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    Clinical Trial Results:
    An Open-label, Randomized, Teriparatide-controlled Study to Evaluate the Effect of Treatment With Romosozumab in Postmenopausal Women With Osteoporosis Previously Treated With Bisphosphonate Therapy

    Summary
    EudraCT number
    		 2012-002948-24
    Trial protocol
    		 BE   DK   ES   GB   CZ   HU  
    Global end of trial date
    23 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Aug 2016
    First version publication date
    13 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20080289
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01796301
    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
    23 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the effect of treatment with romosozumab for 12 months, compared with teriparatide (TPTD), on total hip bone mineral density (BMD), as assessed by dual energy X-ray absorptiometry (DXA), in postmenopausal women with osteoporosis, previously treated with bisphosphonate therapy.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    United Kingdom: 80
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Czech Republic: 91
    Country: Number of subjects enrolled
    Denmark: 69
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Colombia: 47
    Country: Number of subjects enrolled
    Argentina: 32
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    Canada: 12
    Worldwide total number of subjects
    436
    EEA total number of subjects
    325
    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)
    98
    From 65 to 84 years
    320
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 46 sites in North America, Latin America, and Europe. Participants were enrolled from 31 January 2013 to 29 April 2014.

    Pre-assignment
    Screening details
    		 A total of 777 subjects were screened for participation; 341 (43.9%) were excluded prior to randomization, primarily due to not meeting inclusion/exclusion criteria (306 [39.4%] subjects). A total of 436 subjects were randomized into the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Teriparatide
    Arm description
    		 Participants received teriparatide 20 µg/day administered by subcutaneous injection for 12 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Teriparatide
    Investigational medicinal product code
    Other name
    Forteo
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    20 µg administered by subcutaneous injection once a day.

    Arm title
    		 Romosozumab
    Arm description
    		 Participants received 210 mg romosozumab administered by subcutaneous injection once a month for 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Romosozumab
    Investigational medicinal product code
    AMG 785
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    210 mg administered subcutaneously once a month.

    Number of subjects in period 1
    		Teriparatide Romosozumab
    Started
    218
    218
    Received Treatment
    214
    218
    Completed
    200
    198
    Not completed
    18
    20
         Consent withdrawn by subject
    15
    15
         Death
    -
    1
         Lost to follow-up
    3
    3
         Sponsor decision
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Teriparatide
    Reporting group description
    		 Participants received teriparatide 20 µg/day administered by subcutaneous injection for 12 months.

    Reporting group title
    Romosozumab
    Reporting group description
    		 Participants received 210 mg romosozumab administered by subcutaneous injection once a month for 12 months.

    Reporting group values
    		 Teriparatide Romosozumab Total
    Number of subjects
    		 218 218 436
    Age categorical
    Units: Subjects
        < 65 years
    		 48 50 98
        ≥ 65 to < 75 years
    		 96 83 179
        ≥ 75 years
    		 74 85 159
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.2 ( 7.7 ) 71.8 ( 7.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 218 218 436
        Male
    		 0 0 0
    Race
    Units: Subjects
        White
    		 196 191 387
        Other
    		 18 23 41
        American Indian or Alaska Native
    		 1 4 5
        Asian
    		 2 0 2
        Multiple
    		 1 0 1
    Prior Fracture
    Units: Subjects
        Yes
    		 217 218 435
        No
    		 1 0 1
    Lumbar Spine 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.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.87 ( 1.04 ) -2.83 ( 1.1 ) -
    Total Hip BMD T-score
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.21 ( 0.72 ) -2.27 ( 0.75 ) -
    Femoral Neck BMD T-score
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.43 ( 0.66 ) -2.49 ( 0.67 ) -
    Serum Type 1 Collagen C-telopeptide (sCTX)
    Units: ng/L
        arithmetic mean (standard deviation)
    		 260.1 ( 124.9 ) 252.3 ( 136.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Teriparatide
    Reporting group description
    		 Participants received teriparatide 20 µg/day administered by subcutaneous injection for 12 months.

