Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment of Osteoporosis

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00523341
• Collaborator: (none)
• Enrollment: 4,550
• Arm: 1
• Actual Duration (Months): 95.4

Study Details

Study Description

Brief Summary

The primary objective was to describe the safety and tolerability of up to 10 years or 7 years denosumab administration as measured by adverse event monitoring, immunogenicity and safety laboratory parameters in participants who previously received denosumab or placebo, respectively.

Condition or Disease	Intervention/Treatment	Phase
Osteopenia; Osteoporosis	Biological: Denosumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 4550 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Single Arm, Extension Study to Evaluate the Long Term Safety and Sustained Efficacy of Denosumab (AMG162) in the Treatment of Postmenopausal Osteoporosis
• Actual Study Start Date: Aug 7, 2007
• Actual Primary Completion Date: Jul 19, 2015
• Actual Study Completion Date: Jul 19, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Denosumab Participants received a 60 mg subcutaneous injection of denosumab every 6 months for seven years.	Biological: Denosumab; Administered by subcutaneous injection once every 6 months.; Other Names: AMG 162 Prolia

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs) [84 months]

   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.

2. Number of Participants With Laboratory Toxicities of Grade ≥ 3 [84 months]

   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.

3. Number of Participants With Antibodies to Denosumab [Every 12 months through Month 84]

Secondary Outcome Measures

1. Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit [Baseline (of extension study) and months 12, 24, 36, 60 and 84]

   Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

2. Percent Change From Baseline in Total Hip Bone Mineral Density by Visit [Baseline (of extension study) and months 12, 24, 36, 60 and 84]

   Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

3. Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit [Baseline (of extension study) and months 12, 24, 36, 60 and 84]

   Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

4. Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit [Baseline (of extension study) and months 12, 24, 36, 60 and 84]

   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.

5. Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit [Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84]

   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.

6. Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit [Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84]

   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.

7. Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit [Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84]

   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.

8. Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit [Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84]

   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.

9. Number of Participants With New Vertebral Fractures [84 months]

   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.

10. Number of Participants With Non-Vertebral Fractures [84 months]

    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.

11. Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit [Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84]

    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.

12. Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit [Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84]

    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.

13. Percent Change From Study 20030216 Baseline in CTX-1 by Visit [Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84]

    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.

14. Percent Change From Study 20030216 Baseline in P1NP by Visit [Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84]

    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.

15. Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10 [Baseline (of extension study) and day 10]

16. Serum Denosumab Concentration [Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)]

    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.

17. Bone Histomorphometry: Cancellous Bone Volume [Month 24 and month 84]

    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.

18. Bone Histomorphometry: Trabecular Number [Month 24 and month 84]

    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.

19. Bone Histomorphometry: Trabecular Separation [Month 24 and month 84]

    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.

20. Bone Histomorphometry: Trabecular Thickness [Month 24 and month 84]

    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.

21. Bone Histomorphometry: Cortical Width [Month 24 and month 84]

    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cortical width is the average width of both inner and outer cortices.

22. Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry [Month 24 and month 84]

    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.

23. Bone Histomorphometry: Surface Density [Month 24 and month 84]

    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Surface density is calculated by total bone (trabecular) surfaces / total tissue volume.

24. Bone Histomorphometry: Osteoblast - Osteoid Interface [Month 24 and month 84]

    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface * 100.

25. Bone Histomorphometry: Osteoid Surface [Month 24 and month 84]

    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid surface is the percent of bone surface covered in osteoid.

26. Bone Histomorphometry: Osteoid Thickness [Month 24 and month 84]

    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).

27. Bone Histomorphometry: Wall Thickness [Month 24 and month 84]

    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.

28. Bone Histomorphometry: Eroded Surface/Bone Surface [Month 24 and month 84]

    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.

29. Bone Histomorphometry: Osteoclast Number - Length Based [Month 24 and month 84]

    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.

30. Bone Histomorphometry: Osteoclast Number - Surface Based [Month 24 and month 84]

    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.

31. Bone Histomorphometry: Osteoclast Number by TRAP - Length Based [Month 24 and month 84]

    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.

32. Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based [Month 24 and month 84]

    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

33. Bone Histomorphometry: Single-label Surface [Month 24 and month 84]

    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.

34. Bone Histomorphometry: Double-label Surface [Month 24 and month 84]

    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.

35. Bone Histomorphometry: Mineralizing Surface [Month 24 and month 84]

    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.

36. Bone Histomorphometry: Mineral Apposition Rate [Month 24 and month 84]

    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.

37. Bone Histomorphometry: Adjusted Apposition Rate [Month 24 and month 84]

    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).

38. Bone Histomorphometry: Bone Formation Rate - Surface Based [Month 24 and month 84]

    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).

39. Bone Histomorphometry: Bone Formation Rate - Volume Based [Month 24 and month 84]

    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).

40. Bone Histomorphometry: Formation Period [Month 24 and month 84]

    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.

41. Bone Histomorphometry: Activation Frequency [Month 24 and month 84]

    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.

42. Bone Histomorphometry: Osteoid Volume [Month 24 and month 84]

    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).

43. Bone Histomorphometry: Mineralization Lag Time [Month 24 and month 84]

    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.

44. Bone Histology at Month 24 [Month 24]

    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.

45. Bone Histology at Month 84 [Month 84]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years to 94 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Postmenopausal women who have attended the 20030216 (NCT00089791) study month 36 visit will be eligible to participate if they meet the inclusion and exclusion criteria given below.

Inclusion Criteria

• Subjects must sign the informed consent before any study specific procedures are performed and agree to receive denosumab 60 mg subcutaneous injection every 6 months

• Subjects must not have discontinued investigational product during the 20030216 study and must have attended the 20030216 study month 36 visit

• Subjects must be re-consented prior to (or at) the 24 month visit for participation beyond month 24.

Exclusion Criteria

• Permanently non-ambulatory subjects (use of an assistive device eg, cane, walker, etc. is permitted)

• Missed 2 or more investigational product doses during the 20030216 study

• Any disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or comply with study procedures

• Developed sensitivity to mammalian cell derived drug products during the 20030216 study

• Unable to tolerate calcium supplementation during the last 6 months of participation in the 20030216 study (between the month 30 and month 36 20030216 study visits)

• Currently receiving any investigational product other than denosumab or having received any investigational product during the 20030216 study

• Current use of the following osteoporosis agents: bisphosphonates, calcitonin, fluoride, parathyroid hormone, selective estrogen receptor modulators, systemic oral or transdermal estrogen (except vaginal preparations and estrogen creams which are acceptable), strontium, or tibolone

• For bone biopsy sub-study subjects only: known or suspected sensitivity or contraindication to tetracycline derivatives

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwiński E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017 Jul;5(7):513-523. doi: 10.1016/S2213-8587(17)30138-9. Epub 2017 May 22.
• Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Törring O, Valter I, Wang AT, Brown JP. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22.
• Dempster DW, Brown JP, Fahrleitner-Pammer A, Kendler D, Rizzo S, Valter I, Wagman RB, Yin X, Yue SV, Boivin G. Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2498-2509. doi: 10.1210/jc.2017-02669.
• Ferrari S, Eastell R, Napoli N, Schwartz A, Hofbauer LC, Chines A, Wang A, Pannacciulli N, Cummings SR. Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension. Bone. 2020 May;134:115268. doi: 10.1016/j.bone.2020.115268. Epub 2020 Feb 10.
• Ferrari S, Lewiecki EM, Butler PW, Kendler DL, Napoli N, Huang S, Crittenden DB, Pannacciulli N, Siris E, Binkley N. Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed. Bone. 2020 May;134:115287. doi: 10.1016/j.bone.2020.115287. Epub 2020 Feb 21.
• Kendler DL, Chines A, Brandi ML, Papapoulos S, Lewiecki EM, Reginster JY, Muñoz Torres M, Wang A, Bone HG. The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. Osteoporos Int. 2019 Jan;30(1):71-78. doi: 10.1007/s00198-018-4687-2. Epub 2018 Sep 22.
• Watts NB, Brown JP, Papapoulos S, Lewiecki EM, Kendler DL, Dakin P, Wagman RB, Wang A, Daizadeh NS, Smith S, Bone HG. Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. J Bone Miner Res. 2017 Jul;32(7):1481-1485. doi: 10.1002/jbmr.3119. Epub 2017 Apr 3.
• Watts NB, Grbic JT, Binkley N, Papapoulos S, Butler PW, Yin X, Tierney A, Wagman RB, McClung M. Invasive Oral Procedures and Events in Postmenopausal Women With Osteoporosis Treated With Denosumab for Up to 10 Years. J Clin Endocrinol Metab. 2019 Jun 1;104(6):2443-2452. doi: 10.1210/jc.2018-01965.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00523341
• Other Study ID Numbers: 20060289
• First Posted: Aug 31, 2007
• Last Update Posted: Jul 20, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Amgen: postmenopausal osteoporosis; low bone density; fractures; low bone mass
• Additional relevant MeSH terms: Osteoporosis; Bone Diseases, Metabolic; Denosumab

Study Results

Participant Flow

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 Detail	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
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

Baseline Characteristics

Arm/Group Title	Placebo / Denosumab	Denosumab / Denosumab	Total
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 Participants	2207	2343	4550
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.8 (5.1)	74.9 (5.0)	74.8 (5.0)
Age, Customized (participants) [Number]
60 - 64 years	58 2.6%	49 2.1%	107 2.4%
65 - 69 years	326 14.8%	320 13.7%	646 14.2%
70 - 74 years	672 30.4%	716 30.6%	1388 30.5%
≥ 75 years	1151 52.2%	1258 53.7%	2409 52.9%
Sex: Female, Male (Count of Participants)
Female	2207 100%	2343 100%	4550 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	2063 93.5%	2169 92.6%	4232 93%
Black	16 0.7%	19 0.8%	35 0.8%
Hispanic or Latino	121 5.5%	145 6.2%	266 5.8%
Asian	2 0.1%	3 0.1%	5 0.1%
Japanese	3 0.1%	5 0.2%	8 0.2%
Native Hawaiian or Other Pacific Islander	1 0%	0 0%	1 0%
Other	1 0%	2 0.1%	3 0.1%
Bone Mineral Density T-score (T-score) [Mean (Standard Deviation) ]
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)
Bone Mineral Density T-score at Study 20030216 Baseline (T-score) [Mean (Standard Deviation) ]
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 (participants) [Number]
Number [participants]	1089 49.3%	1133 48.4%	2222 48.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs)
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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of denosumab.

