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Trial record 1 of 1 for:    NCT01631214
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Study to Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis (ARCH)

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ClinicalTrials.gov Identifier: NCT01631214
Recruitment Status : Completed
First Posted : June 29, 2012
Results First Posted : December 12, 2018
Last Update Posted : December 17, 2018
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Postmenopausal Women With Osteoporosis
Interventions Biological: Romosozumab
Drug: Alendronate
Drug: Placebo to Romosozumab
Drug: Placebo to Alendronate
Enrollment 4093
Recruitment Details The study was conducted at 270 centers in 41 countries globally from 04 May 2012 to 29 June 2017.
Pre-assignment Details Participants were randomized in a 1:1 ratio to receive romosozumab or alendronate for 12 months. Randomization was stratified by age (< 75 vs. ≥ 75 years). After completion of the double-blind trial period, all participants received open-label alendronate until the end of the trial, with blinding to the initial treatment assignment maintained.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Period Title: Overall Study
Started 2047 2046
Received Double-blind Treatment 2040 2038
Completed Double-blind Period [1] 1823 1831
Completed Primary Analysis Period [2] 1576 1574
Completed 1503 1523
Not Completed 544 523
Reason Not Completed
Withdrawal by Subject             276             290
Death             113             106
Lost to Follow-up             54             40
Adverse Event             45             45
Other             22             19
Noncompliance             16             15
Requirement for Alternative Therapy             8             3
Protocol Deviation             4             3
Ineligibility determined             5             2
Administrative Decision             1             0
[1]
Completion of the double-blind period is defined as having attended the month 12 study visit.
[2]
Completion of the primary analysis period is defined as ongoing at the primary analysis cutoff date.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate Total
Hide Arm/Group Description Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. Total of all reporting groups
Overall Number of Baseline Participants 2047 2046 4093
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2047 participants 2046 participants 4093 participants
74.2  (7.5) 74.4  (7.5) 74.3  (7.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2047 participants 2046 participants 4093 participants
Female
2047
 100.0%
2046
 100.0%
4093
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2047 participants 2046 participants 4093 participants
Hispanic or Latino
662
  32.3%
631
  30.8%
1293
  31.6%
Not Hispanic or Latino
1385
  67.7%
1415
  69.2%
2800
  68.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2047 participants 2046 participants 4093 participants
American Indian or Alaska Native
7
   0.3%
5
   0.2%
12
   0.3%
Asian
149
   7.3%
137
   6.7%
286
   7.0%
Black or African American
23
   1.1%
19
   0.9%
42
   1.0%
Native Hawaiian or Other Pacific Islander
2
   0.1%
0
   0.0%
2
   0.0%
White
1415
  69.1%
1447
  70.7%
2862
  69.9%
Multiple
4
   0.2%
2
   0.1%
6
   0.1%
Other
446
  21.8%
436
  21.3%
882
  21.5%
Missing
1
   0.0%
0
   0.0%
1
   0.0%
Age Strata per Randomization  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2047 participants 2046 participants 4093 participants
< 75 years
976
  47.7%
973
  47.6%
1949
  47.6%
≥ 75 years
1071
  52.3%
1073
  52.4%
2144
  52.4%
Severe Vertebral Fracture   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2047 participants 2046 participants 4093 participants
Presence
1321
  64.5%
1369
  66.9%
2690
  65.7%
Absence
726
  35.5%
677
  33.1%
1403
  34.3%
[1]
Measure Description: A participant had a prevalent vertebral fracture if any vertebra from T4 to L4 had a grade of 3 at baseline based on an assessment of spinal radiographs using the Genant Semiquantitative Scoring Method. A grade 3 fracture is defined as approximately 40% or greater reduction in anterior, middle, and/or posterior height.
Total Hip Bone Mineral Density (BMD) T-score   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2047 participants 2046 participants 4093 participants
≤ -2.5
1384
  67.6%
1356
  66.3%
2740
  66.9%
> -2.5
662
  32.3%
690
  33.7%
1352
  33.0%
Missing
1
   0.0%
0
   0.0%
1
   0.0%
[1]
Measure Description: BMD was measured using dual-energy x-ray absorptiometry (DXA). 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.
1.Primary Outcome
Title Percentage of Participants With New Vertebral Fractures Through Month 24
Hide Description

All fracture assessments were performed by blinded central imaging readers.

New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale:

  • Grade 0 (Normal) = no fracture;
  • Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior);
  • Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height;
  • Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height.

Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method.

Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with a baseline and ≥ 1 postbaseline evaluation of vertebral fracture, including participants who had vertebrae with missing Genant semiquantitative scores at baseline whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1834 1825
Measure Type: Number
Unit of Measure: percentage of participants
8.0 4.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The primary endpoints were tested at the 5% level (2-sided), accounting for multiplicity using the Hochberg procedure. If the larger of the 2 p-values was significant at the 0.05 level (2-sided), the statistical testing continued to the secondary endpoint in the testing sequence.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Based on a logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.48
Confidence Interval (2-Sided) 95%
0.36 to 0.64
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.15
Estimation Comments Values < 1 for odds ratio favor romosozumab. The standard error (SE) represents the standard error of log(odds ratio).
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments

The risk ratio (ratio of percentages, Romosozumab:Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T-score at the total hip (≤ -2.5, > -2.5).

Values < 1 for risk ratio favor romosozumab.

Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.50
Confidence Interval (2-Sided) 95%
0.38 to 0.66
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.14
Estimation Comments SE represents the standard error of log (risk ratio).
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments

The absolute risk reduction (difference in percentages, Alendronate - Romosozumab) was based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.

Positive values for absolute risk reduction favor romosozumab.

Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Absolute risk reduction
Estimated Value 4.03
Confidence Interval (2-Sided) 95%
2.50 to 5.57
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.78
Estimation Comments [Not Specified]
2.Primary Outcome
Title Percentage of Participants With a Clinical Fracture at the Primary Analysis
Hide Description All fracture assessments were performed by blinded central imaging readers. Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants. Missing values for clinical fractures were imputed using last observation carried forward.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
13.0 9.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The primary endpoints were tested at the 5% level (2-sided), accounting for multiplicity using the Hochberg procedure. If the larger of the 2 p-values was significant at the 0.05 level (2-sided), the statistical testing continued to the secondary endpoint in the testing sequence.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 95%
0.61 to 0.88
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.09
Estimation Comments Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio)
3.Secondary Outcome
Title Percentage of Participants With a Nonvertebral Fracture at the Primary Analysis
Hide Description A nonvertebral fracture was defined as a documented fracture excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
10.6 8.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments If the 2 primary endpoints and the specified BMD secondary endpoints were all significant, the nonvertebral fracture at the primary analysis was evaluated based on a 1-sided test (overall α=0.025) determined by the Lan-DeMets alpha spending function that approximates a Pocock boundary, 0.0233 (1-sided).
Statistical Test of Hypothesis P-Value 0.040
Comments The adjusted 2-sided p-value is reported.
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.81
Confidence Interval (2-Sided) 95%
0.66 to 0.99
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.10
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

4.Secondary Outcome
Title Percentage of Participants With Any Fracture at the Primary Analysis
Hide Description All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures.
Time Frame The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
19.1 13.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.56 to 0.76
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.08
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

5.Secondary Outcome
Title Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 24
Hide Description

A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4 according to the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale:

  • Grade 0 (Normal) = no fracture;
  • Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior);
  • Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height;
  • Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height.

Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method.

Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with a baseline and ≥ 1 postbaseline evaluation of vertebral fracture, including participants who had vertebrae with missing Genant semiquantitative scores at baseline whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1834 1825
Measure Type: Number
Unit of Measure: percentage of participants
9.2 4.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Based on logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.49
Confidence Interval (2-Sided) 95%
0.37 to 0.64
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.14
Estimation Comments Values < 1 for odds ratio favor romosozumab. The standard error (SE) represents the standard error of log(odds ratio).
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments

The risk ratio (ratio of percentages, Romosozumab:Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T-score at the total hip (≤ -2.5, > -2.5).

Values < 1 for risk ratio favor romosozumab.

Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.52
Confidence Interval (2-Sided) 95%
0.40 to 0.66
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.13
Estimation Comments SE represents the standard error of log (risk ratio).
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments

The absolute risk reduction (difference in percentages, Alendronate - Romosozumab) was based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.

Positive values for absolute risk reduction favor romosozumab.

Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Absolute risk reduction
Estimated Value 4.44
Confidence Interval (2-Sided) 95%
2.80 to 6.08
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.84
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Participants With a Major Nonvertebral Fracture at the Primary Analysis
Hide Description Major nonvertebral fractures included a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip.
Time Frame The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
9.6 7.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 95%
0.59 to 0.90
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.11
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

7.Secondary Outcome
Title Percentage of Participants With a Hip Fracture at the Primary Analysis
Hide Description Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
Time Frame The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
3.2 2.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.015
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.42 to 0.92
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.20
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

8.Secondary Outcome
Title Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 24
Hide Description A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4 according to the Genant Semiquantitative Scoring method. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit. Incident vertebral fractures were confirmed by a second independent reader.
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with a baseline and ≥ 1 postbaseline evaluation of vertebral fracture, including participants who had vertebrae with missing Genant semiquantitative scores at baseline whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1834 1825
Measure Type: Number
Unit of Measure: percentage of participants
2.5 1.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.008
Comments [Not Specified]
Method Regression, Logistic
Comments Based on logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.51
Confidence Interval (2-Sided) 95%
0.31 to 0.85
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.25
Estimation Comments Values < 1 for odds ratio favor romosozumab. The standard error (SE) represents the standard error of log(odds ratio).
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments

The risk ratio (ratio of percentages, Romosozumab:Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T-score at the total hip (≤ -2.5, > -2.5).

Values < 1 for risk ratio favor romosozumab.

Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.52
Confidence Interval (2-Sided) 95%
0.32 to 0.85
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.25
Estimation Comments SE represents the standard error of log (risk ratio).
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments

The absolute risk reduction (difference in percentages, Alendronate - Romosozumab) was based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.

Positive values for absolute risk reduction favor romosozumab.

Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Absolute risk reduction
Estimated Value 1.21
Confidence Interval (2-Sided) 95%
0.33 to 2.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.45
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Percentage of Participants With a Clinical Fracture Through Month 24
Hide Description Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants; Missing values for clinical fractures were imputed using last observation carried forward.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
9.6 7.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.005
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.59 to 0.91
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.11
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

10.Secondary Outcome
Title Percentage of Participants With a Nonvertebral Fracture Through Month 24
Hide Description A nonvertebral fracture was defined as a documented fracture excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
7.8 6.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.074
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.81
Confidence Interval (2-Sided) 95%
0.64 to 1.02
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.12
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

11.Secondary Outcome
Title Percentage of Participants With a Hip Fracture Through Month 24
Hide Description Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
2.1 1.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.17
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
0.46 to 1.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.24
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

12.Secondary Outcome
Title Percentage of Participants With a Clinical Vertebral Fracture Through Month 24
Hide Description A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic.
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants; Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
2.1 0.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.41
Confidence Interval (2-Sided) 95%
0.24 to 0.71
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.28
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

13.Secondary Outcome
Title Percentage of Participants With a Clinical Fracture Through Month 12
Hide Description Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants; Missing values for clinical fractures were imputed using last observation carried forward.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
5.4 3.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.027
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
0.54 to 0.96
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.15
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

14.Secondary Outcome
Title Percentage of Participants With New Vertebral Fractures Through Month 12
Hide Description

New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale:

  • Grade 0 (Normal) = no fracture;
  • Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior);
  • Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height;
  • Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height.

Incident vertebral fractures were confirmed by a second independent reader.

Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with a baseline and ≥ 1 postbaseline evaluation of vertebral fracture, including participants who had vertebrae with missing Genant semiquantitative scores at baseline whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1703 1696
Measure Type: Number
Unit of Measure: percentage of participants
5.0 3.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.008
Comments [Not Specified]
Method Regression, Logistic
Comments Based on a logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.44 to 0.89
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.18
Estimation Comments Values < 1 for odds ratio favor romosozumab. The standard error (SE) represents the standard error of log(odds ratio).
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments

The risk ratio (ratio of percentages, Romosozumab:Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T-score at the total hip (≤ -2.5, > -2.5).

Values < 1 for risk ratio favor romosozumab.

Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.64
Confidence Interval (2-Sided) 95%
0.46 to 0.89
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.17
Estimation Comments SE represents the standard error of log (risk ratio).
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments

The absolute risk reduction (difference in percentages, Alendronate - Romosozumab) was based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline.

Positive values for absolute risk reduction favor romosozumab.

Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Absolute risk reduction
Estimated Value 1.84
Confidence Interval (2-Sided) 95%
0.51 to 3.17
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.68
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Percentage of Participants With Any Fracture Through Month 12
Hide Description All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
9.2 6.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.57 to 0.88
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.11
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

16.Secondary Outcome
Title Percentage of Participants With a Nonvertebral Fracture Through Month 12
Hide Description A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
4.6 3.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.057
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.54 to 1.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.16
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

17.Secondary Outcome
Title Percentage of Participants With a Hip Fracture Through Month 12
Hide Description Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
1.1 0.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.19
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.64
Confidence Interval (2-Sided) 95%
0.33 to 1.26
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.34
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

18.Secondary Outcome
Title Percentage of Participants With a Major Osteoporotic Fracture Through Month 12
Hide Description Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
4.2 3.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.053
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
0.52 to 1.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.17
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

19.Secondary Outcome
Title Percentage of Participants With a Clinical Vertebral Fracture Through Month 12
Hide Description A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants; Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 2047 2046
Measure Type: Number
Unit of Measure: percentage of participants
0.9 0.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value 0.14
Comments [Not Specified]
Method Regression, Cox
Comments Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.56
Confidence Interval (2-Sided) 95%
0.26 to 1.22
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.39
Estimation Comments

Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline.

Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio).

20.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 24
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 24
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1577 1571
Least Squares Mean (Standard Error)
Unit of Measure: percent change
7.2  (0.2) 15.3  (0.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an analysis of covariance (ANCOVA) model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 8.1
Confidence Interval (2-Sided) 95%
7.58 to 8.57
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.3
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 24
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 24
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1627 1622
Least Squares Mean (Standard Error)
Unit of Measure: percent change
3.5  (0.1) 7.2  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.8
Confidence Interval (2-Sided) 95%
3.42 to 4.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.2
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at at Month 24
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 24
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1627 1622
Least Squares Mean (Standard Error)
Unit of Measure: percent change
2.3  (0.2) 6.0  (0.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.8
Confidence Interval (2-Sided) 95%
3.40 to 4.14
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.2
Estimation Comments [Not Specified]
23.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 12
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 12
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1718 1722
Least Squares Mean (Standard Error)
Unit of Measure: percent change
5.0  (0.1) 13.7  (0.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 8.7
Confidence Interval (2-Sided) 95%
8.31 to 9.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.2
Estimation Comments [Not Specified]
24.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density at the Total Hip at Month 12
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 12
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1781 1781
Least Squares Mean (Standard Error)
Unit of Measure: percent change
2.8  (0.1) 6.2  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.3
Confidence Interval (2-Sided) 95%
3.03 to 3.60
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments [Not Specified]
25.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density at the Femoral Neck at Month 12
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 12
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1781 1781
Least Squares Mean (Standard Error)
Unit of Measure: percent change
1.7  (0.1) 4.9  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.2
Confidence Interval (2-Sided) 95%
2.90 to 3.54
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.2
Estimation Comments [Not Specified]
26.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Lumbar Spine at Month 36
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 36
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1597 1593
Least Squares Mean (Standard Error)
Unit of Measure: percent change
7.8  (0.2) 15.2  (0.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 7.4
Confidence Interval (2-Sided) 95%
6.84 to 7.89
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.3
Estimation Comments [Not Specified]
27.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 36
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 36
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1653 1653
Least Squares Mean (Standard Error)
Unit of Measure: percent change
3.5  (0.1) 7.2  (0.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.7
Confidence Interval (2-Sided) 95%
3.29 to 4.02
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.2
Estimation Comments [Not Specified]
28.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 36
Hide Description Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline and month 36
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value.
Arm/Group Title Alendronate/Alendronate Romosozumab/Alendronate
Hide Arm/Group Description:
Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study.
Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Overall Number of Participants Analyzed 1653 1653
Least Squares Mean (Standard Error)
Unit of Measure: percent change
2.4  (0.2) 6.0  (0.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alendronate/Alendronate, Romosozumab/Alendronate
Comments Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.
Type of Statistical Test Superiority
Comments This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided).
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.6
Confidence Interval (2-Sided) 95%
3.18 to 3.97
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.2
Estimation Comments [Not Specified]
Time Frame Double-blind treatment phase: 12 months. Overall study period: From first dose of study drug up to the end of study for participants who received at any open-label dose and up to the end of the double-blind period for participants who did not. The median duration of follow-up time was 36 months.
Adverse Event Reporting Description

