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Trial record 1 of 2 for:    29672714 [PUBMED-IDS]
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Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment of Osteoporosis

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ClinicalTrials.gov Identifier: NCT00523341
Recruitment Status : Completed
First Posted : August 31, 2007
Results First Posted : July 12, 2016
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Osteopenia
Osteoporosis
Intervention Biological: Denosumab
Enrollment 4550
Recruitment Details This was an extension study open to participants who had completed core study 20030216 (NCT00089791). The study was conducted at 178 centers in North America, South America, Europe, Australia, and New Zealand. Participants were enrolled from 7 August 2007 to 20 June 2008.
Pre-assignment Details All participants received open-label denosumab during this study. Results are reported by the Study 20030216 randomized treatment groups (placebo versus denosumab).
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study. Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Period Title: Overall Study
Started 2207 2343
Received Treatment 2206 2343
Completed 1283 1343
Not Completed 924 1000
Reason Not Completed
Withdrawal by Subject             399             427
Other             181             198
Adverse Event             122             155
Death             101             110
Lost to Follow-up             73             61
Non-compliance             20             13
Physician Decision             14             13
Requirement for Alternative Therapy             4             14
Protocol Deviation             6             5
Ineligibility Determined             3             4
Disease Progression             1             0
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab Total
Hide Arm/Group Description Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study. Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment). Total of all reporting groups
Overall Number of Baseline Participants 2207 2343 4550
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2207 participants 2343 participants 4550 participants
74.8  (5.1) 74.9  (5.0) 74.8  (5.0)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2207 participants 2343 participants 4550 participants
60 - 64 years 58 49 107
65 - 69 years 326 320 646
70 - 74 years 672 716 1388
≥ 75 years 1151 1258 2409
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2207 participants 2343 participants 4550 participants
Female
2207
 100.0%
2343
 100.0%
4550
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2207 participants 2343 participants 4550 participants
White 2063 2169 4232
Black 16 19 35
Hispanic or Latino 121 145 266
Asian 2 3 5
Japanese 3 5 8
Native Hawaiian or Other Pacific Islander 1 0 1
Other 1 2 3
Bone Mineral Density T-score   [1] 
Mean (Standard Deviation)
Unit of measure:  T-score
Number Analyzed 2207 participants 2343 participants 4550 participants
Lumbar spine -2.81  (0.75) -2.14  (0.80) -2.47  (0.84)
Total hip -1.93  (0.80) -1.50  (0.79) -1.71  (0.83)
Femoral neck -2.17  (0.72) -1.83  (0.75) -1.99  (0.75)
[1]
Measure Description:

The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old.

Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.