Arm/Group Title	Placebo / Denosumab	Denosumab / Denosumab
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).
Measure Participants	2206	2343
Any adverse event (AE)	2070 93.8%	2173 92.7%
Serious adverse event	945 42.8%	1014 43.3%
Fatal adverse event	101 4.6%	108 4.6%
AE leading to study discontinuation	145 6.6%	173 7.4%
AE leading to discontinuation of denosumab	184 8.3%	216 9.2%
Treatment-related adverse events (TRAE)	185 8.4%	188 8%
Serious treatment-related adverse events	26 1.2%	28 1.2%
Fatal treatment-related adverse events	1 0%	0 0%
TRAE leading to study discontinuation	16 0.7%	9 0.4%
TRAE leading to discontinuation of denosumab	30 1.4%	25 1.1%
Positively adjudicated osteonecrosis of the jaw	6 0.3%	7 0.3%
Positively adjudicated atypical femoral fracture	1 0%	1 0%
Hypocalcaemia	10 0.5%	6 0.3%
AEs potentially related to hypersensitivity	260 11.8%	280 12%
Serious infections	161 7.3%	185 7.9%
Serious bacterial cellulitis	7 0.3%	12 0.5%
Malignancy	227 10.3%	237 10.1%
Cardiac disorders	449 20.3%	492 21%
Vascular disorders	693 31.4%	732 31.2%
Fracture healing complications	0 0%	1 0%
Eczema	99 4.5%	115 4.9%
Acute pancreatitis	4 0.2%	8 0.3%
Musculoskeletal pain	1125 51%	1206 51.5%

2. Primary Outcome

Title	Number of Participants With Laboratory Toxicities of Grade ≥ 3
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

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of denosumab

Arm/Group Title	Placebo / Denosumab	Denosumab / Denosumab
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).
Measure Participants	2206	2343
Low sodium - Grade 3	28 1.3%	25 1.1%
Low sodium - Grade 4	1 0%	0 0%
High potassium - Grade 3	9 0.4%	11 0.5%
High potassium - Grade 4	0 0%	3 0.1%
Low potassium - Grade 3	7 0.3%	7 0.3%
Low magnesium - Grade 3	1 0%	1 0%
Low magnesium - Grade 4	0 0%	1 0%
High calcium - Grade 3	2 0.1%	3 0.1%
High calcium - Grade 4	0 0%	2 0.1%
High corrected calcium - Grade 3	2 0.1%	3 0.1%
High corrected calcium - Grade 4	0 0%	2 0.1%
Low phosphorus - Grade 3	3 0.1%	1 0%
High Creatinine - Grade 3	0 0%	1 0%
High aspartate amino transferase (AST) - Grade 3	5 0.2%	11 0.5%
High aspartate amino transferase (AST) - Grade 4	1 0%	0 0%
High alanine amino transferase (ALT) - Grade 3	8 0.4%	10 0.4%
High alanine amino transferase (ALT) - Grade 4	1 0%	0 0%
High total bilirubin - Grade 3	2 0.1%	3 0.1%
Low albumin - Grade 3	0 0%	1 0%
High glucose - Grade 3	35 1.6%	37 1.6%
High glucose - Grade 4	0 0%	1 0%
Low glucose - Grade 3	4 0.2%	1 0%
Low glucose - Grade 4	1 0%	1 0%
Low hemoglobin - Grade 3	6 0.3%	4 0.2%
Low platelets - Grade 3	3 0.1%	7 0.3%
Low platelets - Grade 4	2 0.1%	4 0.2%
Low white blood cells - Grade 3	5 0.2%	7 0.3%
Low white blood cells - Grade 4	0 0%	1 0%
Low lymphocytes - Grade 3	17 0.8%	16 0.7%
Low lymphocytes - Grade 4	2 0.1%	1 0%

3. Primary Outcome

Title	Number of Participants With Antibodies to Denosumab
Time Frame	Every 12 months through Month 84

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of denosumab

Arm/Group Title	Placebo / Denosumab	Denosumab / Denosumab
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).
Measure Participants	2206	2343
Number [participants]	1 0%	0 0%

4. Secondary Outcome

Title	Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit
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

Outcome Measure Data

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
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).
Measure Participants	2089	2210
Month 12 (n = 2040, 2168)	5.2	2.0
Month 24 (n = 1935, 2061)	7.7	3.5
Month 36 (n = 1497, 1607)	9.4	4.9
Month 60 (n = 1472, 1567)	13.0	7.9
Month 84 (n = 1223, 1264)	16.5	10.8

5. Secondary Outcome

Title	Percent Change From Baseline in Total Hip Bone Mineral Density by Visit
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

Outcome Measure Data

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
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).
Measure Participants	2089	2210
Month 12 (n = 2029, 2160)	3.0	0.8
Month 24 (n = 1918, 2045)	4.1	1.4
Month 36 (n = 1475, 1591)	4.9	1.8
Month 60 (n = 1439, 1538)	6.2	2.6
Month 84 (n = 1200, 1232)	7.4	3.4

6. Secondary Outcome

Title	Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit
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

Outcome Measure Data

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
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).
Measure Participants	2089	2210
Month 12 (n = 2029, 2160)	2.1	0.8
Month 24 (n = 1918, 2045)	3.2	1.2
Month 36 (n = 1475, 1591)	4.0	1.7
Month 60 (n = 1439, 1538)	5.7	2.8
Month 84 (n = 1200, 1232)	7.1	3.8

7. Secondary Outcome

Title	Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit
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

Outcome Measure Data

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
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).
Measure Participants	449	467
Month 12 (n = 114, 134)	0.3	0.6
Month 24 (n = 108, 127)	0.2	0.2
Month 36 (n = 73, 93)	1.3	0.6
Month 60 (n = 59, 84)	1.8	1.4
Month 84 (n = 39, 56)	2.2	1.0

8. Secondary Outcome

Title	Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit
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

Outcome Measure Data

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
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).
Measure Participants	2089	2210
Month 12 (n = 2030, 2148)	5.9	11.9
Month 24 (n = 1924, 2041)	8.4	13.7
Month 36 (n = 1487, 1589)	10.1	15.2
Month 60 (n = 1464, 1551)	13.8	18.4
Month 84 (n = 1216, 1251)	17.3	21.7

9. Secondary Outcome

Title	Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit
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

Outcome Measure Data

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
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).
Measure Participants	2089	2210
Month 12 (n = 2006, 2132)	1.7	6.4
Month 24 (n = 1895, 2017)	2.9	7.1
Month 36 (n = 1457, 1567)	3.6	7.5
Month 60 (n = 1424, 1518)	4.9	8.4
Month 84 (n = 1189, 1215)	6.1	9.2

10. Secondary Outcome

Title	Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit
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

Outcome Measure Data

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
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).
Measure Participants	2089	2210
Month 12 (n = 2006, 2132)	1.4	5.8
Month 24 (n = 1895, 2017)	2.6	6.2
Month 36 (n = 1457, 1567)	3.4	6.7
Month 60 (n = 1424, 1518)	5.0	7.9
Month 84 (n = 1189, 1215)	6.4	9.0

11. Secondary Outcome

Title	Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit
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

Outcome Measure Data

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
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).
Measure Participants	449	467
Month 12 (n = 113, 133)	-1.0	2.6
Month 24 (n = 107, 127)	-1.2	2.1
Month 36 (n = 73, 92)	-0.2	2.4
Month 60 (n = 59, 83)	0.3	3.3
Month 84 (n = 39, 56)	0.6	2.8

12. Secondary Outcome

Title	Number of Participants With New Vertebral Fractures
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

Outcome Measure Data

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
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).
Measure Participants	1991	2116
Number [participants]	145 6.6%	149 6.4%

13. Secondary Outcome

Title	Number of Participants With Non-Vertebral Fractures
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

Outcome Measure Data

Analysis Population Description

All enrolled participants

Arm/Group Title	Placebo / Denosumab	Denosumab / Denosumab
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).
Measure Participants	2207	2343
Number [participants]	219 9.9%	172 7.3%

14. Secondary Outcome

Title	Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit
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

Outcome Measure Data

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
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).
Measure Participants	318	342
Day 10 (n = 26, 47)	-90	-72
Month 6 (n = 30, 56)	-85	-26
Month 12 (n = 27, 56)	-75	-13
Month 24 (n = 27, 47)	-67	10
Month 36 (n = 68, 81)	-59	2
Month 48 (n = 62, 75)	-58	0
Month 60 (n = 59, 70)	-65	0
Month 72 (n = 56, 62)	-60	-1
Month 84 (n = 41, 41)	-64	-6

15. Secondary Outcome

Title	Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit
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

Outcome Measure Data

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
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).
Measure Participants	318	342
Day 10 (n = 30, 51)	6	14
Month 6 (n = 30, 53)	-71	-23
Month 12 (n = 26, 56)	-67	7
Month 24 (n = 27, 47)	-63	11
Month 36 (n = 69, 83)	-57	29
Month 48 (n = 61, 73)	-60	8
Month 60 (n = 61, 71)	-54	30
Month 72 (n = 55, 64)	-50	44
Month 84 (n = 48, 50)	-59	32

16. Secondary Outcome

Title	Percent Change From Study 20030216 Baseline in CTX-1 by Visit
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

Outcome Measure Data

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
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).
Measure Participants	318	342
Day 10 (n = 26, 56)	-90	-91
Month 6 (n = 32, 72)	-83	-77
Month 12 (n = 27, 65)	-77	-63
Month 24 (n = 28, 60)	-65	-53
Month 36 (n = 289, 313)	-71	-52
Month 48 (n = 274, 290)	-70	-61
Month 60 (n = 268, 276)	-67	-53
Month 72 (n = 243, 248)	-69	-59
Month 84 (n = 217, 216)	-63	-53

17. Secondary Outcome

Title	Percent Change From Study 20030216 Baseline in P1NP by Visit
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

Outcome Measure Data

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
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).
Measure Participants	318	342
Day 10 (n = 30, 51)	9	-59
Month 6 (n = 32, 57)	-74	-75
Month 12 (n = 26, 56)	-74	-63
Month 24 (n = 28, 51)	-67	-56
Month 36 (n = 70, 83)	-59	-60
Month 48 (n = 61, 73)	-67	-63
Month 60 (n = 61, 71)	-62	-55
Month 72 (n = 56, 67)	-62	-55
Month 84 (n =49, 53)	-68	-57