The safety analysis set included all randomized subjects who received ≥ 1 active dose of investigational product in the 12-month double-blind alendronate-controlled study period. Two participants randomized to alendronate received romosozumab in error and are counted in the romosozumab group for safety.

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

 
Arm/Group Title Double-blind Period: Alendronate 70 mg QW Double-blind Period: Romosozumab 210 mg QM Overall Study: Alendronate / Alendronate Overall Study: Romosozumab / Alendronate
Hide Arm/Group Description Participants received 70 mg alendronate once a week (QW) and placebo to romosozumab subcutaneously once a month for 12 months during the double-blind treatment period. Participants received 210 mg romosozumab subcutaneously once a month (QM) and placebo to alendronate orally once a week for the first 12 months during the double-blind treatment period. Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. Participants received 210 romosozumab mg subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
All-Cause Mortality
Double-blind Period: Alendronate 70 mg QW Double-blind Period: Romosozumab 210 mg QM Overall Study: Alendronate / Alendronate Overall Study: Romosozumab / Alendronate
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   22/2014 (1.09%)   30/2040 (1.47%)   103/2014 (5.11%)   101/2040 (4.95%) 
Hide Serious Adverse Events
Double-blind Period: Alendronate 70 mg QW Double-blind Period: Romosozumab 210 mg QM Overall Study: Alendronate / Alendronate Overall Study: Romosozumab / Alendronate
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   278/2014 (13.80%)   262/2040 (12.84%)   638/2014 (31.68%)   611/2040 (29.95%) 
Blood and lymphatic system disorders         
Anaemia  1  3/2014 (0.15%)  1/2040 (0.05%)  9/2014 (0.45%)  7/2040 (0.34%) 
Anaemia of chronic disease  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Anaemia vitamin B12 deficiency  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Haemorrhagic anaemia  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Hypochromic anaemia  1  1/2014 (0.05%)  0/2040 (0.00%)  3/2014 (0.15%)  0/2040 (0.00%) 
Iron deficiency anaemia  1  2/2014 (0.10%)  1/2040 (0.05%)  4/2014 (0.20%)  2/2040 (0.10%) 
Leukopenia  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Microcytic anaemia  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Neutropenia  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Normochromic normocytic anaemia  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Splenomegaly  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Thrombocytopenia  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  2/2040 (0.10%) 
Cardiac disorders         
Acute coronary syndrome  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Acute left ventricular failure  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Acute myocardial infarction  1  2/2014 (0.10%)  8/2040 (0.39%)  15/2014 (0.74%)  16/2040 (0.78%) 
Angina pectoris  1  3/2014 (0.15%)  2/2040 (0.10%)  6/2014 (0.30%)  7/2040 (0.34%) 
Angina unstable  1  2/2014 (0.10%)  2/2040 (0.10%)  7/2014 (0.35%)  5/2040 (0.25%) 
Aortic valve stenosis  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Arrhythmia  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  2/2040 (0.10%) 
Arrhythmia supraventricular  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  2/2040 (0.10%) 
Arteriospasm coronary  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Atrial fibrillation  1  4/2014 (0.20%)  3/2040 (0.15%)  17/2014 (0.84%)  12/2040 (0.59%) 
Atrial flutter  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  2/2040 (0.10%) 
Atrioventricular block complete  1  3/2014 (0.15%)  0/2040 (0.00%)  4/2014 (0.20%)  1/2040 (0.05%) 
Bradyarrhythmia  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Bradycardia  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Cardiac arrest  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  2/2040 (0.10%) 
Cardiac disorder  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Cardiac failure  1  5/2014 (0.25%)  5/2040 (0.25%)  25/2014 (1.24%)  18/2040 (0.88%) 
Cardiac failure acute  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Cardiac failure chronic  1  1/2014 (0.05%)  0/2040 (0.00%)  5/2014 (0.25%)  1/2040 (0.05%) 
Cardiac failure congestive  1  5/2014 (0.25%)  2/2040 (0.10%)  12/2014 (0.60%)  9/2040 (0.44%) 
Cardiac tamponade  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Cardiac valve disease  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  1/2040 (0.05%) 
Cardio-respiratory arrest  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Cardiogenic shock  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  3/2040 (0.15%) 
Cardiomyopathy  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Cardiopulmonary failure  1  1/2014 (0.05%)  1/2040 (0.05%)  3/2014 (0.15%)  1/2040 (0.05%) 
Coronary artery disease  1  0/2014 (0.00%)  1/2040 (0.05%)  5/2014 (0.25%)  3/2040 (0.15%) 
Coronary artery occlusion  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Ischaemic cardiomyopathy  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  1/2040 (0.05%) 
Left ventricular failure  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  1/2040 (0.05%) 
Mitral valve incompetence  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Myocardial fibrosis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Myocardial infarction  1  3/2014 (0.15%)  5/2040 (0.25%)  8/2014 (0.40%)  8/2040 (0.39%) 
Myocardial ischaemia  1  1/2014 (0.05%)  3/2040 (0.15%)  4/2014 (0.20%)  6/2040 (0.29%) 
Palpitations  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Pericardial effusion  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Sinus bradycardia  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Sinus node dysfunction  1  1/2014 (0.05%)  0/2040 (0.00%)  5/2014 (0.25%)  1/2040 (0.05%) 
Stress cardiomyopathy  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  2/2040 (0.10%) 