Bone Mineral Density T-score at Study 20030216 Baseline  
Mean (Standard Deviation)
Unit of measure:  T-score
Number Analyzed 2207 participants 2343 participants 4550 participants
Lumbar spine -2.84  (0.68) -2.83  (0.67) -2.83  (0.68)
Total hip -1.85  (0.79) -1.85  (0.79) -1.85  (0.79)
Femoral neck -2.11  (0.71) -2.11  (0.71) -2.11  (0.71)
Any Historical Fracture at Age ≥ 55 Years  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2207 participants 2343 participants 4550 participants
1089 1133 2222
1.Primary Outcome
Title Number of Participants With Adverse Events (AEs)
Hide Description A serious adverse event (SAE) is defined as an adverse event that: • is fatal • is life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is other significant medical hazard. Treatment-related adverse events includes only events for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. The following were classified as adverse events of interest (events that are considered to be identified or potential risks of denosumab treatment): positively adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral fracture, hypocalcemia, adverse events potentially related to hypersensitivity, serious infection (including bacterial cellulitis), malignancy, cardiac disorders, vascular disorders, fracture healing complications, eczema, acute pancreatitis, and musculoskeletal pain.
Time Frame 84 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of denosumab.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2206 2343
Measure Type: Number
Unit of Measure: participants
Any adverse event (AE) 2070 2173
Serious adverse event 945 1014
Fatal adverse event 101 108
AE leading to study discontinuation 145 173
AE leading to discontinuation of denosumab 184 216
Treatment-related adverse events (TRAE) 185 188
Serious treatment-related adverse events 26 28
Fatal treatment-related adverse events 1 0
TRAE leading to study discontinuation 16 9
TRAE leading to discontinuation of denosumab 30 25
Positively adjudicated osteonecrosis of the jaw 6 7
Positively adjudicated atypical femoral fracture 1 1
Hypocalcaemia 10 6
AEs potentially related to hypersensitivity 260 280
Serious infections 161 185
Serious bacterial cellulitis 7 12
Malignancy 227 237
Cardiac disorders 449 492
Vascular disorders 693 732
Fracture healing complications 0 1
Eczema 99 115
Acute pancreatitis 4 8
Musculoskeletal pain 1125 1206
2.Primary Outcome
Title Number of Participants With Laboratory Toxicities of Grade ≥ 3
Hide Description Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity.
Time Frame 84 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of denosumab
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2206 2343
Measure Type: Number
Unit of Measure: participants
Low sodium - Grade 3 28 25
Low sodium - Grade 4 1 0
High potassium - Grade 3 9 11
High potassium - Grade 4 0 3
Low potassium - Grade 3 7 7
Low magnesium - Grade 3 1 1
Low magnesium - Grade 4 0 1
High calcium - Grade 3 2 3
High calcium - Grade 4 0 2
High corrected calcium - Grade 3 2 3
High corrected calcium - Grade 4 0 2
Low phosphorus - Grade 3 3 1
High Creatinine - Grade 3 0 1
High aspartate amino transferase (AST) - Grade 3 5 11
High aspartate amino transferase (AST) - Grade 4 1 0
High alanine amino transferase (ALT) - Grade 3 8 10
High alanine amino transferase (ALT) - Grade 4 1 0
High total bilirubin - Grade 3 2 3
Low albumin - Grade 3 0 1
High glucose - Grade 3 35 37
High glucose - Grade 4 0 1
Low glucose - Grade 3 4 1
Low glucose - Grade 4 1 1
Low hemoglobin - Grade 3 6 4
Low platelets - Grade 3 3 7
Low platelets - Grade 4 2 4
Low white blood cells - Grade 3 5 7
Low white blood cells - Grade 4 0 1
Low lymphocytes - Grade 3 17 16
Low lymphocytes - Grade 4 2 1
3.Primary Outcome
Title Number of Participants With Antibodies to Denosumab
Hide Description [Not Specified]
Time Frame Every 12 months through Month 84
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of denosumab
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2206 2343
Measure Type: Number
Unit of Measure: participants
1 0
4.Secondary Outcome
Title Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit
Hide Description Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline (of extension study) and months 12, 24, 36, 60 and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2089 2210
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Month 12 (n = 2040, 2168)
5.2
(5.0 to 5.3)
2.0
(1.8 to 2.2)
Month 24 (n = 1935, 2061)
7.7
(7.5 to 7.9)
3.5
(3.4 to 3.7)
Month 36 (n = 1497, 1607)
9.4
(9.1 to 9.6)
4.9
(4.7 to 5.1)
Month 60 (n = 1472, 1567)
13.0
(12.7 to 13.3)
7.9
(7.6 to 8.2)
Month 84 (n = 1223, 1264)
16.5
(16.1 to 16.9)
10.8
(10.4 to 11.2)
5.Secondary Outcome
Title Percent Change From Baseline in Total Hip Bone Mineral Density by Visit
Hide Description Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline (of extension study) and months 12, 24, 36, 60 and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2089 2210
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Month 12 (n = 2029, 2160)
3.0
(2.8 to 3.1)
0.8
(0.7 to 0.9)
Month 24 (n = 1918, 2045)
4.1
(4.0 to 4.2)
1.4
(1.3 to 1.5)
Month 36 (n = 1475, 1591)
4.9
(4.7 to 5.0)
1.8
(1.7 to 2.0)
Month 60 (n = 1439, 1538)
6.2
(6.0 to 6.4)
2.6
(2.4 to 2.8)
Month 84 (n = 1200, 1232)
7.4
(7.1 to 7.6)
3.4
(3.2 to 3.7)
6.Secondary Outcome
Title Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit
Hide Description Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline (of extension study) and months 12, 24, 36, 60 and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2089 2210
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Month 12 (n = 2029, 2160)
2.1
(1.9 to 2.3)
0.8
(0.7 to 1.0)
Month 24 (n = 1918, 2045)
3.2
(3.1 to 3.4)
1.2
(1.0 to 1.4)
Month 36 (n = 1475, 1591)
4.0
(3.8 to 4.3)
1.7
(1.5 to 1.9)
Month 60 (n = 1439, 1538)
5.7
(5.4 to 5.9)
2.8
(2.6 to 3.1)
Month 84 (n = 1200, 1232)
7.1
(6.8 to 7.4)
3.8
(3.5 to 4.2)
7.Secondary Outcome
Title Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit
Hide Description 1/3 radius bone mineral density was measured in a subset of participants by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame Baseline (of extension study) and months 12, 24, 36, 60 and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the DXA substudy with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 449 467
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Month 12 (n = 114, 134)
0.3
(-0.2 to 0.9)
0.6
(0.1 to 1.2)
Month 24 (n = 108, 127)
0.2
(-0.4 to 0.9)
0.2
(-0.4 to 0.8)
Month 36 (n = 73, 93)
1.3
(0.5 to 2.0)
0.6
(-0.1 to 1.3)
Month 60 (n = 59, 84)
1.8
(0.9 to 2.7)
1.4
(0.6 to 2.2)
Month 84 (n = 39, 56)
2.2
(0.9 to 3.6)
1.0
(-0.1 to 2.2)
8.Secondary Outcome
Title Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit
Hide Description Lumbar spine bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
Time Frame Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2089 2210
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Month 12 (n = 2030, 2148)
5.9
(5.6 to 6.1)
11.9
(11.7 to 12.2)
Month 24 (n = 1924, 2041)
8.4
(8.1 to 8.7)
13.7
(13.4 to 13.9)
Month 36 (n = 1487, 1589)
10.1
(9.8 to 10.4)
15.2
(14.9 to 15.5)
Month 60 (n = 1464, 1551)
13.8
(13.4 to 14.1)
18.4
(18.1 to 18.8)
Month 84 (n = 1216, 1251)
17.3
(16.8 to 17.8)
21.7
(21.2 to 22.2)
9.Secondary Outcome
Title Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit
Hide Description Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
Time Frame Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2089 2210
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Month 12 (n = 2006, 2132)
1.7
(1.6 to 1.9)
6.4
(6.3 to 6.6)
Month 24 (n = 1895, 2017)
2.9
(2.7 to 3.0)
7.1
(6.9 to 7.2)
Month 36 (n = 1457, 1567)
3.6
(3.4 to 3.8)
7.5
(7.3 to 7.7)
Month 60 (n = 1424, 1518)
4.9
(4.7 to 5.2)
8.4
(8.1 to 8.6)
Month 84 (n = 1189, 1215)
6.1
(5.8 to 6.4)
9.2
(8.9 to 9.5)
10.Secondary Outcome
Title Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit
Hide Description Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
Time Frame Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2089 2210
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Month 12 (n = 2006, 2132)
1.4
(1.2 to 1.7)
5.8
(5.6 to 6.0)
Month 24 (n = 1895, 2017)
2.6
(2.3 to 2.8)
6.2
(6.0 to 6.5)
Month 36 (n = 1457, 1567)
3.4
(3.1 to 3.6)
6.7
(6.5 to 7.0)
Month 60 (n = 1424, 1518)
5.0
(4.7 to 5.3)
7.9
(7.6 to 8.2)
Month 84 (n = 1189, 1215)
6.4
(6.0 to 6.8)
9.0
(8.6 to 9.4)
11.Secondary Outcome
Title Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit
Hide Description 1/3 radius BMD was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
Time Frame Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the DXA substudy with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 449 467
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Month 12 (n = 113, 133)
-1.0
(-1.7 to -0.3)
2.6
(1.9 to 3.2)
Month 24 (n = 107, 127)
-1.2
(-1.9 to -0.4)
2.1
(1.4 to 2.8)
Month 36 (n = 73, 92)
-0.2
(-1.1 to 0.7)
2.4
(1.6 to 3.2)
Month 60 (n = 59, 83)
0.3
(-0.7 to 1.3)
3.3
(2.4 to 4.2)
Month 84 (n = 39, 56)
0.6
(-0.8 to 2.1)
2.8
(1.6 to 4.1)
12.Secondary Outcome
Title Number of Participants With New Vertebral Fractures
Hide Description A new vertebral fracture, assessed by lateral spine X-ray using Genant semiquantitative scoring method, was identified as an ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4, excluding any fracture associated with high trauma severity or a pathologic fracture.
Time Frame 84 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled in the extension study who have vertebral X-ray assessment at the extension baseline and at least 1 post-extension baseline visit.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 1991 2116
Measure Type: Number
Unit of Measure: participants
145 149
13.Secondary Outcome
Title Number of Participants With Non-Vertebral Fractures
Hide Description Non-vertebral fractures (osteoporotic) were defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging (MRI) confirming the fracture, 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 84 months
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2207 2343
Measure Type: Number
Unit of Measure: participants
219 172
14.Secondary Outcome
Title Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit
Hide Description Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
Time Frame Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of denosumab and enrolled in the bone turnover marker substudy at screening or Month 24 in Study 20060289. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 318 342
Median (Inter-Quartile Range)
Unit of Measure: percent change
Day 10 (n = 26, 47)
-90
(-93 to -85)
-72
(-86 to -47)
Month 6 (n = 30, 56)
-85
(-91 to -73)
-26
(-63 to 1)
Month 12 (n = 27, 56)
-75
(-90 to -54)
-13
(-37 to 24)
Month 24 (n = 27, 47)
-67
(-84 to -29)
10
(-27 to 55)
Month 36 (n = 68, 81)
-59
(-84 to -28)
2
(-32 to 68)
Month 48 (n = 62, 75)
-58
(-84 to -12)
0
(-46 to 56)
Month 60 (n = 59, 70)
-65
(-90 to -19)
0
(-47 to 83)
Month 72 (n = 56, 62)
-60
(-85 to -16)
-1
(-47 to 76)
Month 84 (n = 41, 41)
-64
(-86 to -28)
-6
(-26 to 68)
15.Secondary Outcome
Title Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit
Hide Description Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new sparticipants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
Time Frame Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of denosumab and enrolled in the bone turnover marker substudy at screening or Month 24 in Study 20060289. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 318 342
Median (Inter-Quartile Range)
Unit of Measure: percent change
Day 10 (n = 30, 51)
6
(-5 to 30)
14
(-1 to 25)
Month 6 (n = 30, 53)
-71
(-78 to -62)
-23
(-50 to -2)
Month 12 (n = 26, 56)
-67
(-76 to -57)
7
(-15 to 30)
Month 24 (n = 27, 47)
-63
(-77 to -41)
11
(-17 to 42)
Month 36 (n = 69, 83)
-57
(-67 to -29)
29
(-6 to 91)
Month 48 (n = 61, 73)
-60
(-70 to -41)
8
(-21 to 49)
Month 60 (n = 61, 71)
-54
(-72 to -35)
30
(-6 to 67)
Month 72 (n = 55, 64)
-50
(-60 to -36)
44
(3 to 103)
Month 84 (n = 48, 50)
-59
(-73 to -40)
32
(-4 to 75)
16.Secondary Outcome
Title Percent Change From Study 20030216 Baseline in CTX-1 by Visit
Hide Description Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
Time Frame Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of denosumab and enrolled in the bone turnover marker substudy at screening or Month 24 in Study 20060289. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 318 342
Median (Inter-Quartile Range)
Unit of Measure: percent change
Day 10 (n = 26, 56)
-90
(-91 to -78)
-91
(-93 to -86)
Month 6 (n = 32, 72)
-83
(-90 to -72)
-77
(-87 to -49)
Month 12 (n = 27, 65)
-77
(-91 to -45)
-63
(-87 to -11)
Month 24 (n = 28, 60)
-65
(-80 to -24)
-53
(-82 to 0)
Month 36 (n = 289, 313)
-71
(-88 to -40)
-52
(-86 to -4)
Month 48 (n = 274, 290)
-70
(-88 to -36)
-61
(-85 to -24)
Month 60 (n = 268, 276)
-67
(-88 to -25)
-53
(-86 to -18)
Month 72 (n = 243, 248)
-69
(-88 to -32)
-59
(-86 to -21)
Month 84 (n = 217, 216)
-63
(-88 to -19)
-53
(-84 to -12)
17.Secondary Outcome
Title Percent Change From Study 20030216 Baseline in P1NP by Visit
Hide Description Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
Time Frame Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of denosumab and enrolled in the bone turnover marker substudy at screening or Month 24 in Study 20060289. "n" indicates the number of participants with available data at each time point.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 318 342
Median (Inter-Quartile Range)
Unit of Measure: percent change
Day 10 (n = 30, 51)
9
(-14 to 34)
-59
(-74 to -22)
Month 6 (n = 32, 57)
-74
(-80 to -67)
-75
(-80 to -55)
Month 12 (n = 26, 56)
-74
(-79 to -51)
-63
(-76 to -36)
Month 24 (n = 28, 51)
-67
(-75 to -51)
-56
(-72 to -30)
Month 36 (n = 70, 83)
-59
(-75 to -37)
-60
(-71 to -40)
Month 48 (n = 61, 73)
-67
(-75 to -46)
-63
(-77 to -42)
Month 60 (n = 61, 71)
-62
(-75 to -42)
-55
(-74 to -30)
Month 72 (n = 56, 67)
-62
(-71 to -35)
-55
(-70 to -27)
Month 84 (n =49, 53)
-68
(-78 to -56)
-57
(-74 to -38)
18.Secondary Outcome
Title Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
Hide Description [Not Specified]
Time Frame Baseline (of extension study) and day 10
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had a calcium corrected by albumin measurement within the Day 10 visit window up to May 31, 2008.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 2027 2154
Median (Inter-Quartile Range)
Unit of Measure: percent change
-3.1
(-6.1 to 0.0)
-2.0
(-5.1 to 1.1)
19.Secondary Outcome
Title Serum Denosumab Concentration
Hide Description Serum concentrations of denosumab were measured by a validated conventional sandwich enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 0.8 ng/mL. Values of 0 in the table below indicate data below the lower limit of quantification.
Time Frame Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who participated in the Study 20030216 PK substudy, for whom dosing information was not missing and for whom sampling was within 14 days of specified sampling times.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 97 113
Mean (Standard Deviation)
Unit of Measure: ng/mL
Baseline (n = 97, 113) 0  (0) 113  (107)
Day 10 (n = 92, 106) 5890  (2010) 6010  (2530)
Month 3 (n = 81, 92) 1000  (560) 1190  (690)
Month 4 (n = 87, 104) 429  (378) 554  (480)
Month 6 (n = 87, 103) 20.8  (61.7) 66.0  (147.2)
20.Secondary Outcome
Title Bone Histomorphometry: Cancellous Bone Volume
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by quantitative histomorphometry.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cancellous bone volume data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: percentage of total bone tissue volume
Month 24 (n = 13, 25) 15.253  (6.065) 14.640  (6.979)
Month 84 (n = 0, 19) NA [1]   (NA) 16.358  (4.438)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
21.Secondary Outcome
Title Bone Histomorphometry: Trabecular Number
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular number is the number of trabeculae present per lineal mm and is calculated as trabecular bone volume/trabecular thickness. Trabecular number is a measure of trabecular connectivity and decreases with bone loss.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular number data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: 1/mm
Month 24 (n = 13, 25) 1.005  (0.242) 0.904  (0.243)
Month 24 (n = 0, 19) NA [1]   (NA) 1.235  (0.254)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
22.Secondary Outcome
Title Bone Histomorphometry: Trabecular Separation
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular separation is the mean distance between trabeculae (measured by integrated computer graphics). Trabecular separation increases with trabecular bone loss.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular separation data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: μm
Month 24 (n = 13, 25) 919.693  (358.238) 1033.416  (352.259)
Month 84 (n = 0, 19) NA [1]   (NA) 708.669  (171.782)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
23.Secondary Outcome
Title Bone Histomorphometry: Trabecular Thickness
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Mean trabecular thickness is a measure of trabecular structure and is calculated as the reciprocal of total bone (trabecular) surfaces. Trabecular thickness is reduced by aging and osteoporosis.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular thickness data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: μm
Month 24 (n = 13, 25) 153.878  (51.859) 156.335  (48.567)
Month 84 (n = 0, 19) NA [1]   (NA) 132.965  (28.064)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
24.Secondary Outcome
Title Bone Histomorphometry: Cortical Width
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cortical width is the average width of both inner and outer cortices.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cortical width data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 45
Mean (Standard Deviation)
Unit of Measure: μm
Month 24 (n = 13, 28) 622.22  (246.70) 707.69  (237.97)
Month 84 (n = 0, 21) NA [1]   (NA) 786.19  (279.81)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
25.Secondary Outcome
Title Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by tartrate-resistant acid phosphatase (TRAP) staining histomorphometry.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cancellous bone volume data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: percentage of total bone tissue volume
Month 24 (n = 13, 25) 16.678  (7.270) 15.606  (6.986)
Month 84 (n = 0, 19) NA [1]   (NA) 17.631  (4.387)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
26.Secondary Outcome
Title Bone Histomorphometry: Surface Density
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Surface density is calculated by total bone (trabecular) surfaces / total tissue volume.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available surface density data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: mm²/mm³
Month 24 (n = 13, 25) 2.009  (0.486) 1.807  (0.486)
Month 84 (n = 0, 19) NA [1]   (NA) 2.472  (0.506)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
27.Secondary Outcome
Title Bone Histomorphometry: Osteoblast - Osteoid Interface
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface * 100.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoblast - osteoid interface data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: percentage of osteoid surface
Month 24 (n = 13, 25) 22.124  (34.879) 17.813  (28.381)
Month 84 (n = 0, 19) NA [1]   (NA) 5.951  (15.223)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
28.Secondary Outcome
Title Bone Histomorphometry: Osteoid Surface
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid surface is the percent of bone surface covered in osteoid.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid surface data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: percentage of total bone surface
Month 24 (n = 13, 25) 0.915  (1.382) 0.982  (2.489)
Month 84 (n = 0, 19) NA [1]   (NA) 0.421  (1.068)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
29.Secondary Outcome
Title Bone Histomorphometry: Osteoid Thickness
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid thickness (width) is the mean thickness of osteoid seams on cancellous surfaces. Osteoid thickness is normally <12.5 µm. Increased osteoid thickness suggests abnormal mineralization (osteomalacia).
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid thickness data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: μm
Month 24 (n = 13, 25) 5.139  (3.261) 4.548  (4.973)
Month 84 (n = 0, 19) NA [1]   (NA) 4.108  (3.476)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
30.Secondary Outcome
Title Bone Histomorphometry: Wall Thickness
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Wall thickness is the average thickness of trabecular bone structural units (BSU) and is used to assess the overall balance between resorption and formation.
Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available wall thickness data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: μm
Month 24 (n = 13, 25) 43.11  (6.08) 49.74  (10.51)
Month 84 (n = 0, 19) NA [1]   (NA) 39.59  (7.49)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
31.Secondary Outcome
Title Bone Histomorphometry: Eroded Surface/Bone Surface
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

