.

    Reporting group title
    Risedronate: Glucocorticoid-continuing
    Reporting group description
    		 Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18.

    Reporting group title
    Denosumab: Glucocorticoid-continuing
    Reporting group description
    		 Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months.

    Reporting group values
    		 Risedronate: Glucocorticoid-initiating Denosumab: Glucocorticoid-initiating Risedronate: Glucocorticoid-continuing Denosumab: Glucocorticoid-continuing Total
    Number of subjects
    		 145 145 252 253 795
    Age Categorical
    Units: Subjects
        < 50 years
    		 5 2 26 33 66
        50 - 64 years
    		 75 55 130 114 374
        65 - 74 years
    		 38 50 62 73 223
        ≥ 75 years
    		 27 38 34 33 132
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ± 10.0 67.5 ± 10.1 61.3 ± 11.1 61.5 ± 11.6 -
    Gender Categorical
    Units: Subjects
        Female
    		 93 93 185 185 556
        Male
    		 52 52 67 68 239
    Race
    Units: Subjects
        White
    		 123 122 223 230 698
        Other
    		 11 12 11 13 47
        Asian
    		 9 9 12 6 36
        Black or African American
    		 2 2 4 4 12
        American Indian or Alaska Native
    		 0 0 1 0 1
        Multiple
    		 0 0 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 18 20 54 43 135
        Not Hispanic or Latino
    		 127 125 198 210 660
    Menopausal Status
    Units: Subjects
        Premenopause
    		 7 10 25 24 66
        Postmenopause
    		 83 82 157 159 481
        Unknown
    		 3 1 3 2 9
        NA - Male
    		 52 52 67 68 239
    Lumbar Spine Bone Mineral Density (BMD) T-score
    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. Data are reported for participants with observed values (143, 144, 252, and 249 subjects in each reporting group respectively).
    Units: T-score
        arithmetic mean (standard deviation)
    		 -1.06 ± 1.57 -0.92 ± 1.86 -1.96 ± 1.38 -1.92 ± 1.38 -
    Total Hip BMD T-score
    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. Data are reported for participants with observed values (142, 142, 250, and 249 subjects in each reporting group respectively).
    Units: T-score
        arithmetic mean (standard deviation)
    		 -0.98 ± 1.07 -1.14 ± 1.00 -1.56 ± 0.96 -1.66 ± 0.96 -

    End points

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    End points reporting groups
    Reporting group title
    Risedronate: Glucocorticoid-initiating
    Reporting group description
    		 Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18.

    Reporting group title
    Denosumab: Glucocorticoid-initiating
    Reporting group description
    		 Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months.

    Reporting group title
    Risedronate: Glucocorticoid-continuing
    Reporting group description
    		 Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18.

    Reporting group title
    Denosumab: Glucocorticoid-continuing
    Reporting group description
    		 Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months.

    Primary: Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Non-inferiority Analysis)

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    End point title
    		 Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Non-inferiority Analysis)
    End point description
    Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA).
    End point type
    Primary
    End point timeframe
    Baseline and month 12
    End point values
    		 Risedronate: Glucocorticoid-initiating Denosumab: Glucocorticoid-initiating Risedronate: Glucocorticoid-continuing Denosumab: Glucocorticoid-continuing
    Number of subjects analysed
    126 [1]
    119 [2]
    211 [3]
    209 [4]
    Units: percent change
        least squares mean (confidence interval 95%)
    0.8 (0.2 to 1.5)
    3.8 (3.1 to 4.5)
    2.3 (1.7 to 2.9)
    4.4 (3.8 to 5.0)
    Notes
    [1] - Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
    [2] - Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
    [3] - Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
    [4] - Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
    Statistical analysis title
    		 GC-I Subpopulation Non-inferiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently in the glucocorticoid-continuing and glucocorticoid-initiating subpopulations. A fixed-sequence testing procedure was used to control the experiment-wise type 1 error rate at a two-sided 5% significance level within each subpopulation. The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD, sex, machine type, and baseline BMD-by-machine type interaction.
    Comparison groups
    Risedronate: Glucocorticoid-initiating v Denosumab: Glucocorticoid-initiating
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 3.9
    Notes
    [5] - Non-inferiority was shown if the lower bound of the two-sided 95% CI for the difference between the least-squares means (denosumab minus risedronate) was higher than the prespecified non-inferiority margin of –1.1 percentage points for the glucocorticoid-initiating subpopulation.
    [6] - One-sided p-value based on the prespecified noninferiority margin for lumbar spine of -1.1%.
    Statistical analysis title
    		 GC-C Subpopulation Non-inferiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use (< 12 months vs ≥ 12 months).
    Comparison groups
    Risedronate: Glucocorticoid-continuing v Denosumab: Glucocorticoid-continuing
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 < 0.001 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 3
    Notes
    [7] - Non-inferiority was shown if the lower bound of the two-sided 95% CI for the difference between the least-squares means (denosumab minus risedronate) was higher than the prespecified non-inferiority margin of –0.7 percentage points for the glucocorticoid-continuing subpopulation.
    [8] - One-sided p-value based on the prespecified noninferiority margins for lumbar spine of -0.7%.