Supraventricular extrasystoles  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Supraventricular tachycardia  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Tachycardia  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Tricuspid valve incompetence  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Ventricular extrasystoles  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Ventricular tachycardia  1  0/2014 (0.00%)  2/2040 (0.10%)  0/2014 (0.00%)  2/2040 (0.10%) 
Ear and labyrinth disorders         
Vertigo  1  1/2014 (0.05%)  2/2040 (0.10%)  2/2014 (0.10%)  5/2040 (0.25%) 
Vertigo positional  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Vestibular ataxia  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Endocrine disorders         
Basedow's disease  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Goitre  1  2/2014 (0.10%)  0/2040 (0.00%)  4/2014 (0.20%)  1/2040 (0.05%) 
Hypercorticoidism  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Hyperparathyroidism  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Hyperthyroidism  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Toxic goitre  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Eye disorders         
Amaurosis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Cataract  1  4/2014 (0.20%)  3/2040 (0.15%)  9/2014 (0.45%)  11/2040 (0.54%) 
Diplopia  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Endocrine ophthalmopathy  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Entropion  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Glaucoma  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Macular fibrosis  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Neovascular age-related macular degeneration  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Retinal artery thrombosis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Retinal detachment  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Retinal haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Strabismus  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Visual impairment  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Vitreous prolapse  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Gastrointestinal disorders         
Abdominal adhesions  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Abdominal hernia  1  2/2014 (0.10%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Abdominal pain  1  1/2014 (0.05%)  1/2040 (0.05%)  3/2014 (0.15%)  5/2040 (0.25%) 
Abdominal pain upper  1  1/2014 (0.05%)  2/2040 (0.10%)  1/2014 (0.05%)  2/2040 (0.10%) 
Anal incontinence  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Chronic gastritis  1  1/2014 (0.05%)  2/2040 (0.10%)  2/2014 (0.10%)  2/2040 (0.10%) 
Colitis ulcerative  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Constipation  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  3/2040 (0.15%) 
Crohn's disease  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Diarrhoea  1  0/2014 (0.00%)  4/2040 (0.20%)  3/2014 (0.15%)  6/2040 (0.29%) 
Diverticulum  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Diverticulum intestinal  1  2/2014 (0.10%)  1/2040 (0.05%)  3/2014 (0.15%)  2/2040 (0.10%) 
Diverticulum intestinal haemorrhagic  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Duodenal polyp  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Duodenal ulcer  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  1/2040 (0.05%) 
Duodenal ulcer perforation  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Dyspepsia  1  0/2014 (0.00%)  2/2040 (0.10%)  1/2014 (0.05%)  2/2040 (0.10%) 
Dysphagia  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Enteritis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Enterocolitis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Erosive oesophagitis  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Femoral hernia  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Femoral hernia incarcerated  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Food poisoning  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Gastric ulcer  1  1/2014 (0.05%)  1/2040 (0.05%)  3/2014 (0.15%)  4/2040 (0.20%) 
Gastric ulcer haemorrhage  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Gastritis  1  1/2014 (0.05%)  1/2040 (0.05%)  6/2014 (0.30%)  4/2040 (0.20%) 
Gastrointestinal haemorrhage  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  6/2040 (0.29%) 
Gastrointestinal inflammation  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Gastrooesophageal reflux disease  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  4/2040 (0.20%) 
Haemorrhoidal haemorrhage  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  2/2040 (0.10%) 
Hiatus hernia  1  0/2014 (0.00%)  2/2040 (0.10%)  0/2014 (0.00%)  2/2040 (0.10%) 
Ileus  1  1/2014 (0.05%)  0/2040 (0.00%)  3/2014 (0.15%)  0/2040 (0.00%) 
Inguinal hernia  1  1/2014 (0.05%)  1/2040 (0.05%)  4/2014 (0.20%)  2/2040 (0.10%) 
Inguinal hernia strangulated  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Intestinal haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Intestinal obstruction  1  0/2014 (0.00%)  2/2040 (0.10%)  2/2014 (0.10%)  4/2040 (0.20%) 
Intestinal ulcer  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Intra-abdominal haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Intussusception  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Irritable bowel syndrome  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Large intestinal stenosis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Large intestinal ulcer  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Large intestine polyp  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Lower gastrointestinal haemorrhage  1  0/2014 (0.00%)  1/2040 (0.05%)  2/2014 (0.10%)  2/2040 (0.10%) 
Mechanical ileus  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Melaena  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Mesenteric arterial occlusion  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Nausea  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Obstruction gastric  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Oesophageal ulcer  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Pancreatitis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  2/2040 (0.10%) 
Pancreatitis acute  1  1/2014 (0.05%)  2/2040 (0.10%)  2/2014 (0.10%)  2/2040 (0.10%) 