Eroded surface/bone surface is the percentage of bone surface occupied by eroded (resorption) cavities (Howships lacunae), with or without osteoclasts.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available eroded surface/bone surface data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: percentage of bone surface
Month 24 (n = 13, 25) 0.414  (0.701) 0.328  (0.613)
Month 84 (n = 0, 19) NA [1]   (NA) 0.511  (0.579)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
32.Secondary Outcome
Title Bone Histomorphometry: Osteoclast Number - Length Based
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

Osteoclast number was measured by quantitative histomorphometry and is expressed per mm of bone.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: 1/mm
Month 24 (n = 13, 25) 0.086  (0.119) 0.107  (0.198)
Month 84 (n = 0, 19) NA [1]   (NA) 0.074  (0.101)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
33.Secondary Outcome
Title Bone Histomorphometry: Osteoclast Number - Surface Based
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

Osteoclast number was measured by quantitative histomorphometry and is expressed per 100 mm of bone surface area.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: 1/100 mm
Month 24 (n = 13, 25) 8.6  (11.9) 10.7  (19.8)
Month 84 (n = 0, 19) NA [1]   (NA) 7.4  (10.1)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
34.Secondary Outcome
Title Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

Osteoclast number was measured using TRAP staining and is expressed per mm of bone.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: 1/mm
Month 24 (n = 13, 25) 0.096  (0.134) 0.110  (0.185)
Month 84 (n = 0, 19) NA [1]   (NA) 0.077  (0.107)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
35.Secondary Outcome
Title Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

Osteoclast number was measured using TRAP staining and is expressed per 100 mm of bone surface.

Da

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: 1/100 mm
Month 24 (n = 13, 25) 9.6  (13.4) 11.0  (18.5)
Month 84 (n = 0, 19) NA [1]   (NA) 7.7  (10.7)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
36.Secondary Outcome
Title Bone Histomorphometry: Single-label Surface
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. A single label is deposited if formation either started or ended during the interval between the uses of the two courses of tetracycline administration. Single-label surface is expressed as a percentage of total bone surface.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available single-label surface data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: percentage of bone surface
Month 24 (n = 5, 10) 0.304  (0.302) 0.643  (0.661)
Month 84 (n = 0, 10) NA [1]   (NA) 0.611  (0.726)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
37.Secondary Outcome
Title Bone Histomorphometry: Double-label Surface
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The presence of double labels indicates that normal bone mineralization was actively occurring over the entire labeling interval. Double-label surface is expressed as a percentage of total bone surface.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available double-label surface data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: percentage of bone surface
Month 24 (n = 5, 10) 0.258  (0.207) 0.356  (0.295)
Month 84 (n = 0, 10) NA [1]   (NA) 0.106  (0.237)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
38.Secondary Outcome
Title Bone Histomorphometry: Mineralizing Surface
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Total mineralizing surfaces (MS) include all double and half of single-labeled surfaces. MS is expressed as a percentage of total bone surface.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineralizing surface data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: percentage of bone surface
Month 24 (n = 5, 10) 0.406  (0.323) 0.681  (0.453)
Month 84 (n = 0, 10) NA [1]   (NA) 0.412  (0.458)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
39.Secondary Outcome
Title Bone Histomorphometry: Mineral Apposition Rate
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the avarage rate at which new bone mineral is being added on any actively forming surface. MAR is calculated as the average distance between visible labels, divided by the labeling interval.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineral apposition rate data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: μm/day
Month 24 (n = 5, 10) 0.616  (0.219) 0.722  (0.573)
Month 84 (n = 0, 10) NA [1]   (NA) 0.394  (0.233)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
40.Secondary Outcome
Title Bone Histomorphometry: Adjusted Apposition Rate
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the average rate at which new bone mineral is being added on any actively forming surface. Adjusted MAR is calculated as: (average distance between visible labels / labeling interval) * (total mineralizing surface/total bone surface).

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available adjusted apposition rate data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 19
Mean (Standard Deviation)
Unit of Measure: μm/day
Month 24 (n = 5, 9) 0.394  (0.471) 0.517  (0.537)
Month 84 (n = 0, 10) NA [1]   (NA) 0.818  (1.207)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
41.Secondary Outcome
Title Bone Histomorphometry: Bone Formation Rate - Surface Based
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - surface based is the calculated rate at which cancellous bone surface is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone surface).

