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    Clinical Trial Results:
    A Randomized Double-blind Study to Evaluate the Safety and Efficacy of Denosumab Compared With Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates

    Summary
    EudraCT number
    		 2012-001821-28
    Trial protocol
    		 BE   DE   ES   DK   PL  
    Global end of trial date
    09 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jul 2016
    First version publication date
    08 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20110153
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01732770
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thoudand 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
    09 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will compare the effectiveness of denosumab treatment every 6 months with once yearly zoledronic acid treatment on bone mineral density (BMD) at various skeletal sites.
    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
    07 Nov 2012
    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
    Denmark: 208
    Country: Number of subjects enrolled
    Poland: 157
    Country: Number of subjects enrolled
    Spain: 54
    Country: Number of subjects enrolled
    Belgium: 42
    Country: Number of subjects enrolled
    Canada: 83
    Country: Number of subjects enrolled
    United States: 73
    Country: Number of subjects enrolled
    Australia: 26
    Worldwide total number of subjects
    643
    EEA total number of subjects
    461
    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)
    190
    From 65 to 84 years
    434
    85 years and over
    19

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 37 centers in Belgium, Denmark, Poland, Spain, Canada, United States of America, and Australia. The first participant enrolled on 07 November 2012 and the last participant enrolled on 15 January 2014.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 allocation ratio to receive either denosumab or zoledronic acid. Randomization was stratified by screening serum type I collagen C-telopeptide (sCTX) values (< 0.3 ng/mL, 0.3 to 0.5 ng/mL).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronic Acid 5 mg Q12M
    Arm description
    		 Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Zoledronic Acid
    Investigational medicinal product code
    Other name
    Zometa
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered as an intravenous infusion, 5 mg in 100 mL of normal saline.

    Investigational medicinal product name
    Placebo to Denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by 1 mL subcutaneous injection

    Arm title
    		 Denosumab 60 mg Q6M
    Arm description
    		 Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Prolia®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection , 60 mg in 1 mL

    Investigational medicinal product name
    Placebo to Zoledronic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion, 100 mL of normal saline.

    Number of subjects in period 1
    		Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
    Started
    322
    321
    Received Study Treatment
    320
    320
    Completed
    312
    313
    Not completed
    10
    8
         Consent withdrawn by subject
    5
    3
         Decision by Sponsor
    2
    2
         Death
    1
    -
         Lost to follow-up
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zoledronic Acid 5 mg Q12M
    Reporting group description
    		 Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.

    Reporting group title
    Denosumab 60 mg Q6M
    Reporting group description
    		 Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.

    Reporting group values
    		 Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M Total
    Number of subjects
    		 322 321 643
    Age categorical
    Units: Subjects
        < 65 years
    		 89 101 190
        ≥ 65 years
    		 233 220 453
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.5 ± 7.7 68.5 ± 7.1 -
    Gender, Male/Female
    Units: participants
        Female
    		 322 321 643
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 314 309 623
        Asian
    		 4 5 9
        Other
    		 2 4 6
        Native Hawaiian or Other Pacific Islander
    		 1 2 3
        Black or African American
    		 0 1 1
        Multiple
    		 1 0 1
    Screening serum CTX
    Units: Subjects
        < 0.3 ng/mL
    		 242 239 481
        ≥ 0.3 ng/mL
    		 78 82 160
        Missing
    		 2 0 2
    Lumbar Spine Bone Mineral Density (BMD) T-score
    BMD was measured using dual-energy x-ray absorptiometry (DXA) of the lumbar spine. The T-score is a comparison of a person's bone density with that of a healthy 30-year-old of the same sex. Lower scores (more negative) mean lower bone density: A T-score of -2.5 or lower qualifies as osteoporosis and a T-score of -1.0 to -2.5 signifies osteopenia, meaning below-normal bone density without full osteoporosis.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.64 ± 0.86 -2.74 ± 0.83 -
    Total Hip BMD T-score
    Units: T-score
        arithmetic mean (standard deviation)
    		 -1.93 ± 0.8 -1.93 ± 0.74 -
    Femoral Neck BMD T-score
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.17 ± 0.68 -2.17 ± 0.66 -
    Prior Oral Bisphosphonate Duration
    Units: years
        arithmetic mean (standard deviation)
    		 6.35 ± 3.68 6.21 ± 3.84 -
    Body Mass Index (BMI)
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 24.31 ± 4.18 24.27 ± 3.99 -

    End points

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    End points reporting groups
    Reporting group title
    Zoledronic Acid 5 mg Q12M
    Reporting group description
    		 Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.

    Reporting group title
    Denosumab 60 mg Q6M
    Reporting group description
    		 Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.

