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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebo controlled efficacy and safety trial of intravenous zoledronic acid twice yearly compared to placebo in osteoporotic children treated with glucocorticoids.

    Summary
    EudraCT number
    		 2008-001252-52
    Trial protocol
    		 GB   FI   BE   DE   PL   Outside EU/EEA   HU   IT  
    Global end of trial date
    05 Mar 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Mar 2019
    First version publication date
    20 Sep 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CZOL446H2337
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00799266
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000057-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate that 0.05 mg/kg (max 5 mg) zoledronic acid administered every 6 months was superior to placebo for the change in lumbar spine bone mineral density (BMD) Z-score at Month 12 relative to baseline.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Dec 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    34
    EEA total number of subjects
    5
    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)
    12
    Adolescents (12-17 years)
    22
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 12 centers in 6 countries: Australia (1), Canada (5), Hungary (1), United Kingdom (2), Russian Federation (2), and South Africa (1).

    Pre-assignment
    Screening details
    		 The Participant Flow and Baseline Characteristics were done on the Intention-to-treat (ITT) population. All efficacy analyses were done on the Modified Intention-to-treat (MITT) population and all safety analyses were based on Safety population.

    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, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronic acid
    Arm description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Arm title
    		 Placebo
    Arm description
    		 Twice yearly i.v of infusion of Placebo (similar dosing as active drug)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    Twice yearly i.v of infusion of Placebo (similar dosing as active drug)

    Number of subjects in period 1
    		Zoledronic acid Placebo
    Started
    18
    16
    Modified Intention-to-treat (MITT)
    17
    16
    Safety Set
    18
    16
    Completed
    15
    15
    Not completed
    3
    1
         Subject withdrew consent
    3
    -
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Reporting group title
    Placebo
    Reporting group description
    		 Twice yearly i.v of infusion of Placebo (similar dosing as active drug)

    Reporting group values
    		 Zoledronic acid Placebo Total
    Number of subjects
    		 18 16 34
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 5 7 12
        Adolescents (12-17 years)
    		 13 9 22
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 13.0 ( 3.50 ) 12.3 ( 3.42 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 6 5 11
        Male
    		 12 11 23
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 13 14 27
        Black
    		 2 1 3
        Asian
    		 2 0 2
        Native American
    		 1 1 2
        Pacific Islander
    		 0 0 0
        Othe
    		 0 0 0
    Lumbar Spine Bone Mineral Density (BMD) Z-score
    Lumbar Spine Bone Mineral Density (BMD) Z-score in the Modified Intention-to-treat (MITT) population. No imputation done at Baseline.
    Units: Z-score
        arithmetic mean (standard deviation)
    		 -2.127 ( 0.7863 ) -2.379 ( 0.8975 ) -
    Lumbar Spine Bone Mineral Content (BMC)
    Lumbar Spine Bone Mineral Content (BMC) in the Modified Intention-to-treat (MITT) population. No imputation done at Baseline.
    Units: gram (g)
        arithmetic mean (standard deviation)
    		 31.886 ( 15.1062 ) 22.605 ( 6.6054 ) -
    Total body Bone Mineral Content (BMC)
    Total body Bone Mineral Content (BMC) in the Modified Intention-to-treat (MITT) population. No imputation done at Baseline.
    Units: gram (g)
        arithmetic mean (standard deviation)
    		 1550.556 ( 592.0670 ) 1050.610 ( 253.0759 ) -
    Serum Procollagen type 1 amino-terminal propeptide (P1NP)
    Serum Procollagen type 1 amino-terminal propeptide (P1NP) in the Modified Intention-to-treat (MITT) population. No imputation done at Baseline.
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    		 313.54 ( 284.541 ) 368.90 ( 235.226 ) -
    Serum Bone specific alkaline phosphatase (BSAP)
    Serum Bone specific alkaline phosphatase (BSAP) in the Modified Intention-to-treat (MITT) population. No imputation done at Baseline.
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    		 31.559 ( 22.6619 ) 43.414 ( 32.8200 ) -
    Serum Cross linked N-telopeptide (NTX)
    Serum Cross linked N-telopeptide (NTX) in the Modified Intention-to-treat (MITT) population. No imputation done at Baseline.
    Units: nmol BCE/L
        arithmetic mean (standard deviation)
    		 34.359 ( 22.0490 ) 39.192 ( 14.5823 ) -
    Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP-5b)
    Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP-5b) in the Modified Intention-to-treat (MITT) population. No imputation done at Baseline.
    Units: U/L
        arithmetic mean (standard deviation)
    		 7.010 ( 2.9998 ) 8.595 ( 4.5650 ) -
    Vertebral Morphometry (mid-to-posterior height ratio)
    Vertebral Morphometry (mid-to-posterior height ratio) in the Modified Intention-to-treat (MITT) population. Calculation was done using average ratio between mid-height and posterior height from L1 to L4 and analysis of covariance model was used with treatment, pooled centers, underlying condition treated with glucocordicoids and baseline value as explanatory variables and pooled centers as random effect.
    Units: mid-to-posterior height ratio
        arithmetic mean (standard deviation)
    		 0.982 ( 0.0428 ) 0.976 ( 0.0788 ) -
    Second metacarpal cortical width
    Second metacarpal cortical width in the Modified Intention-to-treat (MITT) population. Metacarpal cortical width of "0" was not included. An analysis of covariance model used with treatment, pooled centers, underlying condition treated with glucocorticoids at baseline value as explanatory variables and pooled centers as random effect.
    Units: millimeter (mm)
        arithmetic mean (standard deviation)
    		 0.40 ( 0.194 ) 0.41 ( 0.144 ) -