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available bone formation rate data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: μm³/μm²/year
Month 24 (n = 5, 10) 0.898  (0.706) 2.153  (2.468)
Month 84 (n = 0, 10) NA [1]   (NA) 0.691  (0.868)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
42.Secondary Outcome
Title Bone Histomorphometry: Bone Formation Rate - Volume Based
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - volume based is the calculated rate at which cancellous bone volume is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone volume).

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available bone formation rate data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: percent of bone volume per year
Month 24 (n = 5, 10) 1.454  (1.265) 3.162  (3.773)
Month 84 (n = 0, 10) NA [1]   (NA) 1.071  (1.308)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
43.Secondary Outcome
Title Bone Histomorphometry: Formation Period
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Formation period (FP) is the mean time required to rebuild a new bone structural unit or osteon from the cement line back to the bone surface at a single location, and is given by wall width / adjusted apposition rate.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available formation period data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: days
Month 24 (n = 5, 10) 593.5  (996.8) 287.3  (391.5)
Month 84 (n = 0, 10) NA [1]   (NA) 229.7  (512.0)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
44.Secondary Outcome
Title Bone Histomorphometry: Activation Frequency
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The average time that it takes for a new remodeling cycle to begin on any point on a cancellous surface is called the activation frequency. Activation frequency is calculated as the bone formation rate / wall width.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available activation frequency data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: /year
Month 24 (n = 5, 10) 0.022  (0.019) 0.045  (0.049)
Month 84 (n = 0, 10) NA [1]   (NA) 0.014  (0.024)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
45.Secondary Outcome
Title Bone Histomorphometry: Osteoid Volume
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry.

Osteoid volume is the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid).

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid volume data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 41
Mean (Standard Deviation)
Unit of Measure: percentage of total bone tissue
Month 24 (n = 13, 25) 0.108  (0.193) 0.146  (0.382)
Month 84 (n = 0, 19) NA [1]   (NA) 0.048  (0.133)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
46.Secondary Outcome
Title Bone Histomorphometry: Mineralization Lag Time
Hide Description

Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken.

Mineralization lag time is the average time interval between osteoid formation and its subsequent mineralization and is calculated by dividing the osteoid width by the apposition rate.

Time Frame Month 24 and month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineralization lag time data.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 5 20
Mean (Standard Deviation)
Unit of Measure: days
Month 24 (n = 5, 10) 84.9  (136.8) 54.3  (76.1)
Month 84 (n = 0, 10) NA [1]   (NA) 52.3  (114.5)
[1]
No participants in this arm had a bone biopsy evaluable for histomorphometry at month 84
47.Secondary Outcome
Title Bone Histology at Month 24
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone.
Time Frame Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, and had at least 1 bone biopsy evaluable for histology at extension month 24.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 13 28
Overall Number of Units Analyzed
Type of Units Analyzed: Biopsies
13 28
Measure Type: Number
Unit of Measure: biopsies
Normal lamellar bone 13 28
Normal mineralization 13 28
Osteoid 13 23
Osteomalacia 0 0
Marrow fibrosis 0 0
Woven bone 0 0
48.Secondary Outcome
Title Bone Histology at Month 84
Hide Description Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone.
Time Frame Month 84
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, and had at least 1 bone biopsy evaluable for histology at extension month 84.
Arm/Group Title Placebo / Denosumab Denosumab / Denosumab
Hide Arm/Group Description:
Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
Overall Number of Participants Analyzed 0 22
Overall Number of Units Analyzed
Type of Units Analyzed: Biopsies
0 22
Measure Type: Number
Unit of Measure: biopsies
Normal lamellar bone 22
Normal mineralization 22
Osteoid 18
Osteomalacia 0
Marrow fibrosis 0
Woven bone 0
Time Frame 84 months
Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
 