    Reporting group title
    Romosozumab
    Reporting group description
    		 Participants received 210 mg romosozumab administered by subcutaneous injection once a month for 12 months.

    Primary: Percent Change From Baseline Through Month 12 in Total Hip Bone Mineral Density (BMD)

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    End point title
    		 Percent Change From Baseline Through Month 12 in Total Hip Bone Mineral Density (BMD)
    End point description
    Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA). Percent change from baseline through month 12 is the average of the treatment effect at months 6 and 12. The primary efficacy analysis set includes randomized subjects with a non-missing baseline and at least one post-baseline measurement.
    End point type
    Primary
    End point timeframe
    Baseline, month 6 and month 12
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    209
    206
    Units: percent change
        least squares mean (standard error)
    -0.6 ( 0.2 )
    2.6 ( 0.2 )
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The primary analysis to assess the treatment difference (Romosozumab – Teriparatide) employed a linear mixed effects model for repeated measures. The model included main effects for treatment group, visit (categorical), baseline sCTX, baseline hip DXA BMD value, machine type (categorical), and machine type-by-baseline value interaction (to adjust for the effect of machine type on baseline DXA BMD value) as fixed main effects using an unstructured within-subject variance-covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    415
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects model for repeated
    Parameter type
    		 Treatment difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.7
         upper limit
    		 3.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [1] - A two-step, step-down, fixed-sequential testing procedure was used to test the primary and key secondary efficacy endpoints for the comparison of romosozumab to teriparatide groups in the order presented for multiplicity adjustment to maintain the overall significance level at 0.05

    Secondary: Percent Change From Baseline in Total Hip BMD at Month 6

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    End point title
    		 Percent Change From Baseline in Total Hip BMD at Month 6
    End point description
    Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA). The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 6
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    203 [2]
    203 [3]
    Units: percent change
        least squares mean (standard error)
    -0.8 ( 0.2 )
    2.3 ( 0.2 )
    Notes
    [2] - Participants with values at baseline and month 6
    [3] - Participants with values at baseline and month 6
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, baseline BMD value, machine type, baseline BMD value-by machine type interaction, treatment-by-visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 3.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Secondary: Percent Change From Baseline in Total Hip BMD at Month 12

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    End point title
    		 Percent Change From Baseline in Total Hip BMD at Month 12
    End point description
    Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA). The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    202 [4]
    197 [5]
    Units: percent
        least squares mean (standard error)
    -0.5 ( 0.2 )
    2.9 ( 0.2 )
    Notes
    [4] - Participants with values at baseline and month 12
    [5] - Participants with values at baseline and month 12
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, baseline BMD value, machine type, baseline BMD value-by machine type interaction, treatment-by-visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Secondary: Percent Change From Baseline in Cortical BMD by Quantitative Computed Tomography (QCT) at the Total Hip at Month 6

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    End point title
    		 Percent Change From Baseline in Cortical BMD by Quantitative Computed Tomography (QCT) at the Total Hip at Month 6
    End point description
    Cortical BMD was measured by quantitative computed tomography (QCT) at the total hip. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 6
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    156 [6]
    163 [7]
    Units: percent change
        least squares mean (standard error)
    -2.7 ( 0.2 )
    0.7 ( 0.2 )
    Notes
    [6] - Participants with values at baseline and month 6
    [7] - Participants with values at baseline and month 6
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Secondary: Percent Change From Baseline in Cortical BMD by QCT at the Total Hip at Month 12

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    End point title
    		 Percent Change From Baseline in Cortical BMD by QCT at the Total Hip at Month 12
    End point description
    Cortical BMD was measured by quantitative computed tomography (QCT) at the total hip. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    159 [8]
    163 [9]
    Units: percent change
        least squares mean (standard error)
    -3.6 ( 0.3 )
    1.1 ( 0.3 )
    Notes
    [8] - Participants with values at baseline and month 12
    [9] - Participants with values at baseline and month 12
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.9
         upper limit
    		 5.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Percent Change From Baseline in Integral BMD by QCT at the Total Hip at Month 6