Peptic ulcer  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  3/2040 (0.15%) 
Peptic ulcer perforation  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Peritoneal adhesions  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Peritoneal haemorrhage  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Rectal haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  2/2040 (0.10%) 
Rectal prolapse  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Salivary gland calculus  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  1/2040 (0.05%) 
Upper gastrointestinal haemorrhage  1  0/2014 (0.00%)  3/2040 (0.15%)  0/2014 (0.00%)  5/2040 (0.25%) 
Volvulus  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Vomiting  1  1/2014 (0.05%)  1/2040 (0.05%)  2/2014 (0.10%)  3/2040 (0.15%) 
General disorders         
Adverse event  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Asthenia  1  1/2014 (0.05%)  1/2040 (0.05%)  1/2014 (0.05%)  3/2040 (0.15%) 
Chest pain  1  0/2014 (0.00%)  2/2040 (0.10%)  2/2014 (0.10%)  3/2040 (0.15%) 
Death  1  2/2014 (0.10%)  1/2040 (0.05%)  21/2014 (1.04%)  14/2040 (0.69%) 
Feeling abnormal  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
General physical health deterioration  1  0/2014 (0.00%)  1/2040 (0.05%)  2/2014 (0.10%)  2/2040 (0.10%) 
Hypothermia  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Impaired healing  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Malaise  1  1/2014 (0.05%)  1/2040 (0.05%)  1/2014 (0.05%)  2/2040 (0.10%) 
Multiple organ dysfunction syndrome  1  0/2014 (0.00%)  1/2040 (0.05%)  2/2014 (0.10%)  3/2040 (0.15%) 
Non-cardiac chest pain  1  2/2014 (0.10%)  1/2040 (0.05%)  4/2014 (0.20%)  1/2040 (0.05%) 
Oedema peripheral  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  1/2040 (0.05%) 
Pain  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  1/2040 (0.05%) 
Peripheral swelling  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Pyrexia  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Strangulated hernia  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Sudden death  1  2/2014 (0.10%)  1/2040 (0.05%)  4/2014 (0.20%)  6/2040 (0.29%) 
Ulcer haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Vessel puncture site haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Hepatobiliary disorders         
Ampulla of Vater stenosis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Bile duct stenosis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Bile duct stone  1  1/2014 (0.05%)  1/2040 (0.05%)  1/2014 (0.05%)  1/2040 (0.05%) 
Biliary cirrhosis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Biliary colic  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Biliary fibrosis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Cholangitis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Cholangitis acute  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Cholecystitis  1  1/2014 (0.05%)  1/2040 (0.05%)  3/2014 (0.15%)  2/2040 (0.10%) 
Cholecystitis acute  1  1/2014 (0.05%)  1/2040 (0.05%)  3/2014 (0.15%)  1/2040 (0.05%) 
Cholecystitis chronic  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Cholelithiasis  1  6/2014 (0.30%)  5/2040 (0.25%)  9/2014 (0.45%)  7/2040 (0.34%) 
Hepatic cirrhosis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Hyperbilirubinaemia  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Jaundice cholestatic  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Liver injury  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Immune system disorders         
Amyloidosis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Drug hypersensitivity  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Hypersensitivity  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Infections and infestations         
Abdominal abscess  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Abdominal sepsis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Abdominal wall abscess  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Appendicitis  1  0/2014 (0.00%)  0/2040 (0.00%)  3/2014 (0.15%)  0/2040 (0.00%) 
Appendicitis perforated  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Bronchitis  1  3/2014 (0.15%)  1/2040 (0.05%)  8/2014 (0.40%)  11/2040 (0.54%) 
Bronchitis bacterial  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Campylobacter gastroenteritis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Cellulitis  1  3/2014 (0.15%)  1/2040 (0.05%)  6/2014 (0.30%)  5/2040 (0.25%) 
Cholecystitis infective  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Clostridium difficile infection  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Cystitis  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  1/2040 (0.05%) 
Dermatitis infected  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Device related infection  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Diverticulitis  1  0/2014 (0.00%)  1/2040 (0.05%)  1/2014 (0.05%)  6/2040 (0.29%) 
Empyema  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Endocarditis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Enterocolitis bacterial  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Erysipelas  1  0/2014 (0.00%)  1/2040 (0.05%)  2/2014 (0.10%)  2/2040 (0.10%) 
Escherichia sepsis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Gangrene  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Gastritis viral  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Gastroenteritis  1  2/2014 (0.10%)  2/2040 (0.10%)  6/2014 (0.30%)  5/2040 (0.25%) 
Gastroenteritis viral  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  2/2040 (0.10%) 
Gastrointestinal infection  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Haematoma infection  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Hepatitis C  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Herpes zoster  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  1/2040 (0.05%) 
Infected bite  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Infected fistula  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Infected skin ulcer  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Infection  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Infective exacerbation of chronic obstructive airways disease  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Influenza  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  3/2040 (0.15%) 