Arm/Group Title Placebo/ Denosumab 60 mg Q6M Denosumab/ Denosumab 60 mg Q6M
Hide Arm/Group Description Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years. Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years (total of 10 years treatment).
All-Cause Mortality
Placebo/ Denosumab 60 mg Q6M Denosumab/ Denosumab 60 mg Q6M
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo/ Denosumab 60 mg Q6M Denosumab/ Denosumab 60 mg Q6M
Affected / at Risk (%) Affected / at Risk (%)
Total   945/2206 (42.84%)   1014/2343 (43.28%) 
Blood and lymphatic system disorders     
Anaemia  1  11/2206 (0.50%)  11/2343 (0.47%) 
Bone marrow oedema  1  2/2206 (0.09%)  1/2343 (0.04%) 
Haemorrhagic disorder  1  1/2206 (0.05%)  0/2343 (0.00%) 
Iron deficiency anaemia  1  3/2206 (0.14%)  3/2343 (0.13%) 
Leukopenia  1  1/2206 (0.05%)  1/2343 (0.04%) 
Lymphadenitis  1  1/2206 (0.05%)  1/2343 (0.04%) 
Lymphadenopathy  1  1/2206 (0.05%)  0/2343 (0.00%) 
Microcytic anaemia  1  2/2206 (0.09%)  0/2343 (0.00%) 
Neutropenia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Pancytopenia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Polycythaemia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Splenomegaly  1  1/2206 (0.05%)  0/2343 (0.00%) 
Thrombocytopenia  1  3/2206 (0.14%)  0/2343 (0.00%) 
Thrombocytosis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Cardiac disorders     
Acute coronary syndrome  1  2/2206 (0.09%)  1/2343 (0.04%) 
Acute myocardial infarction  1  8/2206 (0.36%)  18/2343 (0.77%) 
Adams-Stokes syndrome  1  1/2206 (0.05%)  0/2343 (0.00%) 
Angina pectoris  1  17/2206 (0.77%)  19/2343 (0.81%) 
Angina unstable  1  7/2206 (0.32%)  12/2343 (0.51%) 
Aortic valve disease  1  0/2206 (0.00%)  3/2343 (0.13%) 
Aortic valve incompetence  1  1/2206 (0.05%)  0/2343 (0.00%) 
Aortic valve stenosis  1  4/2206 (0.18%)  3/2343 (0.13%) 
Arrhythmia  1  3/2206 (0.14%)  4/2343 (0.17%) 
Arrhythmia supraventricular  1  1/2206 (0.05%)  0/2343 (0.00%) 
Arteriosclerosis coronary artery  1  3/2206 (0.14%)  1/2343 (0.04%) 
Atrial fibrillation  1  50/2206 (2.27%)  40/2343 (1.71%) 
Atrial flutter  1  0/2206 (0.00%)  4/2343 (0.17%) 
Atrioventricular block  1  0/2206 (0.00%)  2/2343 (0.09%) 
Atrioventricular block complete  1  5/2206 (0.23%)  4/2343 (0.17%) 
Atrioventricular block second degree  1  2/2206 (0.09%)  2/2343 (0.09%) 
Bradycardia  1  5/2206 (0.23%)  3/2343 (0.13%) 
Bundle branch block left  1  0/2206 (0.00%)  1/2343 (0.04%) 
Cardiac arrest  1  4/2206 (0.18%)  4/2343 (0.17%) 
Cardiac disorder  1  0/2206 (0.00%)  1/2343 (0.04%) 
Cardiac failure  1  15/2206 (0.68%)  21/2343 (0.90%) 
Cardiac failure acute  1  1/2206 (0.05%)  3/2343 (0.13%) 
Cardiac failure chronic  1  1/2206 (0.05%)  3/2343 (0.13%) 
Cardiac failure congestive  1  10/2206 (0.45%)  9/2343 (0.38%) 
Cardiac fibrillation  1  1/2206 (0.05%)  0/2343 (0.00%) 
Cardiac valve disease  1  0/2206 (0.00%)  2/2343 (0.09%) 
Cardiac valve sclerosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Cardio-respiratory arrest  1  1/2206 (0.05%)  2/2343 (0.09%) 
Cardiogenic shock  1  0/2206 (0.00%)  2/2343 (0.09%) 
Cardiomyopathy  1  1/2206 (0.05%)  0/2343 (0.00%) 
Cardiopulmonary failure  1  4/2206 (0.18%)  1/2343 (0.04%) 
Cardiovascular insufficiency  1  1/2206 (0.05%)  0/2343 (0.00%) 
Chronic right ventricular failure  1  0/2206 (0.00%)  1/2343 (0.04%) 
Coronary artery disease  1  9/2206 (0.41%)  17/2343 (0.73%) 
Coronary artery insufficiency  1  3/2206 (0.14%)  0/2343 (0.00%) 
Coronary artery occlusion  1  1/2206 (0.05%)  0/2343 (0.00%) 
Coronary artery stenosis  1  1/2206 (0.05%)  6/2343 (0.26%) 
Extrasystoles  1  0/2206 (0.00%)  1/2343 (0.04%) 
Heart valve calcification  1  2/2206 (0.09%)  0/2343 (0.00%) 
Heart valve incompetence  1  1/2206 (0.05%)  0/2343 (0.00%) 
Hypertensive heart disease  1  2/2206 (0.09%)  1/2343 (0.04%) 
Ischaemic cardiomyopathy  1  1/2206 (0.05%)  1/2343 (0.04%) 
Left atrial dilatation  1  0/2206 (0.00%)  1/2343 (0.04%) 
Left ventricular failure  1  2/2206 (0.09%)  3/2343 (0.13%) 
Mitral valve disease  1  1/2206 (0.05%)  1/2343 (0.04%) 
Mitral valve disease mixed  1  0/2206 (0.00%)  1/2343 (0.04%) 
Mitral valve incompetence  1  1/2206 (0.05%)  2/2343 (0.09%) 
Myocardial infarction  1  21/2206 (0.95%)  24/2343 (1.02%) 
Myocardial ischaemia  1  4/2206 (0.18%)  13/2343 (0.55%) 
Palpitations  1  2/2206 (0.09%)  2/2343 (0.09%) 
Pericardial effusion  1  1/2206 (0.05%)  2/2343 (0.09%) 
Pericardial haemorrhage  1  1/2206 (0.05%)  0/2343 (0.00%) 
Pericarditis  1  2/2206 (0.09%)  0/2343 (0.00%) 
Right ventricular failure  1  0/2206 (0.00%)  2/2343 (0.09%) 
Sinoatrial block  1  2/2206 (0.09%)  0/2343 (0.00%) 
Sinus arrest  1  0/2206 (0.00%)  2/2343 (0.09%) 
Sinus bradycardia  1  0/2206 (0.00%)  2/2343 (0.09%) 
Sinus node dysfunction  1  6/2206 (0.27%)  10/2343 (0.43%) 
Supraventricular extrasystoles  1  1/2206 (0.05%)  1/2343 (0.04%) 
Supraventricular tachyarrhythmia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Supraventricular tachycardia  1  2/2206 (0.09%)  2/2343 (0.09%) 
Tachyarrhythmia  1  2/2206 (0.09%)  0/2343 (0.00%) 
Tachycardia  1  0/2206 (0.00%)  1/2343 (0.04%) 
Tachycardia induced cardiomyopathy  1  1/2206 (0.05%)  0/2343 (0.00%) 
Tricuspid valve disease  1  0/2206 (0.00%)  1/2343 (0.04%) 
Ventricular arrhythmia  1  0/2206 (0.00%)  1/2343 (0.04%) 
Ventricular extrasystoles  1  2/2206 (0.09%)  1/2343 (0.04%) 
Ventricular fibrillation  1  0/2206 (0.00%)  1/2343 (0.04%) 
Ventricular tachycardia  1  1/2206 (0.05%)  1/2343 (0.04%) 
Congenital, familial and genetic disorders     
Cancer gene carrier  1  0/2206 (0.00%)  1/2343 (0.04%) 
Congenital ureteric anomaly  1  1/2206 (0.05%)  0/2343 (0.00%) 
Corneal dystrophy  1  0/2206 (0.00%)  1/2343 (0.04%) 
Muscular dystrophy  1  0/2206 (0.00%)  1/2343 (0.04%) 
Ear and labyrinth disorders     
Deafness unilateral  1  1/2206 (0.05%)  0/2343 (0.00%) 
Hypoacusis  1  0/2206 (0.00%)  3/2343 (0.13%) 
Meniere's disease  1  0/2206 (0.00%)  1/2343 (0.04%) 
Otosclerosis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Vertigo  1  14/2206 (0.63%)  8/2343 (0.34%) 
Vertigo positional  1  0/2206 (0.00%)  1/2343 (0.04%) 
Vestibular disorder  1  1/2206 (0.05%)  1/2343 (0.04%) 
Endocrine disorders     
Adrenal mass  1  0/2206 (0.00%)  1/2343 (0.04%) 
Basedow's disease  1  0/2206 (0.00%)  1/2343 (0.04%) 
Goitre  1  6/2206 (0.27%)  5/2343 (0.21%) 
Hyperthyroidism  1  2/2206 (0.09%)  0/2343 (0.00%) 
Inappropriate antidiuretic hormone secretion  1  0/2206 (0.00%)  1/2343 (0.04%) 
Thyroiditis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Toxic nodular goitre  1  1/2206 (0.05%)  0/2343 (0.00%) 
Eye disorders     
Blepharochalasis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Blindness  1  1/2206 (0.05%)  0/2343 (0.00%) 
Blindness unilateral  1  1/2206 (0.05%)  0/2343 (0.00%) 
Cataract  1  17/2206 (0.77%)  15/2343 (0.64%) 
Cataract diabetic  1  1/2206 (0.05%)  0/2343 (0.00%) 
Detachment of macular retinal pigment epithelium  1  0/2206 (0.00%)  1/2343 (0.04%) 
Diplopia  1  0/2206 (0.00%)  1/2343 (0.04%) 
Ectropion  1  0/2206 (0.00%)  1/2343 (0.04%) 
Eye haemorrhage  1  1/2206 (0.05%)  0/2343 (0.00%) 
Glaucoma  1  3/2206 (0.14%)  3/2343 (0.13%) 
Iridocyclitis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Keratopathy  1  0/2206 (0.00%)  1/2343 (0.04%) 
Macular fibrosis  1  0/2206 (0.00%)  3/2343 (0.13%) 
Maculopathy  1  1/2206 (0.05%)  0/2343 (0.00%) 
Open angle glaucoma  1  0/2206 (0.00%)  1/2343 (0.04%) 