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    End point title
    		 Percent Change From Baseline in Integral BMD by QCT at the Total Hip at Month 6
    End point description
    Integral BMD was measured by quantitative computed tomography (QCT) at the total hip. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 6
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    156 [10]
    163 [11]
    Units: percent change
        least squares mean (standard error)
    -0.8 ( 0.2 )
    2.3 ( 0.2 )
    Notes
    [10] - Participants with values at baseline and month 6
    [11] - Participants with values at baseline and month 6
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 3.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Secondary: Percent Change From Baseline in Integral BMD by QCT at the Total Hip at Month 12

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    End point title
    		 Percent Change From Baseline in Integral BMD by QCT at the Total Hip at Month 12
    End point description
    Integral BMD was measured by quantitative computed tomography (QCT) at the total hip. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    159 [12]
    163 [13]
    Units: percent change
        least squares mean (standard error)
    -0.2 ( 0.2 )
    3.4 ( 0.2 )
    Notes
    [12] - Participants with values at baseline and month 12
    [13] - Participants with values at baseline and month 12
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.9
         upper limit
    		 4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Secondary: Percent Change From Baseline in Estimated Strength by FEA at the Total Hip at Month 6

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    End point title
    		 Percent Change From Baseline in Estimated Strength by FEA at the Total Hip at Month 6
    End point description
    Total hip estimated strength was assessed by finite element analysis (FEA) of QCT scans. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 6
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    163 [14]
    164 [15]
    Units: percent change
        least squares mean (standard error)
    -1 ( 0.2 )
    2.1 ( 0.2 )
    Notes
    [14] - Participants with values at baseline and month 6
    [15] - Participants with values at baseline and month 6
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.4
         upper limit
    		 3.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Secondary: Percent Change From Baseline in Estimated Strength by FEA at the Total Hip at Month 12

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    End point title
    		 Percent Change From Baseline in Estimated Strength by FEA at the Total Hip at Month 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    155 [16]
    159 [17]
    Units: percent change
        least squares mean (standard error)
    -0.7 ( 0.4 )
    2.5 ( 0.4 )
    Notes
    [16] - Participants with values at baseline and month 12
    [17] - Participants with values at baseline and month 12
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 4.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6

    Secondary: Percent Change From Baseline in Total Hip Integral Bone Mineral Content (BMC) by QCT at Month 6

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    End point title
    		 Percent Change From Baseline in Total Hip Integral Bone Mineral Content (BMC) by QCT at Month 6
    End point description
    Total hip integral BMC was measured using quantitative computed tomography (QCT). The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 6
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    156 [18]
    163 [19]
    Units: percent change
        least squares mean (standard error)
    -0.7 ( 0.2 )
    2.4 ( 0.2 )
    Notes
    [18] - Participants with values at baseline and month 6
    [19] - Participants with values at baseline and month 6
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.6
         upper limit
    		 3.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Secondary: Percent Change From Baseline in Total Hip Integral Bone Mineral Content (BMC) by QCT at Month 12

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    End point title
    		 Percent Change From Baseline in Total Hip Integral Bone Mineral Content (BMC) by QCT at Month 12
    End point description
    Total hip integral BMC was measured using quantitative computed tomography (QCT). The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    159 [20]
    163 [21]
    Units: percent change
        least squares mean (standard error)
    0 ( 0.2 )
    3.6 ( 0.2 )
    Notes
    [20] - Participants with values at baseline and month 12
    [21] - Participants with values at baseline and month 12
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.9
         upper limit
    		 4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Secondary: Percent Change From Baseline in Femoral Neck BMD at Month 6