    Secondary: Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Superiority Analysis)

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    End point title
    		 Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Superiority Analysis)
    End point description
    Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA).
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Risedronate: Glucocorticoid-initiating Denosumab: Glucocorticoid-initiating Risedronate: Glucocorticoid-continuing Denosumab: Glucocorticoid-continuing
    Number of subjects analysed
    126 [9]
    119 [10]
    211 [11]
    209 [12]
    Units: percent change
        least squares mean (confidence interval 95%)
    0.8 (0.2 to 1.5)
    3.8 (3.1 to 4.5)
    2.3 (1.7 to 2.9)
    4.4 (3.8 to 5.0)
    Notes
    [9] - Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
    [10] - Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
    [11] - Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
    [12] - Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
    Statistical analysis title
    		 GC-I Subpopulation Superiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction. LS Mean difference was calculated as Denosumab - Risedronate.
    Comparison groups
    Risedronate: Glucocorticoid-initiating v Denosumab: Glucocorticoid-initiating
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [13]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 3.9
    Notes
    [13] - 2-sided p-value corresponding to the 2-sided 95% confidence interval
    Statistical analysis title
    		 GC-C Subpopulation Superiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use. LS Mean difference = Denosumab - Risedronate.
    Comparison groups
    Risedronate: Glucocorticoid-continuing v Denosumab: Glucocorticoid-continuing
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [14]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 3
    Notes
    [14] - 2-sided p-value corresponding to the 2-sided 95% confidence interval

    Secondary: Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12

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    End point title
    		 Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12
    End point description
    Bone mineral density at the total hip was measured by dual-energy x-ray absorptiometry (DXA).
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Risedronate: Glucocorticoid-initiating Denosumab: Glucocorticoid-initiating Risedronate: Glucocorticoid-continuing Denosumab: Glucocorticoid-continuing
    Number of subjects analysed
    128 [15]
    119 [16]
    215 [17]
    217 [18]
    Units: percent change
        least squares mean (confidence interval 95%)
    0.2 (-0.2 to 0.7)
    1.7 (1.2 to 2.2)
    0.6 (0.2 to 1.0)
    2.1 (1.7 to 2.5)
    Notes
    [15] - Randomized participants with a baseline and month 12 measurement for the total hip BMD.
    [16] - Randomized participants with a baseline and month 12 measurement for the total hip BMD.
    [17] - Randomized participants with a baseline and month 12 measurement for the total hip BMD.
    [18] - Randomized participants with a baseline and month 12 measurement for the total hip BMD.
    Statistical analysis title
    		 GC-I Subpopulation Superiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction. LS mean difference = Denosumab - Risedronate.
    Comparison groups
    Risedronate: Glucocorticoid-initiating v Denosumab: Glucocorticoid-initiating
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [19]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 2.1
    Notes
    [19] - 2-sided p-value corresponding to the 2-sided 95% confidence interval
    Statistical analysis title
    		 GC-C Subpopulation Superiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use. LS Mean difference = Denosumab - Risedronate.
    Comparison groups
    Risedronate: Glucocorticoid-continuing v Denosumab: Glucocorticoid-continuing
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [20]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.1
    Notes
    [20] - 2-sided p-value corresponding to the 2-sided 95% confidence interval