    End points

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    End points reporting groups
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Reporting group title
    Placebo
    Reporting group description
    		 Twice yearly i.v of infusion of Placebo (similar dosing as active drug)

    Primary: Mean Change from Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 12

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    End point title
    		 Mean Change from Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 12
    End point description
    Lumbar Spine Bone Mineral Density (BMD) Z-score was determined by the central imaging vendor before first treatment and at Month 12. The methods to be used to measure Lumbar Spine BMD Z-score were described in the respective DXA Manuals provided by central imaging vendor. Positive changes from baseline indicated an improvement in condition.
    End point type
    Primary
    End point timeframe
    Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: Z-score
        least squares mean (standard error)
    0.582 ( 0.1279 )
    0.168 ( 0.1449 )
    Statistical analysis title
    		 Lumbar Spine BMD Z-score at Month 12
    Comparison groups
    Placebo v Zoledronic acid
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.0392
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    0.414
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.022
         upper limit
    		 0.806
    Notes
    [1] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Mean Change from Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 6

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    End point title
    		 Mean Change from Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 6
    End point description
    Lumbar Spine Bone Mineral Density (BMD) Z-score was determined by the central imaging vendor before first treatment and at Month 6. The methods to be used to measure Lumbar Spine BMD Z-score were described in the respective DXA Manuals provided by central imaging vendor. Positive changes from baseline indicated an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: Z-score
        least squares mean (standard error)
    0.447 ( 0.13 )
    0.157 ( 0.14 )
    Statistical analysis title
    		 Lumbar Spine BMD Z-score at Month 6
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.1322
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.094
         upper limit
    		 0.673
    Notes
    [2] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Mean Change from Baseline in Lumbar Spine BMC at Month 6 and 12

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    End point title
    		 Mean Change from Baseline in Lumbar Spine BMC at Month 6 and 12
    End point description
    Lumbar Spine BMC was determined by the central imaging vendor before first treatment and at Months 6 and 12. The methods to be used to measure BMC were described in the respective DXA Manuals.
    End point type
    Secondary
    End point timeframe
    Month 6, Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: gram (g)
    least squares mean (standard error)
        Lumbar Spine (LS) BMC Change at Month 6
    4.110 ( 0.63 )
    2.131 ( 0.70 )
        Lumbar Spine (LS) BMC Change at Month 12
    6.450 ( 1.18 )
    4.295 ( 1.32 )
    Statistical analysis title
    		 Lumbar Spine BMC at Month 6
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.0409
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    1.979
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.089
         upper limit
    		 3.869
    Notes
    [3] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.
    Statistical analysis title
    		 Lumbar Spine BMC at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.234
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    2.155
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.488
         upper limit
    		 5.798
    Notes
    [4] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Mean Change from Baseline in total body BMC at Month 6 and 12