Retinal detachment  1  0/2206 (0.00%)  3/2343 (0.13%) 
Retinal haemorrhage  1  1/2206 (0.05%)  2/2343 (0.09%) 
Retinal tear  1  0/2206 (0.00%)  1/2343 (0.04%) 
Retinal vascular thrombosis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Ulcerative keratitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Visual impairment  1  2/2206 (0.09%)  1/2343 (0.04%) 
Vitreous haemorrhage  1  1/2206 (0.05%)  1/2343 (0.04%) 
Gastrointestinal disorders     
Abdominal adhesions  1  1/2206 (0.05%)  0/2343 (0.00%) 
Abdominal distension  1  1/2206 (0.05%)  1/2343 (0.04%) 
Abdominal hernia  1  4/2206 (0.18%)  2/2343 (0.09%) 
Abdominal hernia obstructive  1  1/2206 (0.05%)  0/2343 (0.00%) 
Abdominal pain  1  10/2206 (0.45%)  8/2343 (0.34%) 
Abdominal pain upper  1  2/2206 (0.09%)  2/2343 (0.09%) 
Abdominal rigidity  1  1/2206 (0.05%)  0/2343 (0.00%) 
Acquired oesophageal web  1  1/2206 (0.05%)  0/2343 (0.00%) 
Anal haemorrhage  1  0/2206 (0.00%)  1/2343 (0.04%) 
Anal prolapse  1  1/2206 (0.05%)  0/2343 (0.00%) 
Anal sphincter atony  1  1/2206 (0.05%)  0/2343 (0.00%) 
Chronic gastritis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Coeliac disease  1  0/2206 (0.00%)  1/2343 (0.04%) 
Colitis  1  3/2206 (0.14%)  2/2343 (0.09%) 
Colitis ischaemic  1  2/2206 (0.09%)  2/2343 (0.09%) 
Colitis microscopic  1  1/2206 (0.05%)  0/2343 (0.00%) 
Colitis ulcerative  1  3/2206 (0.14%)  0/2343 (0.00%) 
Constipation  1  8/2206 (0.36%)  6/2343 (0.26%) 
Crohn's disease  1  0/2206 (0.00%)  1/2343 (0.04%) 
Diaphragmatic hernia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Diarrhoea  1  9/2206 (0.41%)  3/2343 (0.13%) 
Diverticular perforation  1  1/2206 (0.05%)  0/2343 (0.00%) 
Diverticulum  1  3/2206 (0.14%)  3/2343 (0.13%) 
Diverticulum intestinal  1  1/2206 (0.05%)  6/2343 (0.26%) 
Diverticulum oesophageal  1  0/2206 (0.00%)  1/2343 (0.04%) 
Duodenal stenosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Duodenal ulcer  1  5/2206 (0.23%)  3/2343 (0.13%) 
Duodenal ulcer haemorrhage  1  1/2206 (0.05%)  0/2343 (0.00%) 
Duodenal ulcer perforation  1  1/2206 (0.05%)  0/2343 (0.00%) 
Duodenitis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Dyspepsia  1  3/2206 (0.14%)  3/2343 (0.13%) 
Dysphagia  1  0/2206 (0.00%)  1/2343 (0.04%) 
Enteritis  1  1/2206 (0.05%)  1/2343 (0.04%) 
Enterocolitis haemorrhagic  1  1/2206 (0.05%)  0/2343 (0.00%) 
Epigastric discomfort  1  1/2206 (0.05%)  0/2343 (0.00%) 
Faecal incontinence  1  1/2206 (0.05%)  0/2343 (0.00%) 
Faeces discoloured  1  1/2206 (0.05%)  0/2343 (0.00%) 
Femoral hernia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Gastric ulcer  1  6/2206 (0.27%)  3/2343 (0.13%) 
Gastric ulcer haemorrhage  1  1/2206 (0.05%)  0/2343 (0.00%) 
Gastritis  1  4/2206 (0.18%)  9/2343 (0.38%) 
Gastritis erosive  1  1/2206 (0.05%)  2/2343 (0.09%) 
Gastroduodenal ulcer  1  0/2206 (0.00%)  1/2343 (0.04%) 
Gastrointestinal haemorrhage  1  6/2206 (0.27%)  1/2343 (0.04%) 
Gastrointestinal inflammation  1  0/2206 (0.00%)  1/2343 (0.04%) 
Gastrointestinal motility disorder  1  1/2206 (0.05%)  0/2343 (0.00%) 
Gastrointestinal mucosal disorder  1  1/2206 (0.05%)  0/2343 (0.00%) 
Gastrointestinal obstruction  1  2/2206 (0.09%)  0/2343 (0.00%) 
Gastrointestinal stenosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Gastrooesophageal reflux disease  1  3/2206 (0.14%)  2/2343 (0.09%) 
Haematemesis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Haematochezia  1  1/2206 (0.05%)  2/2343 (0.09%) 
Haemorrhoids  1  1/2206 (0.05%)  2/2343 (0.09%) 
Hernial eventration  1  1/2206 (0.05%)  0/2343 (0.00%) 
Hiatus hernia  1  2/2206 (0.09%)  4/2343 (0.17%) 
Ileus  1  7/2206 (0.32%)  3/2343 (0.13%) 
Inguinal hernia  1  14/2206 (0.63%)  7/2343 (0.30%) 
Intestinal angina  1  0/2206 (0.00%)  1/2343 (0.04%) 
Intestinal fistula  1  1/2206 (0.05%)  0/2343 (0.00%) 
Intestinal haemorrhage  1  4/2206 (0.18%)  1/2343 (0.04%) 
Intestinal ischaemia  1  1/2206 (0.05%)  1/2343 (0.04%) 
Intestinal obstruction  1  5/2206 (0.23%)  1/2343 (0.04%) 
Intestinal perforation  1  0/2206 (0.00%)  1/2343 (0.04%) 
Intestinal strangulation  1  0/2206 (0.00%)  1/2343 (0.04%) 
Irritable bowel syndrome  1  2/2206 (0.09%)  1/2343 (0.04%) 
Large intestinal haemorrhage  1  1/2206 (0.05%)  0/2343 (0.00%) 
Large intestinal stenosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Large intestine polyp  1  4/2206 (0.18%)  5/2343 (0.21%) 
Lower gastrointestinal haemorrhage  1  0/2206 (0.00%)  1/2343 (0.04%) 
Malabsorption  1  0/2206 (0.00%)  1/2343 (0.04%) 
Mechanical ileus  1  0/2206 (0.00%)  2/2343 (0.09%) 
Melaena  1  2/2206 (0.09%)  2/2343 (0.09%) 
Mesenteric artery embolism  1  0/2206 (0.00%)  2/2343 (0.09%) 
Nausea  1  2/2206 (0.09%)  2/2343 (0.09%) 
Oesophageal polyp  1  0/2206 (0.00%)  1/2343 (0.04%) 
Oesophagitis  1  1/2206 (0.05%)  1/2343 (0.04%) 
Pancreatic cyst  1  2/2206 (0.09%)  0/2343 (0.00%) 
Pancreatic necrosis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Pancreatitis  1  0/2206 (0.00%)  4/2343 (0.17%) 
Pancreatitis acute  1  1/2206 (0.05%)  4/2343 (0.17%) 
Pancreatitis chronic  1  1/2206 (0.05%)  1/2343 (0.04%) 
Pancreatitis necrotising  1  1/2206 (0.05%)  0/2343 (0.00%) 
Peptic ulcer  1  1/2206 (0.05%)  0/2343 (0.00%) 
Periodontal disease  1  0/2206 (0.00%)  1/2343 (0.04%) 
Peritoneal perforation  1  0/2206 (0.00%)  1/2343 (0.04%) 
Pharyngo-oesophageal diverticulum  1  1/2206 (0.05%)  1/2343 (0.04%) 
Rectal haemorrhage  1  2/2206 (0.09%)  0/2343 (0.00%) 
Rectal polyp  1  2/2206 (0.09%)  3/2343 (0.13%) 
Rectal prolapse  1  1/2206 (0.05%)  4/2343 (0.17%) 
Retroperitoneal haematoma  1  0/2206 (0.00%)  1/2343 (0.04%) 
Small intestinal obstruction  1  2/2206 (0.09%)  0/2343 (0.00%) 
Stomatitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Subileus  1  1/2206 (0.05%)  1/2343 (0.04%) 
Tongue oedema  1  1/2206 (0.05%)  0/2343 (0.00%) 
Toothache  1  0/2206 (0.00%)  1/2343 (0.04%) 
Umbilical hernia  1  2/2206 (0.09%)  1/2343 (0.04%) 
Upper gastrointestinal haemorrhage  1  2/2206 (0.09%)  1/2343 (0.04%) 
Volvulus  1  0/2206 (0.00%)  1/2343 (0.04%) 
Volvulus of small bowel  1  0/2206 (0.00%)  1/2343 (0.04%) 
Vomiting  1  4/2206 (0.18%)  2/2343 (0.09%) 
General disorders     
Adverse drug reaction  1  0/2206 (0.00%)  1/2343 (0.04%) 
Asthenia  1  3/2206 (0.14%)  4/2343 (0.17%) 
Chest pain  1  9/2206 (0.41%)  8/2343 (0.34%) 
Chronic fatigue syndrome  1  1/2206 (0.05%)  0/2343 (0.00%) 
Death  1  16/2206 (0.73%)  13/2343 (0.55%) 
Device dislocation  1  3/2206 (0.14%)  5/2343 (0.21%) 
Device failure  1  0/2206 (0.00%)  1/2343 (0.04%) 
Device malfunction  1  0/2206 (0.00%)  2/2343 (0.09%) 
Face oedema  1  1/2206 (0.05%)  0/2343 (0.00%) 
Fatigue  1  1/2206 (0.05%)  0/2343 (0.00%) 
Foreign body reaction  1  0/2206 (0.00%)  1/2343 (0.04%) 
Gait disturbance  1  0/2206 (0.00%)  1/2343 (0.04%) 
General physical health deterioration  1  4/2206 (0.18%)  4/2343 (0.17%) 
Hernia  1  1/2206 (0.05%)  1/2343 (0.04%) 
Incarcerated hernia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Inflammation  1  0/2206 (0.00%)  1/2343 (0.04%) 
Ischaemic ulcer  1  0/2206 (0.00%)  1/2343 (0.04%) 
Malaise  1  2/2206 (0.09%)  2/2343 (0.09%) 
Medical device complication  1  2/2206 (0.09%)  0/2343 (0.00%) 
Multi-organ failure  1  2/2206 (0.09%)  4/2343 (0.17%) 
Nodule  1  0/2206 (0.00%)  1/2343 (0.04%) 
Non-cardiac chest pain  1  7/2206 (0.32%)  5/2343 (0.21%) 
Oedema peripheral  1  0/2206 (0.00%)  1/2343 (0.04%) 
Peripheral swelling  1  0/2206 (0.00%)  2/2343 (0.09%) 