    Secondary: Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 24

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    End point title
    		 Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 24
    End point description
    Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA).
    End point type
    Secondary
    End point timeframe
    Baseline and month 24
    End point values
    		 Risedronate: Glucocorticoid-initiating Denosumab: Glucocorticoid-initiating Risedronate: Glucocorticoid-continuing Denosumab: Glucocorticoid-continuing
    Number of subjects analysed
    113 [21]
    107 [22]
    174 [23]
    183 [24]
    Units: percent change
        least squares mean (confidence interval 95%)
    1.7 (0.8 to 2.7)
    6.2 (5.3 to 7.2)
    3.2 (2.3 to 4.1)
    6.4 (5.5 to 7.2)
    Notes
    [21] - Randomized participants with a baseline and month 24 measurement for the lumbar spine BMD.
    [22] - Randomized participants with a baseline and month 24 measurement for the lumbar spine BMD.
    [23] - Randomized participants with a baseline and month 24 measurement for the lumbar spine BMD.
    [24] - Randomized participants with a baseline and month 24 measurement for the lumbar spine BMD.
    Statistical analysis title
    		 GC-I Subpopulation Superiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction. LS mean difference = Denosumab - Risedronate.
    Comparison groups
    Risedronate: Glucocorticoid-initiating v Denosumab: Glucocorticoid-initiating
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [25]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.2
         upper limit
    		 5.8
    Notes
    [25] - 2-sided p-value corresponding to the 2-sided 95% confidence interval
    Statistical analysis title
    		 GC-C Subpopulation Superiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use. LS Mean difference = Denosumab - Risedronate.
    Comparison groups
    Risedronate: Glucocorticoid-continuing v Denosumab: Glucocorticoid-continuing
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [26]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 4.3
    Notes
    [26] - 2-sided p-value corresponding to the 2-sided 95% confidence interval

    Secondary: Percent Change From Baseline in Total Hip Bone Mineral Density at Month 24

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    End point title
    		 Percent Change From Baseline in Total Hip Bone Mineral Density at Month 24
    End point description
    Bone mineral density at the total hip was measured by dual-energy x-ray absorptiometry (DXA).
    End point type
    Secondary
    End point timeframe
    Baseline and month 24
    End point values
    		 Risedronate: Glucocorticoid-initiating Denosumab: Glucocorticoid-initiating Risedronate: Glucocorticoid-continuing Denosumab: Glucocorticoid-continuing
    Number of subjects analysed
    111 [27]
    104 [28]
    176 [29]
    181 [30]
    Units: percent change
        least squares mean (confidence interval 95%)
    -0.0 (-0.6 to 0.6)
    3.1 (2.4 to 3.7)
    0.5 (-0.1 to 1.0)
    2.9 (2.4 to 3.5)
    Notes
    [27] - Randomized participants with a baseline and month 24 measurement for the total hip BMD.
    [28] - Randomized participants with a baseline and month 24 measurement for the total hip BMD.
    [29] - Randomized participants with a baseline and month 24 measurement for the total hip BMD.
    [30] - Randomized participants with a baseline and month 24 measurement for the total hip BMD.
    Statistical analysis title
    		 CG-I Subpopulation Superiority Analsyis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction. LS mean difference = Denosumab - Risedronate.
    Comparison groups
    Risedronate: Glucocorticoid-initiating v Denosumab: Glucocorticoid-initiating
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [31]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 3.9
    Notes
    [31] - 2-sided p-value corresponding to the 2-sided 95% confidence interval
    Statistical analysis title
    		 GC-C Subpopulation Superiority Analysis
    Statistical analysis description
    Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level. The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use. LS Mean difference = Denosumab - Risedronate.
    Comparison groups
    Risedronate: Glucocorticoid-continuing v Denosumab: Glucocorticoid-continuing
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [32]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 3.2
    Notes
    [32] - 2-sided p-value corresponding to the 2-sided 95% confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 Months
    Adverse event reporting additional description
    One participant was randomized to risedronate but received denosumab in error; this participant was included in the denosumab group for safety analyses.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months.