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    End point title
    		 Percent Change From Baseline in Femoral Neck BMD at Month 6
    End point description
    Femoral neck BMD was measured by DXA. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 6
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    203 [22]
    203 [23]
    Units: percent change
        least squares mean (standard error)
    -1.1 ( 0.3 )
    2.1 ( 0.3 )
    Notes
    [22] - Participants with values at baseline and month 6
    [23] - Participants with values at baseline and month 6
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 3.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Percent Change From Baseline in Femoral Neck BMD at Month 12

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    End point title
    		 Percent Change From Baseline in Femoral Neck BMD at Month 12
    End point description
    Femoral neck BMD was measured by DXA. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    202 [24]
    197 [25]
    Units: percent change
        least squares mean (standard error)
    -0.2 ( 0.3 )
    3.2 ( 0.3 )
    Notes
    [24] - Participants with values at baseline and month 12
    [25] - Participants with values at baseline and month 12
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.6
         upper limit
    		 4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Percent Change From Baseline in Lumbar Spine BMD at Month 6

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    End point title
    		 Percent Change From Baseline in Lumbar Spine BMD at Month 6
    End point description
    Lumbar spine BMD was measured by DXA. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 6
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    204 [26]
    203 [27]
    Units: percent change
        least squares mean (standard error)
    3.5 ( 0.3 )
    7.2 ( 0.3 )
    Notes
    [26] - Participants with values at baseline and month 6
    [27] - Participants with values at baseline and month 6
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.9
         upper limit
    		 4.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Percent Change From Baseline in Lumbar Spine BMD at Month 12

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    End point title
    		 Percent Change From Baseline in Lumbar Spine BMD at Month 12
    End point description
    Lumbar spine BMD was measured by DXA. The primary efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Teriparatide Romosozumab
    Number of subjects analysed
    201 [28]
    197 [29]
    Units: percent change
        least squares mean (standard error)
    5.4 ( 0.4 )
    9.8 ( 0.4 )
    Notes
    [28] - Participants with values at baseline and month 12
    [29] - Participants with values at baseline and month 12
    Statistical analysis title
    		 Difference from Teriparatide
    Statistical analysis description
    Treatment difference (Romosozumab – Teriparatide) was analyzed using a linear mixed effects model for repeated measures adjusting for treatment, visit, baseline serum type 1 collagen C-telopeptide value, parameter baseline value, treatment-by visit interaction, and using an unstructured variance covariance structure.
    Comparison groups
    Romosozumab v Teriparatide
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effects repeated measures
    Parameter type
    		 Treatment difference
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.4
         upper limit
    		 5.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Romosozumab
    Reporting group description
    		 Participants received 210 mg romosozumab administered by subcutaneous injection once a month for 12 months.

    Reporting group title
    Teriparatide
    Reporting group description
    		 Participants received teriparatide 20 µg/day administered by subcutaneous injection for 12 months.