Polyp  1  1/2206 (0.05%)  0/2343 (0.00%) 
Pyrexia  1  4/2206 (0.18%)  5/2343 (0.21%) 
Sudden cardiac death  1  1/2206 (0.05%)  0/2343 (0.00%) 
Sudden death  1  4/2206 (0.18%)  1/2343 (0.04%) 
Ulcer haemorrhage  1  1/2206 (0.05%)  0/2343 (0.00%) 
Hepatobiliary disorders     
Autoimmune hepatitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Bile duct obstruction  1  0/2206 (0.00%)  2/2343 (0.09%) 
Bile duct stenosis  1  1/2206 (0.05%)  2/2343 (0.09%) 
Bile duct stone  1  0/2206 (0.00%)  4/2343 (0.17%) 
Biliary cirrhosis primary  1  0/2206 (0.00%)  1/2343 (0.04%) 
Biliary colic  1  2/2206 (0.09%)  5/2343 (0.21%) 
Cholangitis  1  4/2206 (0.18%)  1/2343 (0.04%) 
Cholecystitis  1  6/2206 (0.27%)  4/2343 (0.17%) 
Cholecystitis acute  1  4/2206 (0.18%)  2/2343 (0.09%) 
Cholelithiasis  1  22/2206 (1.00%)  30/2343 (1.28%) 
Gallbladder necrosis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Gallbladder oedema  1  0/2206 (0.00%)  1/2343 (0.04%) 
Gallbladder polyp  1  0/2206 (0.00%)  1/2343 (0.04%) 
Hepatic cirrhosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Hepatic cyst  1  0/2206 (0.00%)  1/2343 (0.04%) 
Hepatic failure  1  0/2206 (0.00%)  1/2343 (0.04%) 
Jaundice  1  0/2206 (0.00%)  2/2343 (0.09%) 
Jaundice cholestatic  1  0/2206 (0.00%)  1/2343 (0.04%) 
Liver disorder  1  1/2206 (0.05%)  2/2343 (0.09%) 
Immune system disorders     
Anaphylactic reaction  1  1/2206 (0.05%)  1/2343 (0.04%) 
Autoimmune disorder  1  1/2206 (0.05%)  0/2343 (0.00%) 
Drug hypersensitivity  1  0/2206 (0.00%)  1/2343 (0.04%) 
Hypersensitivity  1  0/2206 (0.00%)  1/2343 (0.04%) 
Sarcoidosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Infections and infestations     
Abdominal abscess  1  1/2206 (0.05%)  0/2343 (0.00%) 
Abdominal sepsis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Abscess  1  0/2206 (0.00%)  1/2343 (0.04%) 
Abscess limb  1  1/2206 (0.05%)  0/2343 (0.00%) 
Abscess neck  1  0/2206 (0.00%)  1/2343 (0.04%) 
Appendiceal abscess  1  1/2206 (0.05%)  1/2343 (0.04%) 
Appendicitis  1  4/2206 (0.18%)  5/2343 (0.21%) 
Appendicitis perforated  1  2/2206 (0.09%)  1/2343 (0.04%) 
Arthritis bacterial  1  1/2206 (0.05%)  2/2343 (0.09%) 
Arthritis infective  1  1/2206 (0.05%)  0/2343 (0.00%) 
Atypical pneumonia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Bacteraemia  1  1/2206 (0.05%)  1/2343 (0.04%) 
Bacterial infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Bacterial pyelonephritis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Bronchitis  1  8/2206 (0.36%)  7/2343 (0.30%) 
Bronchitis fungal  1  0/2206 (0.00%)  1/2343 (0.04%) 
Bronchopneumonia  1  6/2206 (0.27%)  6/2343 (0.26%) 
Cellulitis  1  3/2206 (0.14%)  2/2343 (0.09%) 
Cholecystitis infective  1  0/2206 (0.00%)  3/2343 (0.13%) 
Chronic sinusitis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Chronic tonsillitis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Clostridium difficile infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Cystitis  1  6/2206 (0.27%)  5/2343 (0.21%) 
Dengue fever  1  2/2206 (0.09%)  1/2343 (0.04%) 
Device related infection  1  2/2206 (0.09%)  1/2343 (0.04%) 
Diverticulitis  1  11/2206 (0.50%)  10/2343 (0.43%) 
Ear infection  1  1/2206 (0.05%)  0/2343 (0.00%) 
Endocarditis  1  0/2206 (0.00%)  2/2343 (0.09%) 
Enterocolitis bacterial  1  0/2206 (0.00%)  1/2343 (0.04%) 
Erysipelas  1  4/2206 (0.18%)  9/2343 (0.38%) 
Gangrene  1  1/2206 (0.05%)  1/2343 (0.04%) 
Gastroenteritis  1  9/2206 (0.41%)  9/2343 (0.38%) 
Gastroenteritis viral  1  2/2206 (0.09%)  0/2343 (0.00%) 
Gastrointestinal infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
H1N1 influenza  1  0/2206 (0.00%)  1/2343 (0.04%) 
Haemophilus infection  1  1/2206 (0.05%)  0/2343 (0.00%) 
Helicobacter gastritis  1  2/2206 (0.09%)  0/2343 (0.00%) 
Hepatic cyst infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Hepatitis C  1  1/2206 (0.05%)  0/2343 (0.00%) 
Herpes zoster  1  2/2206 (0.09%)  2/2343 (0.09%) 
Infected skin ulcer  1  1/2206 (0.05%)  1/2343 (0.04%) 
Infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Infective exacerbation of chronic obstructive airways disease  1  1/2206 (0.05%)  1/2343 (0.04%) 
Influenza  1  2/2206 (0.09%)  0/2343 (0.00%) 
Klebsiella bacteraemia  1  0/2206 (0.00%)  1/2343 (0.04%) 
Klebsiella infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Laryngitis  1  2/2206 (0.09%)  0/2343 (0.00%) 
Listeriosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Liver abscess  1  0/2206 (0.00%)  3/2343 (0.13%) 
Lobar pneumonia  1  2/2206 (0.09%)  4/2343 (0.17%) 
Localised infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Lower respiratory tract infection  1  2/2206 (0.09%)  6/2343 (0.26%) 
Lung infection  1  3/2206 (0.14%)  1/2343 (0.04%) 
Lymph node tuberculosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Meningitis aseptic  1  0/2206 (0.00%)  1/2343 (0.04%) 
Meningitis viral  1  0/2206 (0.00%)  1/2343 (0.04%) 
Mycobacterium avium complex infection  1  1/2206 (0.05%)  1/2343 (0.04%) 
Necrotising fasciitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Neutropenic sepsis  1  1/2206 (0.05%)  1/2343 (0.04%) 
Onychomycosis  1  1/2206 (0.05%)  1/2343 (0.04%) 
Osteomyelitis  1  2/2206 (0.09%)  2/2343 (0.09%) 
Otitis media  1  1/2206 (0.05%)  0/2343 (0.00%) 
Parotitis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Peritonitis  1  0/2206 (0.00%)  2/2343 (0.09%) 
Pneumonia  1  44/2206 (1.99%)  48/2343 (2.05%) 
Pneumonia bacterial  1  3/2206 (0.14%)  4/2343 (0.17%) 
Pneumonia haemophilus  1  1/2206 (0.05%)  1/2343 (0.04%) 
Pneumonia influenzal  1  1/2206 (0.05%)  0/2343 (0.00%) 
Pneumonia pneumococcal  1  3/2206 (0.14%)  2/2343 (0.09%) 
Pneumonia pseudomonal  1  0/2206 (0.00%)  1/2343 (0.04%) 
Pneumonia staphylococcal  1  1/2206 (0.05%)  1/2343 (0.04%) 
Pneumonia streptococcal  1  1/2206 (0.05%)  0/2343 (0.00%) 
Post procedural infection  1  0/2206 (0.00%)  2/2343 (0.09%) 
Postoperative wound infection  1  1/2206 (0.05%)  0/2343 (0.00%) 
Pseudomembranous colitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Pulmonary tuberculosis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Pyelonephritis  1  5/2206 (0.23%)  3/2343 (0.13%) 
Pyelonephritis acute  1  0/2206 (0.00%)  1/2343 (0.04%) 
Pyelonephritis chronic  1  0/2206 (0.00%)  1/2343 (0.04%) 
Respiratory tract infection  1  2/2206 (0.09%)  2/2343 (0.09%) 
Salmonellosis  1  1/2206 (0.05%)  2/2343 (0.09%) 
Salpingitis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Salpingo-oophoritis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Sepsis  1  6/2206 (0.27%)  15/2343 (0.64%) 
Septic shock  1  5/2206 (0.23%)  5/2343 (0.21%) 
Sinusitis  1  3/2206 (0.14%)  1/2343 (0.04%) 
Skin infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Small intestine gangrene  1  0/2206 (0.00%)  1/2343 (0.04%) 
Soft tissue infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Staphylococcal bacteraemia  1  0/2206 (0.00%)  1/2343 (0.04%) 
Staphylococcal sepsis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Stenotrophomonas infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Subcutaneous abscess  1  1/2206 (0.05%)  0/2343 (0.00%) 
Subdural empyema  1  0/2206 (0.00%)  1/2343 (0.04%) 
Tick-borne viral encephalitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Tonsillitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Tooth infection  1  1/2206 (0.05%)  0/2343 (0.00%) 