18. Secondary Outcome

Title	Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
Time Frame	Baseline (of extension study) and day 10

Outcome Measure Data

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
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).
Measure Participants	2027	2154
Median (Inter-Quartile Range) [percent change]	-3.1	-2.0

19. Secondary Outcome

Title	Serum Denosumab Concentration
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)

Outcome Measure Data

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
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).
Measure Participants	97	113
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
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	15.253 (6.065)	14.640 (6.979)
Month 84 (n = 0, 19)	NA (NA)	16.358 (4.438)

21. Secondary Outcome

Title	Bone Histomorphometry: Trabecular Number
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	1.005 (0.242)	0.904 (0.243)
Month 24 (n = 0, 19)	NA (NA)	1.235 (0.254)

22. Secondary Outcome

Title	Bone Histomorphometry: Trabecular Separation
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	919.693 (358.238)	1033.416 (352.259)
Month 84 (n = 0, 19)	NA (NA)	708.669 (171.782)

23. Secondary Outcome

Title	Bone Histomorphometry: Trabecular Thickness
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	153.878 (51.859)	156.335 (48.567)
Month 84 (n = 0, 19)	NA (NA)	132.965 (28.064)

24. Secondary Outcome

Title	Bone Histomorphometry: Cortical Width
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

Outcome Measure Data

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
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).
Measure Participants	13	45
Month 24 (n = 13, 28)	622.22 (246.70)	707.69 (237.97)
Month 84 (n = 0, 21)	NA (NA)	786.19 (279.81)

25. Secondary Outcome

Title	Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	16.678 (7.270)	15.606 (6.986)
Month 84 (n = 0, 19)	NA (NA)	17.631 (4.387)

26. Secondary Outcome

Title	Bone Histomorphometry: Surface Density
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	2.009 (0.486)	1.807 (0.486)
Month 84 (n = 0, 19)	NA (NA)	2.472 (0.506)

27. Secondary Outcome

Title	Bone Histomorphometry: Osteoblast - Osteoid Interface
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	22.124 (34.879)	17.813 (28.381)
Month 84 (n = 0, 19)	NA (NA)	5.951 (15.223)

28. Secondary Outcome

Title	Bone Histomorphometry: Osteoid Surface
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	0.915 (1.382)	0.982 (2.489)
Month 84 (n = 0, 19)	NA (NA)	0.421 (1.068)

29. Secondary Outcome

Title	Bone Histomorphometry: Osteoid Thickness
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	5.139 (3.261)	4.548 (4.973)
Month 84 (n = 0, 19)	NA (NA)	4.108 (3.476)

30. Secondary Outcome

Title	Bone Histomorphometry: Wall Thickness
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	43.11 (6.08)	49.74 (10.51)
Month 84 (n = 0, 19)	NA (NA)	39.59 (7.49)

31. Secondary Outcome

Title	Bone Histomorphometry: Eroded Surface/Bone Surface
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	0.414 (0.701)	0.328 (0.613)
Month 84 (n = 0, 19)	NA (NA)	0.511 (0.579)

32. Secondary Outcome

Title	Bone Histomorphometry: Osteoclast Number - Length Based
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	0.086 (0.119)	0.107 (0.198)
Month 84 (n = 0, 19)	NA (NA)	0.074 (0.101)

33. Secondary Outcome

Title	Bone Histomorphometry: Osteoclast Number - Surface Based
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	8.6 (11.9)	10.7 (19.8)
Month 84 (n = 0, 19)	NA (NA)	7.4 (10.1)

34. Secondary Outcome

Title	Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	0.096 (0.134)	0.110 (0.185)
Month 84 (n = 0, 19)	NA (NA)	0.077 (0.107)

35. Secondary Outcome

Title	Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	9.6 (13.4)	11.0 (18.5)
Month 84 (n = 0, 19)	NA (NA)	7.7 (10.7)

36. Secondary Outcome

Title	Bone Histomorphometry: Single-label Surface
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	0.304 (0.302)	0.643 (0.661)
Month 84 (n = 0, 10)	NA (NA)	0.611 (0.726)

37. Secondary Outcome

Title	Bone Histomorphometry: Double-label Surface
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	0.258 (0.207)	0.356 (0.295)
Month 84 (n = 0, 10)	NA (NA)	0.106 (0.237)

38. Secondary Outcome

Title	Bone Histomorphometry: Mineralizing Surface
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	0.406 (0.323)	0.681 (0.453)
Month 84 (n = 0, 10)	NA (NA)	0.412 (0.458)

39. Secondary Outcome

Title	Bone Histomorphometry: Mineral Apposition Rate
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	0.616 (0.219)	0.722 (0.573)
Month 84 (n = 0, 10)	NA (NA)	0.394 (0.233)

40. Secondary Outcome

Title	Bone Histomorphometry: Adjusted Apposition Rate
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

Outcome Measure Data

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
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).
Measure Participants	5	19
Month 24 (n = 5, 9)	0.394 (0.471)	0.517 (0.537)
Month 84 (n = 0, 10)	NA (NA)	0.818 (1.207)

41. Secondary Outcome

Title	Bone Histomorphometry: Bone Formation Rate - Surface Based
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	0.898 (0.706)	2.153 (2.468)
Month 84 (n = 0, 10)	NA (NA)	0.691 (0.868)

42. Secondary Outcome

Title	Bone Histomorphometry: Bone Formation Rate - Volume Based
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	1.454 (1.265)	3.162 (3.773)
Month 84 (n = 0, 10)	NA (NA)	1.071 (1.308)

43. Secondary Outcome

Title	Bone Histomorphometry: Formation Period
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	593.5 (996.8)	287.3 (391.5)
Month 84 (n = 0, 10)	NA (NA)	229.7 (512.0)

44. Secondary Outcome

Title	Bone Histomorphometry: Activation Frequency
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	0.022 (0.019)	0.045 (0.049)
Month 84 (n = 0, 10)	NA (NA)	0.014 (0.024)

45. Secondary Outcome

Title	Bone Histomorphometry: Osteoid Volume
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

Outcome Measure Data

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
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).
Measure Participants	13	41
Month 24 (n = 13, 25)	0.108 (0.193)	0.146 (0.382)
Month 84 (n = 0, 19)	NA (NA)	0.048 (0.133)

46. Secondary Outcome

Title	Bone Histomorphometry: Mineralization Lag Time
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

Outcome Measure Data

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
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).
Measure Participants	5	20
Month 24 (n = 5, 10)	84.9 (136.8)	54.3 (76.1)
Month 84 (n = 0, 10)	NA (NA)	52.3 (114.5)

47. Secondary Outcome

Title	Bone Histology at Month 24
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

Outcome Measure Data

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
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).
Measure Participants	13	28
Measure biopsies	13	28
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
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

Outcome Measure Data

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
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).
Measure Participants	0	22
Measure biopsies	0	22
Normal lamellar bone	22
Normal mineralization	22
Osteoid	18
Osteomalacia	0
Marrow fibrosis	0
Woven bone	0