    Serious adverse events
    		 Romosozumab Teriparatide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 218 (7.80%)
    23 / 214 (10.75%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign soft tissue neoplasm
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myeloid leukaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer stage III
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical device removal
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (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
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (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 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         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
    Femoral neck fracture
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural nausea
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bifascicular block
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (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 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radicular pain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow failure
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         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 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (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 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestinal ulcer
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         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
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (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
    Hyperglycaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Romosozumab Teriparatide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    160 / 218 (73.39%)
    146 / 214 (68.22%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Benign renal neoplasm
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Colon adenoma
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Haemangioma of bone
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Keratoacanthoma
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Lipoma
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Melanocytic naevus
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Uterine leiomyoma
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Haematoma
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Hot flush
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Hypertension
         subjects affected / exposed
    7 / 218 (3.21%)
    5 / 214 (2.34%)
         occurrences all number
    7
    5
    Hypertensive crisis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Varicose vein
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Breast prosthesis implantation
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Cataract operation
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Dermabrasion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Large intestinal polypectomy
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Medical device removal
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Toe amputation
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Tooth extraction
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 218 (1.83%)
    1 / 214 (0.47%)
         occurrences all number
    4
    1
    Chest pain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Drug intolerance
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    5 / 218 (2.29%)
    9 / 214 (4.21%)
         occurrences all number
    5
    9
    Feeling cold
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Gait disturbance
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Implant site reaction
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Injection site bruising
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Injection site erythema
         subjects affected / exposed
    3 / 218 (1.38%)
    2 / 214 (0.93%)
         occurrences all number
    11
    3
    Injection site haemorrhage
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Injection site inflammation
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Injection site pain
         subjects affected / exposed
    8 / 218 (3.67%)
    2 / 214 (0.93%)
         occurrences all number
    10
    2
    Injection site pruritus
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 214 (0.00%)
         occurrences all number
    6
    0
    Injection site rash
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Injection site reaction
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Injection site swelling
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Injection site warmth
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Medical device complication
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences all number
    1
    2
    Pain
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Vaccination site bruising
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Reproductive system and breast disorders
    Urogenital prolapse
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Uterine prolapse
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Vaginal discharge
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Vulva cyst
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Catarrh
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    3
    Cough
         subjects affected / exposed
    7 / 218 (3.21%)
    9 / 214 (4.21%)
         occurrences all number
    7
    9
    Dysphonia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences all number
    1
    2
    Dyspnoea exertional
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Nasal congestion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Nasal obstruction
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Pleural effusion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Wheezing
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Depressed mood
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    0 / 218 (0.00%)
    5 / 214 (2.34%)
         occurrences all number
    0
    5
    Insomnia
         subjects affected / exposed
    1 / 218 (0.46%)
    3 / 214 (1.40%)
         occurrences all number
    1
    3
    Investigations
    Arthroscopy
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Blood calcium decreased
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Blood potassium increased
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Cardiac murmur
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    White blood cells urine positive
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Chest injury
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Concussion
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Contusion
         subjects affected / exposed
    10 / 218 (4.59%)
    8 / 214 (3.74%)
         occurrences all number
    14
    11
    Epicondylitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Excoriation
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Face injury
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    12 / 218 (5.50%)
    5 / 214 (2.34%)
         occurrences all number
    15
    5
    Foot fracture
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Forearm fracture
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Head injury
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Humerus fracture
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Incisional hernia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Joint dislocation
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Joint injury
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Laceration
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Ligament sprain
         subjects affected / exposed
    5 / 218 (2.29%)
    4 / 214 (1.87%)
         occurrences all number
    5
    5
    Limb injury