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    End point title
    		 Mean Change from Baseline in total body BMC at Month 6 and 12
    End point description
    Total body BMC was all determined by the central imaging vendor before first treatment and at Months 6 and 12. The methods to be used to measure BMC were described in the respective DXA Manuals.
    End point type
    Secondary
    End point timeframe
    Month 6, Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: gram (g)
    least squares mean (standard error)
        Total BMC Change at Month 6
    129.272 ( 24.23 )
    95.214 ( 28.74 )
        Total BMC Change at Month 12
    220.805 ( 42.74 )
    140.064 ( 51.90 )
    Statistical analysis title
    		 Total Body BMC at Month 6
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.3827
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    34.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.385
         upper limit
    		 113.502
    Notes
    [5] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.
    Statistical analysis title
    		 Total Body BMC at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.2634
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    80.741
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.602
         upper limit
    		 227.084
    Notes
    [6] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Mean Change from Baseline in Serum P1NP at Months 6 and 12

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    End point title
    		 Mean Change from Baseline in Serum P1NP at Months 6 and 12
    End point description
    Serum Procollagen type 1 amino-terminal propeptide (P1NP) was collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.
    End point type
    Secondary
    End point timeframe
    Month 6, Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: nanogram per milliliter (ng/mL)
    least squares mean (standard error)
        P1NP Change at Month 6
    -134.285 ( 48.80 )
    77.497 ( 56.15 )
        P1NP Change at Month 12
    -230.966 ( 59.1977 )
    150.166 ( 68.0933 )
    Statistical analysis title
    		 Serum P1NP at Month 6
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.0631
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -211.782
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -363.765
         upper limit
    		 -59.8
    Notes
    [7] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.
    Statistical analysis title
    		 Serum P1NP at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.0049
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -381.132
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -565.416
         upper limit
    		 -196.848
    Notes
    [8] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Mean Change from Baseline in BSAP at Months 6 and 12

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    End point title
    		 Mean Change from Baseline in BSAP at Months 6 and 12
    End point description
    Bone specific alkaline phosphatase (BSAP) were collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.
    End point type
    Secondary
    End point timeframe
    Month 6, Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: nanogram per milliliter (ng/mL)
    least squares mean (standard error)
        BSAP Change at Month 6
    -7.413 ( 3.63 )
    3.810 ( 4.05 )
        BSAP Change at Month 12
    -13.984 ( 4.3814 )
    6.450 ( 4.9010 )
    Statistical analysis title
    		 Serum BSAP at Month 6
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.2129
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -11.223
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.595
         upper limit
    		 0.149
    Notes
    [9] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.
    Statistical analysis title
    		 Serum BSAP at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.0215
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -20.435
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.96
         upper limit
    		 -6.909
    Notes
    [10] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Mean Change from Baseline in Serum NTX at Months 6 and 12

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    End point title
    		 Mean Change from Baseline in Serum NTX at Months 6 and 12
    End point description
    Serum Cross linked N-telopeptide (NTX) were collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.
    End point type
    Secondary
    End point timeframe
    Month 6, Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: nmol BCE/L
    least squares mean (standard error)
        NTX Change at Month 6
    -13.746 ( 4.23 )
    7.192 ( 4.74 )
        NTX Change at Month 12
    -20.134 ( 3.76 )
    7.440 ( 4.23 )
    Statistical analysis title
    		 Serum NTX at Month 6
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.0254
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -20.938
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.766
         upper limit
    		 -8.11
    Notes
    [11] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.
    Statistical analysis title
    		 Serum NTX at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.0002
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -27.574
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.037
         upper limit
    		 -16.111
    Notes
    [12] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Mean Change from Baseline in Serum TRAP-5b at Months 6 and 12

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    End point title
    		 Mean Change from Baseline in Serum TRAP-5b at Months 6 and 12
    End point description
    Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) was collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.
    End point type
    Secondary
    End point timeframe
    Month 6, Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: U/L
    least squares mean (standard error)
        TRAP 5b Change at Month 6
    -1.561 ( 0.65 )
    0.313 ( 0.74 )
        TRAP 5b Change at Month 12
    -1.728 ( 0.73 )
    0.109 ( 0.81 )
    Statistical analysis title
    		 Serum TRAP-5b at Month 6
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.2178
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -1.874
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.931
         upper limit
    		 0.182
    Notes
    [13] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.
    Statistical analysis title
    		 Serum TRAP-5b at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.184
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -1.837
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.103
         upper limit
    		 0.429
    Notes
    [14] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Mean Change from Baseline in Vertebral morphometry at Month 12