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo/ Denosumab 60 mg Q6M		Denosumab/ Denosumab 60 mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	945/2206 (42.8%)		1014/2343 (43.3%)
Blood and lymphatic system disorders
Anaemia	11/2206 (0.5%)		11/2343 (0.5%)
Bone marrow oedema	2/2206 (0.1%)		1/2343 (0%)
Haemorrhagic disorder	1/2206 (0%)		0/2343 (0%)
Iron deficiency anaemia	3/2206 (0.1%)		3/2343 (0.1%)
Leukopenia	1/2206 (0%)		1/2343 (0%)
Lymphadenitis	1/2206 (0%)		1/2343 (0%)
Lymphadenopathy	1/2206 (0%)		0/2343 (0%)
Microcytic anaemia	2/2206 (0.1%)		0/2343 (0%)
Neutropenia	1/2206 (0%)		0/2343 (0%)
Pancytopenia	1/2206 (0%)		0/2343 (0%)
Polycythaemia	1/2206 (0%)		0/2343 (0%)
Splenomegaly	1/2206 (0%)		0/2343 (0%)
Thrombocytopenia	3/2206 (0.1%)		0/2343 (0%)
Thrombocytosis	1/2206 (0%)		0/2343 (0%)
Cardiac disorders
Acute coronary syndrome	2/2206 (0.1%)		1/2343 (0%)
Acute myocardial infarction	8/2206 (0.4%)		18/2343 (0.8%)
Adams-Stokes syndrome	1/2206 (0%)		0/2343 (0%)
Angina pectoris	17/2206 (0.8%)		19/2343 (0.8%)
Angina unstable	7/2206 (0.3%)		12/2343 (0.5%)
Aortic valve disease	0/2206 (0%)		3/2343 (0.1%)
Aortic valve incompetence	1/2206 (0%)		0/2343 (0%)
Aortic valve stenosis	4/2206 (0.2%)		3/2343 (0.1%)
Arrhythmia	3/2206 (0.1%)		4/2343 (0.2%)
Arrhythmia supraventricular	1/2206 (0%)		0/2343 (0%)
Arteriosclerosis coronary artery	3/2206 (0.1%)		1/2343 (0%)
Atrial fibrillation	50/2206 (2.3%)		40/2343 (1.7%)
Atrial flutter	0/2206 (0%)		4/2343 (0.2%)
Atrioventricular block	0/2206 (0%)		2/2343 (0.1%)
Atrioventricular block complete	5/2206 (0.2%)		4/2343 (0.2%)
Atrioventricular block second degree	2/2206 (0.1%)		2/2343 (0.1%)
Bradycardia	5/2206 (0.2%)		3/2343 (0.1%)
Bundle branch block left	0/2206 (0%)		1/2343 (0%)
Cardiac arrest	4/2206 (0.2%)		4/2343 (0.2%)
Cardiac disorder	0/2206 (0%)		1/2343 (0%)
Cardiac failure	15/2206 (0.7%)		21/2343 (0.9%)
Cardiac failure acute	1/2206 (0%)		3/2343 (0.1%)
Cardiac failure chronic	1/2206 (0%)		3/2343 (0.1%)
Cardiac failure congestive	10/2206 (0.5%)		9/2343 (0.4%)
Cardiac fibrillation	1/2206 (0%)		0/2343 (0%)
Cardiac valve disease	0/2206 (0%)		2/2343 (0.1%)
Cardiac valve sclerosis	0/2206 (0%)		1/2343 (0%)
Cardio-respiratory arrest	1/2206 (0%)		2/2343 (0.1%)
Cardiogenic shock	0/2206 (0%)		2/2343 (0.1%)
Cardiomyopathy	1/2206 (0%)		0/2343 (0%)
Cardiopulmonary failure	4/2206 (0.2%)		1/2343 (0%)
Cardiovascular insufficiency	1/2206 (0%)		0/2343 (0%)
Chronic right ventricular failure	0/2206 (0%)		1/2343 (0%)
Coronary artery disease	9/2206 (0.4%)		17/2343 (0.7%)
Coronary artery insufficiency	3/2206 (0.1%)		0/2343 (0%)
Coronary artery occlusion	1/2206 (0%)		0/2343 (0%)
Coronary artery stenosis	1/2206 (0%)		6/2343 (0.3%)
Extrasystoles	0/2206 (0%)		1/2343 (0%)
Heart valve calcification	2/2206 (0.1%)		0/2343 (0%)
Heart valve incompetence	1/2206 (0%)		0/2343 (0%)
Hypertensive heart disease	2/2206 (0.1%)		1/2343 (0%)
Ischaemic cardiomyopathy	1/2206 (0%)		1/2343 (0%)
Left atrial dilatation	0/2206 (0%)		1/2343 (0%)
Left ventricular failure	2/2206 (0.1%)		3/2343 (0.1%)
Mitral valve disease	1/2206 (0%)		1/2343 (0%)
Mitral valve disease mixed	0/2206 (0%)		1/2343 (0%)
Mitral valve incompetence	1/2206 (0%)		2/2343 (0.1%)
Myocardial infarction	21/2206 (1%)		24/2343 (1%)
Myocardial ischaemia	4/2206 (0.2%)		13/2343 (0.6%)
Palpitations	2/2206 (0.1%)		2/2343 (0.1%)
Pericardial effusion	1/2206 (0%)		2/2343 (0.1%)
Pericardial haemorrhage	1/2206 (0%)		0/2343 (0%)
Pericarditis	2/2206 (0.1%)		0/2343 (0%)
Right ventricular failure	0/2206 (0%)		2/2343 (0.1%)
Sinoatrial block	2/2206 (0.1%)		0/2343 (0%)
Sinus arrest	0/2206 (0%)		2/2343 (0.1%)
Sinus bradycardia	0/2206 (0%)		2/2343 (0.1%)
Sinus node dysfunction	6/2206 (0.3%)		10/2343 (0.4%)
Supraventricular extrasystoles	1/2206 (0%)		1/2343 (0%)
Supraventricular tachyarrhythmia	1/2206 (0%)		0/2343 (0%)
Supraventricular tachycardia	2/2206 (0.1%)		2/2343 (0.1%)
Tachyarrhythmia	2/2206 (0.1%)		0/2343 (0%)
Tachycardia	0/2206 (0%)		1/2343 (0%)
Tachycardia induced cardiomyopathy	1/2206 (0%)		0/2343 (0%)
Tricuspid valve disease	0/2206 (0%)		1/2343 (0%)
Ventricular arrhythmia	0/2206 (0%)		1/2343 (0%)
Ventricular extrasystoles	2/2206 (0.1%)		1/2343 (0%)
Ventricular fibrillation	0/2206 (0%)		1/2343 (0%)
Ventricular tachycardia	1/2206 (0%)		1/2343 (0%)
Congenital, familial and genetic disorders
Cancer gene carrier	0/2206 (0%)		1/2343 (0%)
Congenital ureteric anomaly	1/2206 (0%)		0/2343 (0%)
Corneal dystrophy	0/2206 (0%)		1/2343 (0%)
Muscular dystrophy	0/2206 (0%)		1/2343 (0%)
Ear and labyrinth disorders
Deafness unilateral	1/2206 (0%)		0/2343 (0%)
Hypoacusis	0/2206 (0%)		3/2343 (0.1%)
Meniere's disease	0/2206 (0%)		1/2343 (0%)
Otosclerosis	1/2206 (0%)		0/2343 (0%)
Vertigo	14/2206 (0.6%)		8/2343 (0.3%)
Vertigo positional	0/2206 (0%)		1/2343 (0%)
Vestibular disorder	1/2206 (0%)		1/2343 (0%)
Endocrine disorders
Adrenal mass	0/2206 (0%)		1/2343 (0%)
Basedow's disease	0/2206 (0%)		1/2343 (0%)
Goitre	6/2206 (0.3%)		5/2343 (0.2%)
Hyperthyroidism	2/2206 (0.1%)		0/2343 (0%)
Inappropriate antidiuretic hormone secretion	0/2206 (0%)		1/2343 (0%)
Thyroiditis	1/2206 (0%)		0/2343 (0%)
Toxic nodular goitre	1/2206 (0%)		0/2343 (0%)
Eye disorders
Blepharochalasis	1/2206 (0%)		0/2343 (0%)
Blindness	1/2206 (0%)		0/2343 (0%)
Blindness unilateral	1/2206 (0%)		0/2343 (0%)
Cataract	17/2206 (0.8%)		15/2343 (0.6%)
Cataract diabetic	1/2206 (0%)		0/2343 (0%)
Detachment of macular retinal pigment epithelium	0/2206 (0%)		1/2343 (0%)
Diplopia	0/2206 (0%)		1/2343 (0%)
Ectropion	0/2206 (0%)		1/2343 (0%)
Eye haemorrhage	1/2206 (0%)		0/2343 (0%)
Glaucoma	3/2206 (0.1%)		3/2343 (0.1%)
Iridocyclitis	1/2206 (0%)		0/2343 (0%)
Keratopathy	0/2206 (0%)		1/2343 (0%)
Macular fibrosis	0/2206 (0%)		3/2343 (0.1%)
Maculopathy	1/2206 (0%)		0/2343 (0%)
Open angle glaucoma	0/2206 (0%)		1/2343 (0%)
Retinal detachment	0/2206 (0%)		3/2343 (0.1%)
Retinal haemorrhage	1/2206 (0%)		2/2343 (0.1%)
Retinal tear	0/2206 (0%)		1/2343 (0%)
Retinal vascular thrombosis	1/2206 (0%)		0/2343 (0%)
Ulcerative keratitis	0/2206 (0%)		1/2343 (0%)
Visual impairment	2/2206 (0.1%)		1/2343 (0%)
Vitreous haemorrhage	1/2206 (0%)		1/2343 (0%)
Gastrointestinal disorders
Abdominal adhesions	1/2206 (0%)		0/2343 (0%)
Abdominal distension	1/2206 (0%)		1/2343 (0%)
Abdominal hernia	4/2206 (0.2%)		2/2343 (0.1%)
Abdominal hernia obstructive	1/2206 (0%)		0/2343 (0%)
Abdominal pain	10/2206 (0.5%)		8/2343 (0.3%)
Abdominal pain upper	2/2206 (0.1%)		2/2343 (0.1%)
Abdominal rigidity	1/2206 (0%)		0/2343 (0%)
Acquired oesophageal web	1/2206 (0%)		0/2343 (0%)
Anal haemorrhage	0/2206 (0%)		1/2343 (0%)
Anal prolapse	1/2206 (0%)		0/2343 (0%)
Anal sphincter atony	1/2206 (0%)		0/2343 (0%)