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Lip injury
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Muscle injury
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Overdose
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Post-traumatic neck syndrome
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Postoperative hernia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Pubis fracture
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    2
    Radius fracture
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Rib fracture
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Scratch
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Sternal fracture
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    2
    Tendon rupture
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Tooth fracture
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Aortic valve calcification
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Bundle branch block left
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Bundle branch block right
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Cardiac failure
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Cardiac hypertrophy
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Diastolic dysfunction
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Heart valve calcification
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Left atrial dilatation
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Left ventricular hypertrophy
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Mitral valve calcification
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Mitral valve incompetence
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Palpitations
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences all number
    1
    2
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Tachycardia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Amnesia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Aphonia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Balance disorder
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Burning sensation
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Carpal tunnel syndrome
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    9 / 218 (4.13%)
    5 / 214 (2.34%)
         occurrences all number
    12
    6
    Dysaesthesia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Facial neuralgia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    14 / 218 (6.42%)
    9 / 214 (4.21%)
         occurrences all number
    15
    10
    Hypoaesthesia
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Lethargy
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Neuralgia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    4 / 218 (1.83%)
    3 / 214 (1.40%)
         occurrences all number
    4
    3
    Parkinson's disease
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 214 (0.93%)
         occurrences all number
    3
    3
    Seizure
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Transient ischaemic attack
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    White matter lesion
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 218 (1.83%)
    3 / 214 (1.40%)
         occurrences all number
    4
    3
    Bone marrow oedema syndrome
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Eosinophilia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Ear disorder
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Hypoacusis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Meniere's disease
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Mixed deafness
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Tinnitus
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    4 / 218 (1.83%)
    4 / 214 (1.87%)
         occurrences all number
    5
    4
    Vertigo positional
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Cataract
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences all number
    1
    2
    Conjunctival haemorrhage
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Dry eye
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Eye disorder
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Eye haemorrhage
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Eyelid oedema
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Glaucoma
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences all number
    1
    2
    Macular fibrosis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Photopsia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Retinal fibrosis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    4 / 218 (1.83%)
    0 / 214 (0.00%)
         occurrences all number
    4
    0
    Abdominal distension
         subjects affected / exposed
    3 / 218 (1.38%)
    2 / 214 (0.93%)
         occurrences all number
    3
    2
    Abdominal pain
         subjects affected / exposed
    4 / 218 (1.83%)
    5 / 214 (2.34%)
         occurrences all number
    5
    5
    Abdominal pain lower
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 218 (0.46%)
    3 / 214 (1.40%)
         occurrences all number
    1
    3
    Cheilitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    4 / 218 (1.83%)
    4 / 214 (1.87%)
         occurrences all number
    5
    4
    Dental caries
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    4 / 218 (1.83%)
    9 / 214 (4.21%)
         occurrences all number
    4
    9
    Diverticulum
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Diverticulum intestinal
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Dyspepsia
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Enterocolitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Food poisoning
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gastric disorder
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Gastric polyps
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    2
    Gastrointestinal ulcer
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gingival pain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Glossodynia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Hiatus hernia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Loose tooth
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    8 / 218 (3.67%)
    10 / 214 (4.67%)
         occurrences all number
    8
    11
    Noninfective gingivitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Periodontal disease
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Tooth loss
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    3
    Vomiting
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences all number
    1
    3
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Hepatic steatosis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hepatitis toxic
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Actinic keratosis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Alopecia
         subjects affected / exposed
    0 / 218 (0.00%)
    4 / 214 (1.87%)
         occurrences all number
    0
    4
    Dermatitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Drug eruption
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    2
    Dry skin
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Eczema
         subjects affected / exposed
    1 / 218 (0.46%)
    3 / 214 (1.40%)
         occurrences all number
    1
    3
    Erythema
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hair growth abnormal
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hyperkeratosis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    3 / 218 (1.38%)
    1 / 214 (0.47%)
         occurrences all number
    3
    1
    Pruritus generalised
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Rash
         subjects affected / exposed
    3 / 218 (1.38%)
    2 / 214 (0.93%)
         occurrences all number
    3
    2
    Rash macular