    Reporting group title
    Risedronate
    Reporting group description
    		 Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18.

    Serious adverse events
    		 Denosumab Risedronate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 394 (23.35%)
    98 / 385 (25.45%)
         number of deaths (all causes)
    13
    9
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer metastatic
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Capillary leak syndrome
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colectomy
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileostomy
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 394 (0.25%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm surgery
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenectomy
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sigmoidectomy
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal decompression
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Eosinophilic granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food allergy
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervix haematoma uterine
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Alveolitis allergic
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 394 (0.25%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 394 (0.00%)
    5 / 385 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Behaviour disorder due to a general medical condition
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    White blood cell count increased
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 394 (0.76%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (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
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         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 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital megaureter
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve sclerosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic valve stenosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 394 (0.76%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 394 (0.51%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 394 (0.76%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (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
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 394 (0.76%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 394 (0.25%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 394 (0.25%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 394 (0.25%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (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
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erosive oesophagitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar hernia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dyskinesia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatomyositis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus generalised
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus nephritis
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 394 (0.25%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Ankylosing spondylitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 394 (0.25%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exposed bone in jaw
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mixed connective tissue disease
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 394 (0.51%)
    5 / 385 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 394 (0.25%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 394 (0.51%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sjogren's syndrome
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral foraminal stenosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic fever
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 394 (1.78%)
    8 / 385 (2.08%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Serratia infection
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis calcarea
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Denosumab Risedronate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 394 (19.54%)
    76 / 385 (19.74%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 394 (5.33%)
    15 / 385 (3.90%)
         occurrences all number
    23
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    23 / 394 (5.84%)
    33 / 385 (8.57%)
         occurrences all number
    26
    44
    Back pain
         subjects affected / exposed
    24 / 394 (6.09%)
    21 / 385 (5.45%)
         occurrences all number
    24
    22
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    20 / 394 (5.08%)
    19 / 385 (4.94%)
         occurrences all number
    21
    24

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2011
    • Exploratory objectives clarified: HR-pQCT data to be collected in a subset of subjects only, and PK/BTM samples are only to be collected in subjects participating in the PK/BTM substudy • Added statement that subjects in the transiliac bone biopsy substudy are to receive tetracycline or tetracycline derivative prior to the bone biopsy procedure
    15 Feb 2012
    • Entry criteria clarified: - Subjects less than 50 years old and without an osteoporotic fracture will not be eligible to enroll. - Subjects initiating biologics within 4 weeks prior to screening will not be eligible to enroll; however, administration of biologic medications will not be proscribed during the study - Subjects with a history of infection immediately prior to screening will not be eligible to enroll.
    29 Jun 2012
    • Entry criteria clarified: - GC-C subjects ≥ 50 years of are required to have a BMD value equivalent to a T-score ≤ -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD value equivalent to a T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture. - Subjects administering > 1 biologic agent for the treatment of underlying inflammatory disease to be excluded - Subjects with a history of Addison’s disease to be excluded - Clarified the existing exclusion criterion of recent tooth extraction or dental surgery • Secondary objectives were separated with respect to lumbar spine and total hip. • Information on choice of noninferiority margins was updated. • Clarified that safety analyses would be done in the combined subpopulations • Added information regarding a DRT • Added criteria for permanent withholding of denosumab and risedronate due to serious infection • Added urine dipstick pregnancy tests at day 10 and months 6, 12, and 18, and clarified that any female subject who becomes pregnant should permanently discontinue investigational product
    22 Feb 2013
    • Incorporated updated procedures of reporting adverse events and serious adverse events to IRB/IECs and regulatory authorities • Replaced the DRT with a DMC for ongoing monitoring of study data • Clarified that the noninferiority comparison will only be performed for the primary efficacy endpoint within each subpopulation
    30 Jun 2016
    • Bone biopsy assessment added at 24 months for the bone biopsy substudy to bring the number of evaluable specimens closer to the protocol-indicated number (due to difficulties in recruitment to the substudy and some collected specimens being unevaluable) • Noted that analysis of HR-pQCT data will be performed at the end of the study (month 24) • Updated safety language

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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