Chronic gastritis	0/2206 (0%)		1/2343 (0%)
Coeliac disease	0/2206 (0%)		1/2343 (0%)
Colitis	3/2206 (0.1%)		2/2343 (0.1%)
Colitis ischaemic	2/2206 (0.1%)		2/2343 (0.1%)
Colitis microscopic	1/2206 (0%)		0/2343 (0%)
Colitis ulcerative	3/2206 (0.1%)		0/2343 (0%)
Constipation	8/2206 (0.4%)		6/2343 (0.3%)
Crohn's disease	0/2206 (0%)		1/2343 (0%)
Diaphragmatic hernia	1/2206 (0%)		0/2343 (0%)
Diarrhoea	9/2206 (0.4%)		3/2343 (0.1%)
Diverticular perforation	1/2206 (0%)		0/2343 (0%)
Diverticulum	3/2206 (0.1%)		3/2343 (0.1%)
Diverticulum intestinal	1/2206 (0%)		6/2343 (0.3%)
Diverticulum oesophageal	0/2206 (0%)		1/2343 (0%)
Duodenal stenosis	0/2206 (0%)		1/2343 (0%)
Duodenal ulcer	5/2206 (0.2%)		3/2343 (0.1%)
Duodenal ulcer haemorrhage	1/2206 (0%)		0/2343 (0%)
Duodenal ulcer perforation	1/2206 (0%)		0/2343 (0%)
Duodenitis	1/2206 (0%)		0/2343 (0%)
Dyspepsia	3/2206 (0.1%)		3/2343 (0.1%)
Dysphagia	0/2206 (0%)		1/2343 (0%)
Enteritis	1/2206 (0%)		1/2343 (0%)
Enterocolitis haemorrhagic	1/2206 (0%)		0/2343 (0%)
Epigastric discomfort	1/2206 (0%)		0/2343 (0%)
Faecal incontinence	1/2206 (0%)		0/2343 (0%)
Faeces discoloured	1/2206 (0%)		0/2343 (0%)
Femoral hernia	1/2206 (0%)		0/2343 (0%)
Gastric ulcer	6/2206 (0.3%)		3/2343 (0.1%)
Gastric ulcer haemorrhage	1/2206 (0%)		0/2343 (0%)
Gastritis	4/2206 (0.2%)		9/2343 (0.4%)
Gastritis erosive	1/2206 (0%)		2/2343 (0.1%)
Gastroduodenal ulcer	0/2206 (0%)		1/2343 (0%)
Gastrointestinal haemorrhage	6/2206 (0.3%)		1/2343 (0%)
Gastrointestinal inflammation	0/2206 (0%)		1/2343 (0%)
Gastrointestinal motility disorder	1/2206 (0%)		0/2343 (0%)
Gastrointestinal mucosal disorder	1/2206 (0%)		0/2343 (0%)
Gastrointestinal obstruction	2/2206 (0.1%)		0/2343 (0%)
Gastrointestinal stenosis	0/2206 (0%)		1/2343 (0%)
Gastrooesophageal reflux disease	3/2206 (0.1%)		2/2343 (0.1%)
Haematemesis	0/2206 (0%)		1/2343 (0%)
Haematochezia	1/2206 (0%)		2/2343 (0.1%)
Haemorrhoids	1/2206 (0%)		2/2343 (0.1%)
Hernial eventration	1/2206 (0%)		0/2343 (0%)
Hiatus hernia	2/2206 (0.1%)		4/2343 (0.2%)
Ileus	7/2206 (0.3%)		3/2343 (0.1%)
Inguinal hernia	14/2206 (0.6%)		7/2343 (0.3%)
Intestinal angina	0/2206 (0%)		1/2343 (0%)
Intestinal fistula	1/2206 (0%)		0/2343 (0%)
Intestinal haemorrhage	4/2206 (0.2%)		1/2343 (0%)
Intestinal ischaemia	1/2206 (0%)		1/2343 (0%)
Intestinal obstruction	5/2206 (0.2%)		1/2343 (0%)
Intestinal perforation	0/2206 (0%)		1/2343 (0%)
Intestinal strangulation	0/2206 (0%)		1/2343 (0%)
Irritable bowel syndrome	2/2206 (0.1%)		1/2343 (0%)
Large intestinal haemorrhage	1/2206 (0%)		0/2343 (0%)
Large intestinal stenosis	0/2206 (0%)		1/2343 (0%)
Large intestine polyp	4/2206 (0.2%)		5/2343 (0.2%)
Lower gastrointestinal haemorrhage	0/2206 (0%)		1/2343 (0%)
Malabsorption	0/2206 (0%)		1/2343 (0%)
Mechanical ileus	0/2206 (0%)		2/2343 (0.1%)
Melaena	2/2206 (0.1%)		2/2343 (0.1%)
Mesenteric artery embolism	0/2206 (0%)		2/2343 (0.1%)
Nausea	2/2206 (0.1%)		2/2343 (0.1%)
Oesophageal polyp	0/2206 (0%)		1/2343 (0%)
Oesophagitis	1/2206 (0%)		1/2343 (0%)
Pancreatic cyst	2/2206 (0.1%)		0/2343 (0%)
Pancreatic necrosis	1/2206 (0%)		0/2343 (0%)
Pancreatitis	0/2206 (0%)		4/2343 (0.2%)
Pancreatitis acute	1/2206 (0%)		4/2343 (0.2%)
Pancreatitis chronic	1/2206 (0%)		1/2343 (0%)
Pancreatitis necrotising	1/2206 (0%)		0/2343 (0%)
Peptic ulcer	1/2206 (0%)		0/2343 (0%)
Periodontal disease	0/2206 (0%)		1/2343 (0%)
Peritoneal perforation	0/2206 (0%)		1/2343 (0%)
Pharyngo-oesophageal diverticulum	1/2206 (0%)		1/2343 (0%)
Rectal haemorrhage	2/2206 (0.1%)		0/2343 (0%)
Rectal polyp	2/2206 (0.1%)		3/2343 (0.1%)
Rectal prolapse	1/2206 (0%)		4/2343 (0.2%)
Retroperitoneal haematoma	0/2206 (0%)		1/2343 (0%)
Small intestinal obstruction	2/2206 (0.1%)		0/2343 (0%)
Stomatitis	0/2206 (0%)		1/2343 (0%)
Subileus	1/2206 (0%)		1/2343 (0%)
Tongue oedema	1/2206 (0%)		0/2343 (0%)
Toothache	0/2206 (0%)		1/2343 (0%)
Umbilical hernia	2/2206 (0.1%)		1/2343 (0%)
Upper gastrointestinal haemorrhage	2/2206 (0.1%)		1/2343 (0%)
Volvulus	0/2206 (0%)		1/2343 (0%)
Volvulus of small bowel	0/2206 (0%)		1/2343 (0%)
Vomiting	4/2206 (0.2%)		2/2343 (0.1%)
General disorders
Adverse drug reaction	0/2206 (0%)		1/2343 (0%)
Asthenia	3/2206 (0.1%)		4/2343 (0.2%)
Chest pain	9/2206 (0.4%)		8/2343 (0.3%)
Chronic fatigue syndrome	1/2206 (0%)		0/2343 (0%)
Death	16/2206 (0.7%)		13/2343 (0.6%)
Device dislocation	3/2206 (0.1%)		5/2343 (0.2%)
Device failure	0/2206 (0%)		1/2343 (0%)
Device malfunction	0/2206 (0%)		2/2343 (0.1%)
Face oedema	1/2206 (0%)		0/2343 (0%)
Fatigue	1/2206 (0%)		0/2343 (0%)
Foreign body reaction	0/2206 (0%)		1/2343 (0%)
Gait disturbance	0/2206 (0%)		1/2343 (0%)
General physical health deterioration	4/2206 (0.2%)		4/2343 (0.2%)
Hernia	1/2206 (0%)		1/2343 (0%)
Incarcerated hernia	1/2206 (0%)		0/2343 (0%)
Inflammation	0/2206 (0%)		1/2343 (0%)
Ischaemic ulcer	0/2206 (0%)		1/2343 (0%)
Malaise	2/2206 (0.1%)		2/2343 (0.1%)
Medical device complication	2/2206 (0.1%)		0/2343 (0%)
Multi-organ failure	2/2206 (0.1%)		4/2343 (0.2%)
Nodule	0/2206 (0%)		1/2343 (0%)
Non-cardiac chest pain	7/2206 (0.3%)		5/2343 (0.2%)
Oedema peripheral	0/2206 (0%)		1/2343 (0%)
Peripheral swelling	0/2206 (0%)		2/2343 (0.1%)
Polyp	1/2206 (0%)		0/2343 (0%)
Pyrexia	4/2206 (0.2%)		5/2343 (0.2%)
Sudden cardiac death	1/2206 (0%)		0/2343 (0%)
Sudden death	4/2206 (0.2%)		1/2343 (0%)
Ulcer haemorrhage	1/2206 (0%)		0/2343 (0%)
Hepatobiliary disorders
Autoimmune hepatitis	0/2206 (0%)		1/2343 (0%)
Bile duct obstruction	0/2206 (0%)		2/2343 (0.1%)
Bile duct stenosis	1/2206 (0%)		2/2343 (0.1%)
Bile duct stone	0/2206 (0%)		4/2343 (0.2%)
Biliary cirrhosis primary	0/2206 (0%)		1/2343 (0%)
Biliary colic	2/2206 (0.1%)		5/2343 (0.2%)
Cholangitis	4/2206 (0.2%)		1/2343 (0%)
Cholecystitis	6/2206 (0.3%)		4/2343 (0.2%)
Cholecystitis acute	4/2206 (0.2%)		2/2343 (0.1%)
Cholelithiasis	22/2206 (1%)		30/2343 (1.3%)
Gallbladder necrosis	1/2206 (0%)		0/2343 (0%)
Gallbladder oedema	0/2206 (0%)		1/2343 (0%)
Gallbladder polyp	0/2206 (0%)		1/2343 (0%)
Hepatic cirrhosis	0/2206 (0%)		1/2343 (0%)
Hepatic cyst	0/2206 (0%)		1/2343 (0%)
Hepatic failure	0/2206 (0%)		1/2343 (0%)
Jaundice	0/2206 (0%)		2/2343 (0.1%)
Jaundice cholestatic	0/2206 (0%)		1/2343 (0%)
Liver disorder	1/2206 (0%)		2/2343 (0.1%)
Immune system disorders
Anaphylactic reaction	1/2206 (0%)		1/2343 (0%)
Autoimmune disorder	1/2206 (0%)		0/2343 (0%)
Drug hypersensitivity	0/2206 (0%)		1/2343 (0%)
Hypersensitivity	0/2206 (0%)		1/2343 (0%)
Sarcoidosis	0/2206 (0%)		1/2343 (0%)
Infections and infestations
Abdominal abscess	1/2206 (0%)		0/2343 (0%)
Abdominal sepsis	0/2206 (0%)		1/2343 (0%)
Abscess	0/2206 (0%)		1/2343 (0%)
Abscess limb	1/2206 (0%)		0/2343 (0%)
Abscess neck	0/2206 (0%)		1/2343 (0%)