Tracheitis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Tracheobronchitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Tuberculosis  1  1/2206 (0.05%)  0/2343 (0.00%) 
Tuberculosis of peripheral lymph nodes  1  0/2206 (0.00%)  1/2343 (0.04%) 
Upper respiratory tract infection  1  0/2206 (0.00%)  2/2343 (0.09%) 
Urinary tract infection  1  13/2206 (0.59%)  11/2343 (0.47%) 
Urosepsis  1  6/2206 (0.27%)  3/2343 (0.13%) 
Vaginal infection  1  0/2206 (0.00%)  1/2343 (0.04%) 
Vestibular neuronitis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Viral infection  1  2/2206 (0.09%)  0/2343 (0.00%) 
Wound infection  1  3/2206 (0.14%)  0/2343 (0.00%) 
Injury, poisoning and procedural complications     
Acetabulum fracture  1  0/2206 (0.00%)  2/2343 (0.09%) 
Animal bite  1  0/2206 (0.00%)  1/2343 (0.04%) 
Bone fissure  1  1/2206 (0.05%)  0/2343 (0.00%) 
Brain contusion  1  1/2206 (0.05%)  0/2343 (0.00%) 
Carbon monoxide poisoning  1  1/2206 (0.05%)  0/2343 (0.00%) 
Cartilage injury  1  0/2206 (0.00%)  1/2343 (0.04%) 
Cataract traumatic  1  0/2206 (0.00%)  1/2343 (0.04%) 
Cervical vertebral fracture  1  1/2206 (0.05%)  1/2343 (0.04%) 
Clavicle fracture  1  1/2206 (0.05%)  0/2343 (0.00%) 
Concussion  1  7/2206 (0.32%)  8/2343 (0.34%) 
Contusion  1  4/2206 (0.18%)  1/2343 (0.04%) 
Coronary artery restenosis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Craniocerebral injury  1  1/2206 (0.05%)  3/2343 (0.13%) 
Dislocation of vertebra  1  1/2206 (0.05%)  1/2343 (0.04%) 
Eye penetration  1  2/2206 (0.09%)  1/2343 (0.04%) 
Facial bones fracture  1  0/2206 (0.00%)  9/2343 (0.38%) 
Fall  1  13/2206 (0.59%)  16/2343 (0.68%) 
Femoral neck fracture  1  16/2206 (0.73%)  15/2343 (0.64%) 
Femur fracture  1  16/2206 (0.73%)  12/2343 (0.51%) 
Fibula fracture  1  14/2206 (0.63%)  11/2343 (0.47%) 
Foot fracture  1  1/2206 (0.05%)  1/2343 (0.04%) 
Fractured sacrum  1  1/2206 (0.05%)  0/2343 (0.00%) 
Gastrointestinal stoma complication  1  1/2206 (0.05%)  1/2343 (0.04%) 
Graft complication  1  0/2206 (0.00%)  1/2343 (0.04%) 
Hand fracture  1  0/2206 (0.00%)  1/2343 (0.04%) 
Head injury  1  4/2206 (0.18%)  6/2343 (0.26%) 
Hip fracture  1  1/2206 (0.05%)  1/2343 (0.04%) 
Humerus fracture  1  13/2206 (0.59%)  5/2343 (0.21%) 
Ilium fracture  1  1/2206 (0.05%)  0/2343 (0.00%) 
Incisional hernia  1  2/2206 (0.09%)  1/2343 (0.04%) 
Injury corneal  1  1/2206 (0.05%)  0/2343 (0.00%) 
Joint dislocation  1  7/2206 (0.32%)  6/2343 (0.26%) 
Joint injury  1  0/2206 (0.00%)  1/2343 (0.04%) 
Laceration  1  2/2206 (0.09%)  2/2343 (0.09%) 
Ligament injury  1  1/2206 (0.05%)  0/2343 (0.00%) 
Ligament rupture  1  2/2206 (0.09%)  0/2343 (0.00%) 
Ligament sprain  1  2/2206 (0.09%)  0/2343 (0.00%) 
Limb crushing injury  1  0/2206 (0.00%)  1/2343 (0.04%) 
Lumbar vertebral fracture  1  4/2206 (0.18%)  3/2343 (0.13%) 
Meniscus injury  1  5/2206 (0.23%)  2/2343 (0.09%) 
Multiple injuries  1  1/2206 (0.05%)  0/2343 (0.00%) 
Muscle rupture  1  0/2206 (0.00%)  1/2343 (0.04%) 
Overdose  1  3/2206 (0.14%)  1/2343 (0.04%) 
Patella fracture  1  5/2206 (0.23%)  5/2343 (0.21%) 
Perineal injury  1  0/2206 (0.00%)  1/2343 (0.04%) 
Pneumothorax traumatic  1  0/2206 (0.00%)  1/2343 (0.04%) 
Post procedural complication  1  0/2206 (0.00%)  2/2343 (0.09%) 
Post procedural haematoma  1  0/2206 (0.00%)  2/2343 (0.09%) 
Post procedural haemorrhage  1  2/2206 (0.09%)  0/2343 (0.00%) 
Postoperative hernia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Postoperative ileus  1  1/2206 (0.05%)  0/2343 (0.00%) 
Procedural hypotension  1  1/2206 (0.05%)  0/2343 (0.00%) 
Procedural pain  1  1/2206 (0.05%)  2/2343 (0.09%) 
Pubis fracture  1  3/2206 (0.14%)  5/2343 (0.21%) 
Radiation mucositis  1  0/2206 (0.00%)  1/2343 (0.04%) 
Radius fracture  1  25/2206 (1.13%)  22/2343 (0.94%) 
Rib fracture  1  7/2206 (0.32%)  4/2343 (0.17%) 
Road traffic accident  1  1/2206 (0.05%)  3/2343 (0.13%) 
Scar  1  0/2206 (0.00%)  2/2343 (0.09%) 
Shunt malfunction  1  0/2206 (0.00%)  1/2343 (0.04%) 
Skeletal injury  1  0/2206 (0.00%)  1/2343 (0.04%) 
Skin abrasion  1  1/2206 (0.05%)  0/2343 (0.00%) 
Skull fracture  1  5/2206 (0.23%)  0/2343 (0.00%) 
Soft tissue injury  1  0/2206 (0.00%)  2/2343 (0.09%) 
Subdural haematoma  1  8/2206 (0.36%)  1/2343 (0.04%) 
Subdural haemorrhage  1  1/2206 (0.05%)  0/2343 (0.00%) 
Tendon rupture  1  1/2206 (0.05%)  2/2343 (0.09%) 
Thermal burn  1  2/2206 (0.09%)  1/2343 (0.04%) 
Thoracic vertebral fracture  1  1/2206 (0.05%)  9/2343 (0.38%) 
Tibia fracture  1  17/2206 (0.77%)  12/2343 (0.51%) 
Toxicity to various agents  1  4/2206 (0.18%)  2/2343 (0.09%) 
Transplant dysfunction  1  0/2206 (0.00%)  2/2343 (0.09%) 
Traumatic intracranial haemorrhage  1  1/2206 (0.05%)  0/2343 (0.00%) 
Ulna fracture  1  9/2206 (0.41%)  9/2343 (0.38%) 
Ulnar nerve injury  1  0/2206 (0.00%)  1/2343 (0.04%) 
Wound  1  2/2206 (0.09%)  1/2343 (0.04%) 
Wound dehiscence  1  0/2206 (0.00%)  2/2343 (0.09%) 
Wrist fracture  1  1/2206 (0.05%)  1/2343 (0.04%) 
Investigations     
Antinuclear antibody positive  1  0/2206 (0.00%)  1/2343 (0.04%) 
Blood pressure increased  1  0/2206 (0.00%)  1/2343 (0.04%) 
Blood pressure orthostatic  1  1/2206 (0.05%)  0/2343 (0.00%) 
Carcinoembryonic antigen increased  1  0/2206 (0.00%)  1/2343 (0.04%) 
Hepatic enzyme increased  1  1/2206 (0.05%)  0/2343 (0.00%) 
Investigation  1  1/2206 (0.05%)  0/2343 (0.00%) 
Occult blood positive  1  0/2206 (0.00%)  1/2343 (0.04%) 
Protein total decreased  1  1/2206 (0.05%)  0/2343 (0.00%) 
Troponin increased  1  0/2206 (0.00%)  1/2343 (0.04%) 
Weight decreased  1  3/2206 (0.14%)  1/2343 (0.04%) 
Metabolism and nutrition disorders     
Cachexia  1  0/2206 (0.00%)  1/2343 (0.04%) 
Dehydration  1  6/2206 (0.27%)  7/2343 (0.30%) 
Diabetes mellitus  1  2/2206 (0.09%)  3/2343 (0.13%) 
Diabetes mellitus inadequate control  1  0/2206 (0.00%)  1/2343 (0.04%) 
Electrolyte imbalance  1  2/2206 (0.09%)  1/2343 (0.04%) 
Failure to thrive  1  0/2206 (0.00%)  1/2343 (0.04%) 
Hypercalcaemia  1  1/2206 (0.05%)  3/2343 (0.13%) 
Hypercholesterolaemia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Hyperglycaemia  1  1/2206 (0.05%)  1/2343 (0.04%) 
Hyperkalaemia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Hypocalcaemia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Hypoglycaemia  1  0/2206 (0.00%)  2/2343 (0.09%) 
Hypokalaemia  1  2/2206 (0.09%)  0/2343 (0.00%) 
Hyponatraemia  1  4/2206 (0.18%)  2/2343 (0.09%) 
Metabolic acidosis  1  2/2206 (0.09%)  0/2343 (0.00%) 
Type 2 diabetes mellitus  1  2/2206 (0.09%)  1/2343 (0.04%) 
Vitamin B12 deficiency  1  0/2206 (0.00%)  1/2343 (0.04%) 
Musculoskeletal and connective tissue disorders     
Acquired claw toe  1  0/2206 (0.00%)  1/2343 (0.04%) 
Arthralgia  1  10/2206 (0.45%)  15/2343 (0.64%) 
Arthritis  1  6/2206 (0.27%)  4/2343 (0.17%) 
Arthropathy  1  0/2206 (0.00%)  1/2343 (0.04%) 
Back pain  1  16/2206 (0.73%)  10/2343 (0.43%) 
Bone disorder  1  0/2206 (0.00%)  1/2343 (0.04%) 
Bone loss  1  0/2206 (0.00%)  1/2343 (0.04%) 
Bone pain  1  1/2206 (0.05%)  0/2343 (0.00%) 
Bursitis  1  0/2206 (0.00%)  2/2343 (0.09%) 
Chondrocalcinosis  1  1/2206 (0.05%)  1/2343 (0.04%) 
Chondropathy  1  1/2206 (0.05%)  1/2343 (0.04%) 
Compartment syndrome  1  2/2206 (0.09%)  1/2343 (0.04%) 
Dupuytren's contracture  1  1/2206 (0.05%)  0/2343 (0.00%) 
Fibromyalgia  1  1/2206 (0.05%)  0/2343 (0.00%) 
Fistula  1  1/2206 (0.05%)  1/2343 (0.04%) 
Foot deformity  1  4/2206 (0.18%)  7/2343 (0.30%) 
Fracture pain  1  0/2206 (0.00%)  1/2343 (0.04%)