Kidney infection  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Localised infection  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Lower respiratory tract infection  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Lung infection  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Nosocomial infection  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Oesophageal candidiasis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Osteomyelitis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Otitis media chronic  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Pancreas infection  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Peritonitis  1  0/2014 (0.00%)  3/2040 (0.15%)  0/2014 (0.00%)  3/2040 (0.15%) 
Pharyngeal abscess  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Pneumonia  1  17/2014 (0.84%)  16/2040 (0.78%)  46/2014 (2.28%)  54/2040 (2.65%) 
Pneumonia bacterial  1  3/2014 (0.15%)  1/2040 (0.05%)  6/2014 (0.30%)  4/2040 (0.20%) 
Post procedural infection  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Post procedural sepsis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Postoperative abscess  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Postoperative wound infection  1  2/2014 (0.10%)  1/2040 (0.05%)  3/2014 (0.15%)  1/2040 (0.05%) 
Pseudomembranous colitis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Pseudomonal sepsis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Pulmonary sepsis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Pyelonephritis  1  1/2014 (0.05%)  0/2040 (0.00%)  3/2014 (0.15%)  1/2040 (0.05%) 
Pyelonephritis acute  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Pyoderma  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Respiratory tract infection  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  3/2040 (0.15%) 
Rhinitis  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Sepsis  1  0/2014 (0.00%)  0/2040 (0.00%)  3/2014 (0.15%)  3/2040 (0.15%) 
Septic shock  1  0/2014 (0.00%)  1/2040 (0.05%)  2/2014 (0.10%)  2/2040 (0.10%) 
Sialoadenitis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Sinusitis  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  1/2040 (0.05%) 
Staphylococcal sepsis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Subcutaneous abscess  1  1/2014 (0.05%)  1/2040 (0.05%)  1/2014 (0.05%)  1/2040 (0.05%) 
Tracheobronchitis  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Upper respiratory tract infection  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  4/2040 (0.20%) 
Urinary tract infection  1  8/2014 (0.40%)  8/2040 (0.39%)  21/2014 (1.04%)  21/2040 (1.03%) 
Urinary tract infection bacterial  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Urosepsis  1  0/2014 (0.00%)  2/2040 (0.10%)  3/2014 (0.15%)  4/2040 (0.20%) 
Viral diarrhoea  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Viral infection  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  2/2040 (0.10%) 
Wound infection  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Injury, poisoning and procedural complications         
Burns third degree  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Carbon monoxide poisoning  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Clavicle fracture  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Concussion  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  2/2040 (0.10%) 
Contusion  1  1/2014 (0.05%)  1/2040 (0.05%)  7/2014 (0.35%)  2/2040 (0.10%) 
Craniocerebral injury  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  3/2040 (0.15%) 
Extradural haematoma  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Facial bones fracture  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  3/2040 (0.15%) 
Fall  1  4/2014 (0.20%)  2/2040 (0.10%)  11/2014 (0.55%)  13/2040 (0.64%) 
Femoral neck fracture  1  12/2014 (0.60%)  5/2040 (0.25%)  31/2014 (1.54%)  15/2040 (0.74%) 
Femur fracture  1  12/2014 (0.60%)  11/2040 (0.54%)  51/2014 (2.53%)  42/2040 (2.06%) 
Fibula fracture  1  4/2014 (0.20%)  3/2040 (0.15%)  9/2014 (0.45%)  5/2040 (0.25%) 
Foot fracture  1  3/2014 (0.15%)  0/2040 (0.00%)  5/2014 (0.25%)  0/2040 (0.00%) 
Foreign body  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Fracture  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  2/2040 (0.10%) 
Fractured ischium  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Fractured sacrum  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Gastrointestinal anastomotic leak  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Graft complication  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Hand fracture  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Head injury  1  1/2014 (0.05%)  0/2040 (0.00%)  3/2014 (0.15%)  2/2040 (0.10%) 
Hip fracture  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Humerus fracture  1  7/2014 (0.35%)  3/2040 (0.15%)  16/2014 (0.79%)  6/2040 (0.29%) 
Ilium fracture  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Incisional hernia  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Joint injury  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Laceration  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  2/2040 (0.10%) 
Ligament sprain  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Limb injury  1  2/2014 (0.10%)  1/2040 (0.05%)  3/2014 (0.15%)  1/2040 (0.05%) 
Lip injury  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Lumbar vertebral fracture  1  1/2014 (0.05%)  0/2040 (0.00%)  8/2014 (0.40%)  0/2040 (0.00%) 
Meniscus injury  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Muscle rupture  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Overdose  1  1/2014 (0.05%)  1/2040 (0.05%)  2/2014 (0.10%)  1/2040 (0.05%) 
Patella fracture  1  0/2014 (0.00%)  2/2040 (0.10%)  5/2014 (0.25%)  6/2040 (0.29%) 
Post laminectomy syndrome  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Post procedural bile leak  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Post procedural haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  2/2040 (0.10%) 