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    End point title
    		 Mean Change from Baseline in Vertebral morphometry at Month 12
    End point description
    Vertebral morphometry (or concave index) was calculated using the average ratio between mid-height and posterior height from L1 to L4 and performed by a central reader.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: Ratio
        least squares mean (standard error)
    -0.018 ( 0.01 )
    -0.0003 ( 0.01 )
    Statistical analysis title
    		 Vertebral morphometry at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.318
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -0.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.055
         upper limit
    		 0.019
    Notes
    [15] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Percentage of Patients with reduction in Pain at Months 3, 6, 9 and 12

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    End point title
    		 Percentage of Patients with reduction in Pain at Months 3, 6, 9 and 12
    End point description
    Pain was evaluated at each visit (in office and telephone visit) at randomization, Months 3, 6, 9 and 12 using the Faces Pain Scale-Revised (FPS-R). Children were selecting the face that best fits their pain. The pain score ranged from 0 (No Pain) to 10 (Very Much Pain). The reduction in pain from baseline by visit was evaluated based on whether or not patients had a decrease in their FPS-R from baseline. If pain remained the same or worsened from baseline a patient was classified as ‘0’ and if the pain scale decreased then the patient was classified as ‘1’.
    End point type
    Secondary
    End point timeframe
    Month 3, Month 6, Month 9 and Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: Percentage of Patients
    number (not applicable)
        Month 3
    37.5
    53.8
        Month 6
    37.5
    50.0
        Month 9
    33.3
    46.2
        Month 12
    31.3
    57.1
    Statistical analysis title
    		 Reduction in Pain at Month 3
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [16]
    P-value
    		 = 0.5226
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 5.2
    Notes
    [16] - Presented by treatment group and evaluated using a logistic regression model with treatment, pooled centers, underlying condition treated with glucocorticoids and baseline pain score as explanatory variables.
    Statistical analysis title
    		 Reduction in Pain at Month 6
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    P-value
    		 = 0.522 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    999.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 999.99
    Notes
    [17] - Presented by treatment group and evaluated using a logistic regression model with treatment, pooled centers, underlying condition treated with glucocorticoids and baseline pain score as explanatory variables.
    [18] - >999.99 (<0.01, >999.99)
    Statistical analysis title
    		 Reduction in Pain at Month 9
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [19]
    P-value
    		 = 0.6019
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 6.22
    Notes
    [19] - Presented by treatment group and evaluated using a logistic regression model with treatment, pooled centers, underlying condition treated with glucocorticoids and baseline pain score as explanatory variables.
    Statistical analysis title
    		 Reduction in Pain at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [20]
    P-value
    		 = 0.9652 [21]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.45
    Confidence interval
         level
    		 0.97%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 999.99
    Notes
    [20] - Presented by treatment group and evaluated using a logistic regression model with treatment, pooled centers, underlying condition treated with glucocorticoids and baseline pain score as explanatory variables.
    [21] - 0.45 (<0.01, >999.99)

    Secondary: Mean Change from Baseline in 2nd metacarpal cortical width at Month 12

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    End point title
    		 Mean Change from Baseline in 2nd metacarpal cortical width at Month 12
    End point description
    Left posteroanterior (PA) hand/wrist X-ray were taken at Visit 1 and at the Month 12 visit to assess bone age and the between-treatment differences for change in 2nd metacarpal cortical width at Month 12 relative to baseline. If a fracture of the left upper extremity precluded radiographic imaging, then the right hand was evaluated for this purpose. In this case, the right hand was be imaged at both Visit 1 and at Month 12. The information was used in the assessment of bone density.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: millimeter (mm)
        least squares mean (standard error)
    -0.01 ( 0.040 )
    0.03 ( 0.047 )
    Statistical analysis title
    		 2nd metacarpal cortical width at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [22]
    P-value
    		 = 0.5165
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.09
    Notes
    [22] - Difference in least squares (LS) = LS mean for the zoledronic acid group—LS mean for the placebo group.