Appendiceal abscess	1/2206 (0%)		1/2343 (0%)
Appendicitis	4/2206 (0.2%)		5/2343 (0.2%)
Appendicitis perforated	2/2206 (0.1%)		1/2343 (0%)
Arthritis bacterial	1/2206 (0%)		2/2343 (0.1%)
Arthritis infective	1/2206 (0%)		0/2343 (0%)
Atypical pneumonia	1/2206 (0%)		0/2343 (0%)
Bacteraemia	1/2206 (0%)		1/2343 (0%)
Bacterial infection	0/2206 (0%)		1/2343 (0%)
Bacterial pyelonephritis	1/2206 (0%)		0/2343 (0%)
Bronchitis	8/2206 (0.4%)		7/2343 (0.3%)
Bronchitis fungal	0/2206 (0%)		1/2343 (0%)
Bronchopneumonia	6/2206 (0.3%)		6/2343 (0.3%)
Cellulitis	3/2206 (0.1%)		2/2343 (0.1%)
Cholecystitis infective	0/2206 (0%)		3/2343 (0.1%)
Chronic sinusitis	1/2206 (0%)		0/2343 (0%)
Chronic tonsillitis	1/2206 (0%)		0/2343 (0%)
Clostridium difficile infection	0/2206 (0%)		1/2343 (0%)
Cystitis	6/2206 (0.3%)		5/2343 (0.2%)
Dengue fever	2/2206 (0.1%)		1/2343 (0%)
Device related infection	2/2206 (0.1%)		1/2343 (0%)
Diverticulitis	11/2206 (0.5%)		10/2343 (0.4%)
Ear infection	1/2206 (0%)		0/2343 (0%)
Endocarditis	0/2206 (0%)		2/2343 (0.1%)
Enterocolitis bacterial	0/2206 (0%)		1/2343 (0%)
Erysipelas	4/2206 (0.2%)		9/2343 (0.4%)
Gangrene	1/2206 (0%)		1/2343 (0%)
Gastroenteritis	9/2206 (0.4%)		9/2343 (0.4%)
Gastroenteritis viral	2/2206 (0.1%)		0/2343 (0%)
Gastrointestinal infection	0/2206 (0%)		1/2343 (0%)
H1N1 influenza	0/2206 (0%)		1/2343 (0%)
Haemophilus infection	1/2206 (0%)		0/2343 (0%)
Helicobacter gastritis	2/2206 (0.1%)		0/2343 (0%)
Hepatic cyst infection	0/2206 (0%)		1/2343 (0%)
Hepatitis C	1/2206 (0%)		0/2343 (0%)
Herpes zoster	2/2206 (0.1%)		2/2343 (0.1%)
Infected skin ulcer	1/2206 (0%)		1/2343 (0%)
Infection	0/2206 (0%)		1/2343 (0%)
Infective exacerbation of chronic obstructive airways disease	1/2206 (0%)		1/2343 (0%)
Influenza	2/2206 (0.1%)		0/2343 (0%)
Klebsiella bacteraemia	0/2206 (0%)		1/2343 (0%)
Klebsiella infection	0/2206 (0%)		1/2343 (0%)
Laryngitis	2/2206 (0.1%)		0/2343 (0%)
Listeriosis	0/2206 (0%)		1/2343 (0%)
Liver abscess	0/2206 (0%)		3/2343 (0.1%)
Lobar pneumonia	2/2206 (0.1%)		4/2343 (0.2%)
Localised infection	0/2206 (0%)		1/2343 (0%)
Lower respiratory tract infection	2/2206 (0.1%)		6/2343 (0.3%)
Lung infection	3/2206 (0.1%)		1/2343 (0%)
Lymph node tuberculosis	0/2206 (0%)		1/2343 (0%)
Meningitis aseptic	0/2206 (0%)		1/2343 (0%)
Meningitis viral	0/2206 (0%)		1/2343 (0%)
Mycobacterium avium complex infection	1/2206 (0%)		1/2343 (0%)
Necrotising fasciitis	0/2206 (0%)		1/2343 (0%)
Neutropenic sepsis	1/2206 (0%)		1/2343 (0%)
Onychomycosis	1/2206 (0%)		1/2343 (0%)
Osteomyelitis	2/2206 (0.1%)		2/2343 (0.1%)
Otitis media	1/2206 (0%)		0/2343 (0%)
Parotitis	1/2206 (0%)		0/2343 (0%)
Peritonitis	0/2206 (0%)		2/2343 (0.1%)
Pneumonia	44/2206 (2%)		48/2343 (2%)
Pneumonia bacterial	3/2206 (0.1%)		4/2343 (0.2%)
Pneumonia haemophilus	1/2206 (0%)		1/2343 (0%)
Pneumonia influenzal	1/2206 (0%)		0/2343 (0%)
Pneumonia pneumococcal	3/2206 (0.1%)		2/2343 (0.1%)
Pneumonia pseudomonal	0/2206 (0%)		1/2343 (0%)
Pneumonia staphylococcal	1/2206 (0%)		1/2343 (0%)
Pneumonia streptococcal	1/2206 (0%)		0/2343 (0%)
Post procedural infection	0/2206 (0%)		2/2343 (0.1%)
Postoperative wound infection	1/2206 (0%)		0/2343 (0%)
Pseudomembranous colitis	0/2206 (0%)		1/2343 (0%)
Pulmonary tuberculosis	1/2206 (0%)		0/2343 (0%)
Pyelonephritis	5/2206 (0.2%)		3/2343 (0.1%)
Pyelonephritis acute	0/2206 (0%)		1/2343 (0%)
Pyelonephritis chronic	0/2206 (0%)		1/2343 (0%)
Respiratory tract infection	2/2206 (0.1%)		2/2343 (0.1%)
Salmonellosis	1/2206 (0%)		2/2343 (0.1%)
Salpingitis	1/2206 (0%)		0/2343 (0%)
Salpingo-oophoritis	1/2206 (0%)		0/2343 (0%)
Sepsis	6/2206 (0.3%)		15/2343 (0.6%)
Septic shock	5/2206 (0.2%)		5/2343 (0.2%)
Sinusitis	3/2206 (0.1%)		1/2343 (0%)
Skin infection	0/2206 (0%)		1/2343 (0%)
Small intestine gangrene	0/2206 (0%)		1/2343 (0%)
Soft tissue infection	0/2206 (0%)		1/2343 (0%)
Staphylococcal bacteraemia	0/2206 (0%)		1/2343 (0%)
Staphylococcal sepsis	0/2206 (0%)		1/2343 (0%)
Stenotrophomonas infection	0/2206 (0%)		1/2343 (0%)
Subcutaneous abscess	1/2206 (0%)		0/2343 (0%)
Subdural empyema	0/2206 (0%)		1/2343 (0%)
Tick-borne viral encephalitis	0/2206 (0%)		1/2343 (0%)
Tonsillitis	0/2206 (0%)		1/2343 (0%)
Tooth infection	1/2206 (0%)		0/2343 (0%)
Tracheitis	1/2206 (0%)		0/2343 (0%)
Tracheobronchitis	0/2206 (0%)		1/2343 (0%)
Tuberculosis	1/2206 (0%)		0/2343 (0%)
Tuberculosis of peripheral lymph nodes	0/2206 (0%)		1/2343 (0%)
Upper respiratory tract infection	0/2206 (0%)		2/2343 (0.1%)
Urinary tract infection	13/2206 (0.6%)		11/2343 (0.5%)
Urosepsis	6/2206 (0.3%)		3/2343 (0.1%)
Vaginal infection	0/2206 (0%)		1/2343 (0%)
Vestibular neuronitis	0/2206 (0%)		1/2343 (0%)
Viral infection	2/2206 (0.1%)		0/2343 (0%)
Wound infection	3/2206 (0.1%)		0/2343 (0%)
Injury, poisoning and procedural complications
Acetabulum fracture	0/2206 (0%)		2/2343 (0.1%)
Animal bite	0/2206 (0%)		1/2343 (0%)
Bone fissure	1/2206 (0%)		0/2343 (0%)
Brain contusion	1/2206 (0%)		0/2343 (0%)
Carbon monoxide poisoning	1/2206 (0%)		0/2343 (0%)
Cartilage injury	0/2206 (0%)		1/2343 (0%)
Cataract traumatic	0/2206 (0%)		1/2343 (0%)
Cervical vertebral fracture	1/2206 (0%)		1/2343 (0%)
Clavicle fracture	1/2206 (0%)		0/2343 (0%)
Concussion	7/2206 (0.3%)		8/2343 (0.3%)
Contusion	4/2206 (0.2%)		1/2343 (0%)
Coronary artery restenosis	0/2206 (0%)		1/2343 (0%)
Craniocerebral injury	1/2206 (0%)		3/2343 (0.1%)
Dislocation of vertebra	1/2206 (0%)		1/2343 (0%)
Eye penetration	2/2206 (0.1%)		1/2343 (0%)
Facial bones fracture	0/2206 (0%)		9/2343 (0.4%)
Fall	13/2206 (0.6%)		16/2343 (0.7%)
Femoral neck fracture	16/2206 (0.7%)		15/2343 (0.6%)
Femur fracture	16/2206 (0.7%)		12/2343 (0.5%)
Fibula fracture	14/2206 (0.6%)		11/2343 (0.5%)
Foot fracture	1/2206 (0%)		1/2343 (0%)
Fractured sacrum	1/2206 (0%)		0/2343 (0%)
Gastrointestinal stoma complication	1/2206 (0%)		1/2343 (0%)
Graft complication	0/2206 (0%)		1/2343 (0%)
Hand fracture	0/2206 (0%)		1/2343 (0%)
Head injury	4/2206 (0.2%)		6/2343 (0.3%)
Hip fracture	1/2206 (0%)		1/2343 (0%)
Humerus fracture	13/2206 (0.6%)		5/2343 (0.2%)
Ilium fracture	1/2206 (0%)		0/2343 (0%)
Incisional hernia	2/2206 (0.1%)		1/2343 (0%)
Injury corneal	1/2206 (0%)		0/2343 (0%)
Joint dislocation	7/2206 (0.3%)		6/2343 (0.3%)
Joint injury	0/2206 (0%)		1/2343 (0%)
Laceration	2/2206 (0.1%)		2/2343 (0.1%)
Ligament injury	1/2206 (0%)		0/2343 (0%)
Ligament rupture	2/2206 (0.1%)		0/2343 (0%)
Ligament sprain	2/2206 (0.1%)		0/2343 (0%)
Limb crushing injury	0/2206 (0%)		1/2343 (0%)
Lumbar vertebral fracture	4/2206 (0.2%)		3/2343 (0.1%)
Meniscus injury	5/2206 (0.2%)		2/2343 (0.1%)
Multiple injuries	1/2206 (0%)		0/2343 (0%)
Muscle rupture	0/2206 (0%)		1/2343 (0%)
Overdose	3/2206 (0.1%)		1/2343 (0%)