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Skin discolouration
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Skin fibrosis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Stasis dermatitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Bladder irritation
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Bladder wall calcification
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Chronic kidney disease
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Dysuria
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Haematuria
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Renal cyst
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Renal failure
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hypothyroidism
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 218 (10.09%)
    13 / 214 (6.07%)
         occurrences all number
    28
    14
    Arthritis
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    19 / 218 (8.72%)
    12 / 214 (5.61%)
         occurrences all number
    21
    13
    Bone pain
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Bursitis
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences all number
    1
    3
    Fibromyalgia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Foot deformity
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gouty arthritis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Groin pain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Joint crepitation
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Muscle contracture
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    3 / 218 (1.38%)
    6 / 214 (2.80%)
         occurrences all number
    3
    7
    Muscle tightness
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 218 (1.38%)
    1 / 214 (0.47%)
         occurrences all number
    4
    1
    Musculoskeletal pain
         subjects affected / exposed
    11 / 218 (5.05%)
    5 / 214 (2.34%)
         occurrences all number
    12
    6
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Myalgia
         subjects affected / exposed
    9 / 218 (4.13%)
    4 / 214 (1.87%)
         occurrences all number
    9
    4
    Osteitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Osteoarthritis
         subjects affected / exposed
    5 / 218 (2.29%)
    6 / 214 (2.80%)
         occurrences all number
    7
    6
    Osteonecrosis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    11 / 218 (5.05%)
    4 / 214 (1.87%)
         occurrences all number
    14
    4
    Pain in jaw
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Periarthritis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Spinal osteoarthritis
         subjects affected / exposed
    3 / 218 (1.38%)
    1 / 214 (0.47%)
         occurrences all number
    3
    1
    Spinal pain
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Synovitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Tendonitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Trigger finger
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Borrelia infection
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    3 / 218 (1.38%)
    1 / 214 (0.47%)
         occurrences all number
    3
    1
    Cellulitis
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 218 (0.46%)
    4 / 214 (1.87%)
         occurrences all number
    1
    4
    Cystitis
         subjects affected / exposed
    3 / 218 (1.38%)
    2 / 214 (0.93%)
         occurrences all number
    4
    3
    Diverticulitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Ear infection
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Eczema infected
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Erysipelas
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    2
    Eye infection bacterial
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    2
    Folliculitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Gastric infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    5 / 218 (2.29%)
    1 / 214 (0.47%)
         occurrences all number
    5
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Genital infection fungal
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Genital infection viral
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gingivitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Herpes virus infection
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    2 / 218 (0.92%)
    3 / 214 (1.40%)
         occurrences all number
    2
    3
    Hordeolum
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    8 / 218 (3.67%)
    8 / 214 (3.74%)
         occurrences all number
    10
    8
    Labyrinthitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Laryngitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 218 (0.92%)
    3 / 214 (1.40%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    28 / 218 (12.84%)
    22 / 214 (10.28%)
         occurrences all number
    30
    25
    Omphalitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Oral bacterial infection
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Oral infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Paronychia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Parotitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Pneumonia
         subjects affected / exposed
    4 / 218 (1.83%)
    3 / 214 (1.40%)
         occurrences all number
    4
    3
    Respiratory tract infection
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Rhinitis
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Sinusitis
         subjects affected / exposed
    5 / 218 (2.29%)
    1 / 214 (0.47%)
         occurrences all number
    6
    1
    Tonsillitis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    2
    Tooth abscess
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 218 (5.05%)
    9 / 214 (4.21%)
         occurrences all number
    11
    10
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Urethritis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    9 / 218 (4.13%)
    10 / 214 (4.67%)
         occurrences all number
    9
    19
    Varicella
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    4 / 218 (1.83%)
    6 / 214 (2.80%)
         occurrences all number
    4
    6
    Wound infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Diabetes mellitus
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Dyslipidaemia
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Gout
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Hyper HDL cholesterolaemia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    2 / 218 (0.92%)
    22 / 214 (10.28%)
         occurrences all number
    2
    29
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Hyperlipidaemia
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2013
    - Added assessments for formation of anti-romosozumab antibodies at the month 1 and month 3 visits to allow a more comprehensive characterization of the anti-romosozumab antibody response. - Eligibility criteria were modified to allow participation of a wider range of patients; the minimum age was lowered from 60 to 55 years and the protocol-mandated off-treatment times for exclusionary medications were revised. - Retesting of serum calcium would be permitted within the screening window if the initial test indicated an elevated level of serum calcium within 1.1 times the upper limit of normal set by the central laboratory to account for the imprecision of serum calcium laboratory measurements. - Added a subset of up to 20 subjects to be recruited to undergo a transiliac bone biopsy at the month 12 visit to assess the effect of romosozumab treatment on parameters of bone histology and histomorphometry. - Added detail to the justification for romosozumab treatment duration and dosing regimen. - Expectations for serious adverse event reporting were redefined.

    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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