Pubis fracture  1  4/2014 (0.20%)  0/2040 (0.00%)  7/2014 (0.35%)  3/2040 (0.15%) 
Radius fracture  1  12/2014 (0.60%)  8/2040 (0.39%)  20/2014 (0.99%)  14/2040 (0.69%) 
Rib fracture  1  1/2014 (0.05%)  0/2040 (0.00%)  3/2014 (0.15%)  0/2040 (0.00%) 
Road traffic accident  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Scapula fracture  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Skull fracture  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Soft tissue injury  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Spinal compression fracture  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Spinal fracture  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  3/2040 (0.15%) 
Stoma site haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Subarachnoid haematoma  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Subarachnoid haemorrhage  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Subdural haematoma  1  0/2014 (0.00%)  2/2040 (0.10%)  0/2014 (0.00%)  4/2040 (0.20%) 
Subdural haemorrhage  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  1/2040 (0.05%) 
Thoracic vertebral fracture  1  0/2014 (0.00%)  1/2040 (0.05%)  5/2014 (0.25%)  2/2040 (0.10%) 
Tibia fracture  1  5/2014 (0.25%)  3/2040 (0.15%)  8/2014 (0.40%)  6/2040 (0.29%) 
Toxicity to various agents  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  2/2040 (0.10%) 
Ulna fracture  1  6/2014 (0.30%)  3/2040 (0.15%)  11/2014 (0.55%)  5/2040 (0.25%) 
Wound dehiscence  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Wound evisceration  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Wrist fracture  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Investigations         
Alanine aminotransferase increased  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Aspartate aminotransferase increased  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Carcinoembryonic antigen increased  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Coagulation time prolonged  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Creatinine renal clearance decreased  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Heart rate decreased  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  1/2040 (0.05%) 
Liver function test abnormal  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Medical observation normal  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Weight decreased  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Metabolism and nutrition disorders         
Dehydration  1  1/2014 (0.05%)  1/2040 (0.05%)  4/2014 (0.20%)  4/2040 (0.20%) 
Diabetes mellitus  1  2/2014 (0.10%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Diabetes mellitus inadequate control  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Diabetic ketoacidosis  1  2/2014 (0.10%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Diabetic metabolic decompensation  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Electrolyte imbalance  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Failure to thrive  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Fluid overload  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Hypercalcaemia  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Hyperkalaemia  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Hypoglycaemia  1  2/2014 (0.10%)  0/2040 (0.00%)  5/2014 (0.25%)  2/2040 (0.10%) 
Hypokalaemia  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  4/2040 (0.20%) 
Hyponatraemia  1  2/2014 (0.10%)  3/2040 (0.15%)  7/2014 (0.35%)  7/2040 (0.34%) 
Hypovolaemia  1  0/2014 (0.00%)  1/2040 (0.05%)  0/2014 (0.00%)  2/2040 (0.10%) 
Iron deficiency  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Metabolic disorder  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Type 1 diabetes mellitus  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  1/2014 (0.05%)  1/2040 (0.05%)  4/2014 (0.20%)  2/2040 (0.10%) 
Arthritis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  4/2040 (0.20%) 
Arthropathy  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Back pain  1  9/2014 (0.45%)  2/2040 (0.10%)  17/2014 (0.84%)  11/2040 (0.54%) 
Cervical spinal stenosis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Extraskeletal ossification  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Foot deformity  1  0/2014 (0.00%)  0/2040 (0.00%)  2/2014 (0.10%)  1/2040 (0.05%) 
Fracture pain  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  0/2040 (0.00%) 
Groin pain  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Intervertebral disc disorder  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Intervertebral disc displacement  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Intervertebral disc protrusion  1  2/2014 (0.10%)  1/2040 (0.05%)  5/2014 (0.25%)  3/2040 (0.15%) 
Lumbar spinal stenosis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Mobility decreased  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Muscular weakness  1  1/2014 (0.05%)  2/2040 (0.10%)  1/2014 (0.05%)  2/2040 (0.10%) 
Musculoskeletal pain  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  1/2040 (0.05%) 
Neck pain  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Osteoarthritis  1  5/2014 (0.25%)  6/2040 (0.29%)  11/2014 (0.55%)  19/2040 (0.93%) 
Osteochondrosis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Osteonecrosis  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Osteonecrosis of jaw  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Pain in extremity  1  2/2014 (0.10%)  0/2040 (0.00%)  3/2014 (0.15%)  1/2040 (0.05%) 
Pain in jaw  1  1/2014 (0.05%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Rheumatoid arthritis  1  2/2014 (0.10%)  1/2040 (0.05%)  2/2014 (0.10%)  1/2040 (0.05%) 
Rotator cuff syndrome  1  1/2014 (0.05%)  0/2040 (0.00%)  2/2014 (0.10%)  1/2040 (0.05%) 
Spinal column stenosis  1  0/2014 (0.00%)  0/2040 (0.00%)  0/2014 (0.00%)  1/2040 (0.05%) 
Spinal osteoarthritis  1  0/2014 (0.00%)  2/2040 (0.10%)  0/2014 (0.00%)  3/2040 (0.15%) 
Spinal pain  1  3/2014 (0.15%)  3/2040 (0.15%)  4/2014 (0.20%)  3/2040 (0.15%) 
Spondylolisthesis  1  0/2014 (0.00%)  0/2040 (0.00%)  1/2014 (0.05%)  0/2040 (0.00%) 
Tendonitis  1  1/2014 (0.05%)