    Secondary: Urinary concentration of zoledronic acid at Month 12

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    End point title
    		 Urinary concentration of zoledronic acid at Month 12 [23]
    End point description
    Urine was collected overnight or for at least 4 waking hours from all patients able to provide specimens, to measure urinary concentration of zoledronic acid at Month 12. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Month 12
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Urinary concentration of Zoledronic acid is only collected/apllicable for treatment arm "Zoledronic Acid"
    End point values
    		 Zoledronic acid
    Number of subjects analysed
    17
    Units: ng/mL
        arithmetic mean (standard deviation)
    1643.3 ( 2846.34 )
    No statistical analyses for this end point

    Secondary: Safety of zoledronic acid for the treatment of osteoporotic children treated with glucocorticoids

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    End point title
    		 Safety of zoledronic acid for the treatment of osteoporotic children treated with glucocorticoids
    End point description
    Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that zoledronic acid is safe for the treatment of osteoporotic children treated with glucocorticoids through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis done.
    End point type
    Secondary
    End point timeframe
    Baseline through Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    18
    16
    Units: Percentage of Participants
    number (not applicable)
        AEs by Primary System Organ Class (SOC)
    83.3
    75.0
        SAEs by Primary System Organ Class (SOC)
    27.8
    6.3
        Deaths by Primary System Organ Class (SOC)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with new vertebral fractures at Month 12

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    End point title
    		 Number of participants with new vertebral fractures at Month 12
    End point description
    New vertebral fractures were defined as fractures of Genant Grade 1 or higher that occurred at lumbar or thoracic spine from first dose infusion to the end of the study.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    17
    16
    Units: Participants
    0
    2
    Statistical analysis title
    		 New vertebral fractures at Month 12
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 [24]
    P-value
    		 = 0.2258
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [24] - The number and percentage of patients with new vertebral fractures at Month 12 were presented by treatment group and between-treatment differences were evaluated using Fisher’s exact test.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Zoledronic acid

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Zoledronic acid Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 18 (27.78%)
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (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
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (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
    Acute phase reaction
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (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
    Bone pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Zoledronic acid Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 18 (77.78%)
    12 / 16 (75.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Acute phase reaction
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    Chills
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 16 (12.50%)
         occurrences all number
    1
    2
    Pain
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 16 (6.25%)
         occurrences all number
    5
    2
    Thirst
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Sneezing
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Sleep talking
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood iron decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    Fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Fracture displacement
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Joint dislocation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Muscle strain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Tibia fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 16 (6.25%)
         occurrences all number
    3
    1
    Lethargy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Eye disorder
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    2
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    2
    2
    Tooth erosion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 16 (6.25%)
         occurrences all number
    4
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Keratosis pilaris
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Mechanical urticaria
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 16 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 18 (27.78%)
    1 / 16 (6.25%)
         occurrences all number
    5
    1
    Back pain
         subjects affected / exposed
    4 / 18 (22.22%)
    1 / 16 (6.25%)
         occurrences all number
    6
    1
    Flank pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Limb discomfort
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 16 (6.25%)
         occurrences all number
    4
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Polyarthritis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    2
    Influenza
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    Localised infection
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    2
    3
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
         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
    17 Jul 2008
    Amendment 1 clarified and amended the osteoporosis inclusion criteria including one or more low-trauma lower extremity long bone fractures and/or two or more low-trauma upper extremity long bone fractures. The following items were also amended to refine the protocol and further ensure patient safety: measuring bone-age at screening and Month 12; collecting pain assessment by FPS-R at baseline, Months 3, 6, 9 and 12; sitting height measured at baseline, Months 6 and 12 and implementing a DMC.
    23 Sep 2008
    Amendment 2 allowed patients to receive their first study drug infusion (Visit 2) in the out-patient setting at the clinical discretion of the study investigators. In addition, clarification was provided for the definition of “vitamin D and calcium supplementation” and “low trauma fracture”.
    15 Jul 2010
    Amendment 3 updated the original Schwartz Formula to the updated Schwartz formula: GFR (mL/min/1.73 m2) = k [height (m)/Scr (mg/dl)] k = 0.41 Amendment 3 also incorporated changes, which only applied to the UK sites for the enrollment of female patients of childbearing potential. These changes incorporated additional information on theoretical risks to a developing fetus in the pregnancy section and an additional supervised urine pregnancy test at Week 12.
    16 Aug 2013
    Amendment 4 extended the study population to include patients with GIO associated with underlying conditions other than chronic inflammatory disorders, relaxed the lumbar spine BMD Z-score inclusion criteria from -1.0 to -0.5 or worse, and included an assessment of zoledronic acid urine concentrations 6 months after dosing.
    26 Oct 2015
    Amendment 5 (based on Health Authority request) provided a risk/benefit statement previously included in the introduction section and then presented in a separate section in the protocol and allowed more countries to apply the contraceptive wording originally provided for UK sites only.

    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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