Patella fracture	5/2206 (0.2%)		5/2343 (0.2%)
Perineal injury	0/2206 (0%)		1/2343 (0%)
Pneumothorax traumatic	0/2206 (0%)		1/2343 (0%)
Post procedural complication	0/2206 (0%)		2/2343 (0.1%)
Post procedural haematoma	0/2206 (0%)		2/2343 (0.1%)
Post procedural haemorrhage	2/2206 (0.1%)		0/2343 (0%)
Postoperative hernia	1/2206 (0%)		0/2343 (0%)
Postoperative ileus	1/2206 (0%)		0/2343 (0%)
Procedural hypotension	1/2206 (0%)		0/2343 (0%)
Procedural pain	1/2206 (0%)		2/2343 (0.1%)
Pubis fracture	3/2206 (0.1%)		5/2343 (0.2%)
Radiation mucositis	0/2206 (0%)		1/2343 (0%)
Radius fracture	25/2206 (1.1%)		22/2343 (0.9%)
Rib fracture	7/2206 (0.3%)		4/2343 (0.2%)
Road traffic accident	1/2206 (0%)		3/2343 (0.1%)
Scar	0/2206 (0%)		2/2343 (0.1%)
Shunt malfunction	0/2206 (0%)		1/2343 (0%)
Skeletal injury	0/2206 (0%)		1/2343 (0%)
Skin abrasion	1/2206 (0%)		0/2343 (0%)
Skull fracture	5/2206 (0.2%)		0/2343 (0%)
Soft tissue injury	0/2206 (0%)		2/2343 (0.1%)
Subdural haematoma	8/2206 (0.4%)		1/2343 (0%)
Subdural haemorrhage	1/2206 (0%)		0/2343 (0%)
Tendon rupture	1/2206 (0%)		2/2343 (0.1%)
Thermal burn	2/2206 (0.1%)		1/2343 (0%)
Thoracic vertebral fracture	1/2206 (0%)		9/2343 (0.4%)
Tibia fracture	17/2206 (0.8%)		12/2343 (0.5%)
Toxicity to various agents	4/2206 (0.2%)		2/2343 (0.1%)
Transplant dysfunction	0/2206 (0%)		2/2343 (0.1%)
Traumatic intracranial haemorrhage	1/2206 (0%)		0/2343 (0%)
Ulna fracture	9/2206 (0.4%)		9/2343 (0.4%)
Ulnar nerve injury	0/2206 (0%)		1/2343 (0%)
Wound	2/2206 (0.1%)		1/2343 (0%)
Wound dehiscence	0/2206 (0%)		2/2343 (0.1%)
Wrist fracture	1/2206 (0%)		1/2343 (0%)
Investigations
Antinuclear antibody positive	0/2206 (0%)		1/2343 (0%)
Blood pressure increased	0/2206 (0%)		1/2343 (0%)
Blood pressure orthostatic	1/2206 (0%)		0/2343 (0%)
Carcinoembryonic antigen increased	0/2206 (0%)		1/2343 (0%)
Hepatic enzyme increased	1/2206 (0%)		0/2343 (0%)
Investigation	1/2206 (0%)		0/2343 (0%)
Occult blood positive	0/2206 (0%)		1/2343 (0%)
Protein total decreased	1/2206 (0%)		0/2343 (0%)
Troponin increased	0/2206 (0%)		1/2343 (0%)
Weight decreased	3/2206 (0.1%)		1/2343 (0%)
Metabolism and nutrition disorders
Cachexia	0/2206 (0%)		1/2343 (0%)
Dehydration	6/2206 (0.3%)		7/2343 (0.3%)
Diabetes mellitus	2/2206 (0.1%)		3/2343 (0.1%)
Diabetes mellitus inadequate control	0/2206 (0%)		1/2343 (0%)
Electrolyte imbalance	2/2206 (0.1%)		1/2343 (0%)
Failure to thrive	0/2206 (0%)		1/2343 (0%)
Hypercalcaemia	1/2206 (0%)		3/2343 (0.1%)
Hypercholesterolaemia	1/2206 (0%)		0/2343 (0%)
Hyperglycaemia	1/2206 (0%)		1/2343 (0%)
Hyperkalaemia	1/2206 (0%)		0/2343 (0%)
Hypocalcaemia	1/2206 (0%)		0/2343 (0%)
Hypoglycaemia	0/2206 (0%)		2/2343 (0.1%)
Hypokalaemia	2/2206 (0.1%)		0/2343 (0%)
Hyponatraemia	4/2206 (0.2%)		2/2343 (0.1%)
Metabolic acidosis	2/2206 (0.1%)		0/2343 (0%)
Type 2 diabetes mellitus	2/2206 (0.1%)		1/2343 (0%)
Vitamin B12 deficiency	0/2206 (0%)		1/2343 (0%)
Musculoskeletal and connective tissue disorders
Acquired claw toe	0/2206 (0%)		1/2343 (0%)
Arthralgia	10/2206 (0.5%)		15/2343 (0.6%)
Arthritis	6/2206 (0.3%)		4/2343 (0.2%)
Arthropathy	0/2206 (0%)		1/2343 (0%)
Back pain	16/2206 (0.7%)		10/2343 (0.4%)
Bone disorder	0/2206 (0%)		1/2343 (0%)
Bone loss	0/2206 (0%)		1/2343 (0%)
Bone pain	1/2206 (0%)		0/2343 (0%)
Bursitis	0/2206 (0%)		2/2343 (0.1%)
Chondrocalcinosis	1/2206 (0%)		1/2343 (0%)
Chondropathy	1/2206 (0%)		1/2343 (0%)
Compartment syndrome	2/2206 (0.1%)		1/2343 (0%)
Dupuytren's contracture	1/2206 (0%)		0/2343 (0%)
Fibromyalgia	1/2206 (0%)		0/2343 (0%)
Fistula	1/2206 (0%)		1/2343 (0%)
Foot deformity	4/2206 (0.2%)		7/2343 (0.3%)
Fracture pain	0/2206 (0%)		1/2343 (0%)
Haemarthrosis	0/2206 (0%)		1/2343 (0%)
Intervertebral disc degeneration	0/2206 (0%)		1/2343 (0%)
Intervertebral disc disorder	0/2206 (0%)		1/2343 (0%)
Intervertebral disc protrusion	12/2206 (0.5%)		7/2343 (0.3%)
Joint effusion	0/2206 (0%)		1/2343 (0%)
Joint swelling	1/2206 (0%)		1/2343 (0%)
Kyphosis	1/2206 (0%)		0/2343 (0%)
Lumbar spinal stenosis	4/2206 (0.2%)		5/2343 (0.2%)
Mobility decreased	1/2206 (0%)		0/2343 (0%)
Monarthritis	1/2206 (0%)		1/2343 (0%)
Morphoea	1/2206 (0%)		0/2343 (0%)
Muscle disorder	1/2206 (0%)		0/2343 (0%)
Muscular weakness	2/2206 (0.1%)		2/2343 (0.1%)
Musculoskeletal chest pain	1/2206 (0%)		4/2343 (0.2%)
Musculoskeletal pain	4/2206 (0.2%)		4/2343 (0.2%)
Myopathy	1/2206 (0%)		1/2343 (0%)
Neck pain	1/2206 (0%)		0/2343 (0%)
Nodal osteoarthritis	0/2206 (0%)		1/2343 (0%)
Osteoarthritis	79/2206 (3.6%)		99/2343 (4.2%)
Osteoarthropathy	1/2206 (0%)		0/2343 (0%)
Osteochondrosis	1/2206 (0%)		0/2343 (0%)
Osteonecrosis	5/2206 (0.2%)		3/2343 (0.1%)
Osteonecrosis of jaw	3/2206 (0.1%)		6/2343 (0.3%)
Osteoporosis	1/2206 (0%)		0/2343 (0%)
Pain in extremity	5/2206 (0.2%)		2/2343 (0.1%)
Pain in jaw	1/2206 (0%)		0/2343 (0%)
Periarthritis	0/2206 (0%)		1/2343 (0%)
Plica syndrome	1/2206 (0%)		0/2343 (0%)
Polymyalgia rheumatica	1/2206 (0%)		0/2343 (0%)
Pseudarthrosis	0/2206 (0%)		1/2343 (0%)
Rhabdomyolysis	0/2206 (0%)		1/2343 (0%)
Rheumatoid arthritis	2/2206 (0.1%)		2/2343 (0.1%)
Rotator cuff syndrome	4/2206 (0.2%)		4/2343 (0.2%)
Sacroiliitis	1/2206 (0%)		0/2343 (0%)
Seronegative arthritis	1/2206 (0%)		0/2343 (0%)
Sjogren's syndrome	2/2206 (0.1%)		0/2343 (0%)
Spinal column stenosis	14/2206 (0.6%)		22/2343 (0.9%)
Spinal osteoarthritis	4/2206 (0.2%)		4/2343 (0.2%)
Spinal pain	1/2206 (0%)		3/2343 (0.1%)
Spondyloarthropathy	0/2206 (0%)		1/2343 (0%)
Spondylolisthesis	1/2206 (0%)		3/2343 (0.1%)
Synovial cyst	1/2206 (0%)		1/2343 (0%)
Synovial disorder	1/2206 (0%)		0/2343 (0%)
Synovitis	1/2206 (0%)		1/2343 (0%)
Systemic lupus erythematosus	0/2206 (0%)		1/2343 (0%)
Tendonitis	0/2206 (0%)		2/2343 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/2206 (0%)		1/2343 (0%)
Adenocarcinoma	1/2206 (0%)		1/2343 (0%)
Adenocarcinoma of colon	4/2206 (0.2%)		5/2343 (0.2%)
Adenocarcinoma pancreas	1/2206 (0%)		0/2343 (0%)
Adenoma benign	1/2206 (0%)		0/2343 (0%)
Adenosquamous cell lung cancer	1/2206 (0%)		0/2343 (0%)
Adrenal adenoma	1/2206 (0%)		0/2343 (0%)
Adrenal neoplasm	0/2206 (0%)		1/2343 (0%)
Anal cancer	1/2206 (0%)		0/2343 (0%)
B-cell lymphoma	1/2206 (0%)		1/2343 (0%)
Basal cell carcinoma	16/2206 (0.7%)		14/2343 (0.6%)
Benign breast neoplasm	1/2206 (0%)		0/2343 (0%)
Benign gastrointestinal neoplasm	1/2206 (0%)		0/2343 (0%)
Benign hepatic neoplasm	0/2206 (0%)		1/2343 (0%)
Benign lung neoplasm	2/2206 (0.1%)		0/2343 (0%)
Benign neoplasm	1/2206 (0%)		2/2343 (0.1%)
Benign neoplasm of bladder	0/2206 (0%)		1/2343 (0%)
Benign neoplasm of skin	0/2206 (0%)		1/2343 (0%)
Benign neoplasm of thyroid gland	0/2206 (0%)		1/2343 (0%)
Benign pancreatic neoplasm	0/2206 (0%)		1/2343 (0%)