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

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    End point title
    		 Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 - Non-inferiority Analysis
    End point description
    Bone mineral density (BMD) of the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging facility. This endpoint was analyzed in the primary efficacy analysis set which includes all randomized participants who have a baseline BMD measurement and at least one postbaseline BMD measurement. Any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, last observation carried forward [LOCF]).
    End point type
    Primary
    End point timeframe
    Baseline and Month 12
    End point values
    		 Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
    Number of subjects analysed
    312
    314
    Units: percent change
        least squares mean (confidence interval 95%)
    1.1 (0.7 to 1.5)
    3.2 (2.8 to 3.6)
    Statistical analysis title
    		 Primary Analysis of in Lumbar Spine BMD
    Statistical analysis description
    A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the non-inferiority analysis the 1-sided significance level was 2.5%. Treatment difference = denosumab – zoledronic acid.
    Comparison groups
    Zoledronic Acid 5 mg Q12M v Denosumab 60 mg Q6M
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Difference
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 2.6
    Notes
    [1] - The lower bound of the 2-sided 95% confidence interval (CI) of (denosumab – zoledronic acid) was compared with the non-inferiority margin of -0.46% for assessing non-inferiority.
    [2] - The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.

    Secondary: Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis

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    End point title
    		 Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis
    End point description
    BMD of the hip was measured by DXA. DXA scans were analyzed by a central imaging facility. Analyzed in the primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12
    End point values
    		 Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
    Number of subjects analysed
    309
    311
    Units: percent change
        least squares mean (confidence interval 95%)
    0.6 (0.3 to 0.8)
    1.9 (1.7 to 2.2)
    Statistical analysis title
    		 Primary Analysis of Total Hip BMD
    Statistical analysis description
    A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the non-inferiority analysis the 1-sided significance level was 2.5%. Treatment difference = denosumab – zoledronic acid.
    Comparison groups
    Zoledronic Acid 5 mg Q12M v Denosumab 60 mg Q6M
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Difference
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.7
    Notes
    [3] - The lower bound of the 2-sided 95% CI) of (denosumab – zoledronic acid) was compared with the non-inferiority margin of -0.51% for assessing non-inferiority.
    [4] - The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.

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

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    End point title
    		 Percent Change From Baseline in Lumbar Spine BMD at Month 12 - Superiority Analysis
    End point description
    Analysis was performed in the primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12
    End point values
    		 Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
    Number of subjects analysed
    312
    314
    Units: percent change
        least squares mean (confidence interval 95%)
    1.1 (0.7 to 1.5)
    3.2 (2.8 to 3.6)
    Statistical analysis title
    		 Secondary Analysis of Lumbar Spine BMD
    Statistical analysis description
    A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the superiority analysis the 2-sided significance level was 5%. Treatment difference = denosumab – zoledronic acid.
    Comparison groups
    Zoledronic Acid 5 mg Q12M v Denosumab 60 mg Q6M
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Difference
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 2.6
    Notes
    [5] - The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.

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

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    End point title
    		 Percent Change From Baseline in Total Hip BMD at Month 12 - Superiority Analysis
    End point description
    Analysis was performed in the primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12
    End point values
    		 Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
    Number of subjects analysed
    309
    311
    Units: percent change
        least squares mean (confidence interval 95%)
    0.6 (0.3 to 0.8)
    1.9 (1.7 to 2.2)
    Statistical analysis title
    		 Secondary Analysis of Total Hip BMD
    Statistical analysis description
    A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the superiority analysis the 2-sided significance level was 5%. Treatment difference = denosumab – zoledronic acid.
    Comparison groups
    Zoledronic Acid 5 mg Q12M v Denosumab 60 mg Q6M
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Difference
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.7
    Notes
    [6] - The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.

    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
    17.1
    Reporting groups
    Reporting group title
    Denosumab 60 mg Q6M
    Reporting group description
    		 Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.

    Reporting group title
    Zoledronic Acid 5 mg Q12M
    Reporting group description
    		 Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.

    Serious adverse events
    		 Denosumab 60 mg Q6M Zoledronic Acid 5 mg Q12M
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 320 (7.81%)
    29 / 320 (9.06%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer female
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage I
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleomorphic adenoma
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (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
    Tendon operation
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee operation
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein operation
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (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
    Drug interaction
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         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
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         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
    Concussion
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 320 (0.63%)
    2 / 320 (0.63%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         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
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral thrombosis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 320 (0.63%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         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 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 320 (0.31%)
    2 / 320 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (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
    Hyponatraemia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 320 (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: 5%
    Non-serious adverse events
    		 Denosumab 60 mg Q6M Zoledronic Acid 5 mg Q12M
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 320 (4.69%)
    22 / 320 (6.88%)
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 320 (4.69%)
    22 / 320 (6.88%)
         occurrences all number
    18
    29

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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