Benign salivary gland neoplasm	0/2206 (0%)		1/2343 (0%)
Benign vulval neoplasm	0/2206 (0%)		1/2343 (0%)
Bladder cancer	2/2206 (0.1%)		3/2343 (0.1%)
Brain cancer metastatic	1/2206 (0%)		0/2343 (0%)
Brain neoplasm malignant	0/2206 (0%)		1/2343 (0%)
Breast cancer	21/2206 (1%)		24/2343 (1%)
Breast cancer metastatic	2/2206 (0.1%)		0/2343 (0%)
Breast cancer recurrent	3/2206 (0.1%)		0/2343 (0%)
Breast neoplasm	1/2206 (0%)		0/2343 (0%)
Bronchial carcinoma	1/2206 (0%)		1/2343 (0%)
Carcinoma in situ of skin	0/2206 (0%)		1/2343 (0%)
Central nervous system lymphoma	0/2206 (0%)		1/2343 (0%)
Cervix carcinoma	1/2206 (0%)		2/2343 (0.1%)
Cholangiocarcinoma	2/2206 (0.1%)		0/2343 (0%)
Cholesteatoma	0/2206 (0%)		2/2343 (0.1%)
Chronic lymphocytic leukaemia	0/2206 (0%)		2/2343 (0.1%)
Colon adenoma	0/2206 (0%)		1/2343 (0%)
Colon cancer	7/2206 (0.3%)		12/2343 (0.5%)
Colon cancer metastatic	1/2206 (0%)		2/2343 (0.1%)
Colon neoplasm	2/2206 (0.1%)		1/2343 (0%)
Colorectal adenocarcinoma	2/2206 (0.1%)		0/2343 (0%)
Colorectal cancer	0/2206 (0%)		1/2343 (0%)
Dermatofibrosarcoma protuberans	1/2206 (0%)		0/2343 (0%)
Diffuse large B-cell lymphoma	1/2206 (0%)		1/2343 (0%)
Diffuse large B-cell lymphoma stage IV	1/2206 (0%)		0/2343 (0%)
Endometrial adenocarcinoma	0/2206 (0%)		1/2343 (0%)
Endometrial cancer	0/2206 (0%)		2/2343 (0.1%)
Follicular thyroid cancer	1/2206 (0%)		0/2343 (0%)
Gallbladder cancer	1/2206 (0%)		0/2343 (0%)
Gastric cancer	1/2206 (0%)		5/2343 (0.2%)
Gastrointestinal stromal tumour	0/2206 (0%)		1/2343 (0%)
Gastrointestinal tract adenoma	1/2206 (0%)		0/2343 (0%)
Gingival cancer	0/2206 (0%)		1/2343 (0%)
Hairy cell leukaemia	1/2206 (0%)		0/2343 (0%)
Hepatic cancer	1/2206 (0%)		2/2343 (0.1%)
Hepatic neoplasm	0/2206 (0%)		1/2343 (0%)
Hepatocellular carcinoma	1/2206 (0%)		0/2343 (0%)
Intraductal proliferative breast lesion	1/2206 (0%)		0/2343 (0%)
Invasive breast carcinoma	1/2206 (0%)		0/2343 (0%)
Invasive ductal breast carcinoma	10/2206 (0.5%)		2/2343 (0.1%)
Invasive papillary breast carcinoma	1/2206 (0%)		1/2343 (0%)
Laryngeal papilloma	1/2206 (0%)		0/2343 (0%)
Leiomyosarcoma	1/2206 (0%)		1/2343 (0%)
Lentigo maligna	0/2206 (0%)		1/2343 (0%)
Leukaemia	1/2206 (0%)		0/2343 (0%)
Lip neoplasm malignant stage unspecified	0/2206 (0%)		1/2343 (0%)
Lipoma	0/2206 (0%)		1/2343 (0%)
Lung adenocarcinoma	2/2206 (0.1%)		1/2343 (0%)
Lung cancer metastatic	4/2206 (0.2%)		3/2343 (0.1%)
Lung carcinoma cell type unspecified recurrent	0/2206 (0%)		1/2343 (0%)
Lung neoplasm	0/2206 (0%)		1/2343 (0%)
Lung neoplasm malignant	11/2206 (0.5%)		13/2343 (0.6%)
Lung squamous cell carcinoma stage 0	1/2206 (0%)		0/2343 (0%)
Lymphocytic leukaemia	0/2206 (0%)		1/2343 (0%)
Lymphoma	2/2206 (0.1%)		2/2343 (0.1%)
Malignant melanoma	3/2206 (0.1%)		5/2343 (0.2%)
Malignant neoplasm of spinal cord	0/2206 (0%)		1/2343 (0%)
Malignant peritoneal neoplasm	0/2206 (0%)		1/2343 (0%)
Malignant urinary tract neoplasm	0/2206 (0%)		1/2343 (0%)
Mantle cell lymphoma	0/2206 (0%)		1/2343 (0%)
Meningioma	1/2206 (0%)		2/2343 (0.1%)
Mesothelioma	0/2206 (0%)		1/2343 (0%)
Metastases to bone	0/2206 (0%)		1/2343 (0%)
Metastases to central nervous system	0/2206 (0%)		1/2343 (0%)
Metastases to liver	3/2206 (0.1%)		3/2343 (0.1%)
Metastases to lung	0/2206 (0%)		1/2343 (0%)
Metastases to lymph nodes	2/2206 (0.1%)		3/2343 (0.1%)
Metastases to peritoneum	1/2206 (0%)		2/2343 (0.1%)
Metastasis	1/2206 (0%)		0/2343 (0%)
Metastatic carcinoma of the bladder	0/2206 (0%)		1/2343 (0%)
Metastatic gastric cancer	1/2206 (0%)		0/2343 (0%)
Metastatic neoplasm	3/2206 (0.1%)		0/2343 (0%)
Metastatic renal cell carcinoma	1/2206 (0%)		0/2343 (0%)
Metastatic squamous cell carcinoma	1/2206 (0%)		0/2343 (0%)
Monoclonal gammopathy	0/2206 (0%)		1/2343 (0%)
Muscle neoplasm	0/2206 (0%)		1/2343 (0%)
Myeloproliferative disorder	1/2206 (0%)		0/2343 (0%)
Neoplasm malignant	1/2206 (0%)		2/2343 (0.1%)
Neoplasm progression	1/2206 (0%)		0/2343 (0%)
Neuroendocrine carcinoma	1/2206 (0%)		0/2343 (0%)
Neuroma	1/2206 (0%)		0/2343 (0%)
Nodular fasciitis	0/2206 (0%)		1/2343 (0%)
Non-Hodgkin's lymphoma	0/2206 (0%)		1/2343 (0%)
Non-Hodgkin's lymphoma stage IV	1/2206 (0%)		0/2343 (0%)
Non-small cell lung cancer	1/2206 (0%)		0/2343 (0%)
Oesophageal adenocarcinoma	0/2206 (0%)		1/2343 (0%)
Oesophageal carcinoma	0/2206 (0%)		4/2343 (0.2%)
Oesophageal squamous cell carcinoma	0/2206 (0%)		1/2343 (0%)
Oral neoplasm	1/2206 (0%)		0/2343 (0%)
Ovarian adenoma	0/2206 (0%)		2/2343 (0.1%)
Ovarian cancer	1/2206 (0%)		2/2343 (0.1%)
Ovarian cancer metastatic	1/2206 (0%)		0/2343 (0%)
Ovarian cancer stage III	1/2206 (0%)		0/2343 (0%)
Ovarian epithelial cancer	1/2206 (0%)		1/2343 (0%)
Ovarian fibroma	1/2206 (0%)		1/2343 (0%)
Pancreatic carcinoma	6/2206 (0.3%)		5/2343 (0.2%)
Pancreatic neoplasm	1/2206 (0%)		3/2343 (0.1%)
Papillary thyroid cancer	2/2206 (0.1%)		1/2343 (0%)
Parathyroid tumour benign	2/2206 (0.1%)		0/2343 (0%)
Pelvic neoplasm	0/2206 (0%)		1/2343 (0%)
Phyllodes tumour	0/2206 (0%)		1/2343 (0%)
Plasma cell myeloma	3/2206 (0.1%)		4/2343 (0.2%)
Plasmacytoma	1/2206 (0%)		0/2343 (0%)
Polycythaemia vera	2/2206 (0.1%)		0/2343 (0%)
Rectal adenocarcinoma	5/2206 (0.2%)		3/2343 (0.1%)
Rectal adenoma	1/2206 (0%)		0/2343 (0%)
Rectal cancer	1/2206 (0%)		2/2343 (0.1%)
Rectosigmoid cancer	0/2206 (0%)		1/2343 (0%)
Renal cancer	2/2206 (0.1%)		4/2343 (0.2%)
Renal cell carcinoma	1/2206 (0%)		1/2343 (0%)
Renal neoplasm	0/2206 (0%)		2/2343 (0.1%)
Skin cancer	1/2206 (0%)		3/2343 (0.1%)
Squamous cell carcinoma	1/2206 (0%)		1/2343 (0%)
Squamous cell carcinoma of lung	0/2206 (0%)		1/2343 (0%)
Squamous cell carcinoma of skin	3/2206 (0.1%)		3/2343 (0.1%)
Squamous cell carcinoma of the oral cavity	1/2206 (0%)		0/2343 (0%)
Thyroid adenoma	0/2206 (0%)		1/2343 (0%)
Thyroid cancer	1/2206 (0%)		1/2343 (0%)
Tongue neoplasm malignant stage unspecified	2/2206 (0.1%)		0/2343 (0%)
Transitional cell carcinoma	1/2206 (0%)		3/2343 (0.1%)
Ureteric cancer	1/2206 (0%)		0/2343 (0%)
Uterine cancer	6/2206 (0.3%)		2/2343 (0.1%)
Uterine leiomyoma	0/2206 (0%)		1/2343 (0%)
Vulval cancer	1/2206 (0%)		0/2343 (0%)
Nervous system disorders
Acoustic neuritis	0/2206 (0%)		1/2343 (0%)
Akinesia	1/2206 (0%)		0/2343 (0%)
Amnesia	0/2206 (0%)		3/2343 (0.1%)
Amyotrophic lateral sclerosis	0/2206 (0%)		1/2343 (0%)
Aphasia	3/2206 (0.1%)		0/2343 (0%)
Ataxia	1/2206 (0%)		1/2343 (0%)
Carotid artery occlusion	1/2206 (0%)		0/2343 (0%)
Carotid artery stenosis	1/2206 (0%)		2/2343 (0.1%)
Carotid artery thrombosis	0/2206 (0%)		1/2343 (0%)
Carpal tunnel syndrome	1/2206 (0%)		5/2343 (0.2%)
Cauda equina syndrome	1/2206 (0%)		0/2343 (0%)
Cerebellar haemorrhage	0/2206 (0%)		1/2343 (0%)
Cerebellar infarction	1/2206 (0%)		0/2343 (0%)
Cerebral arteriosclerosis	1/2206 (0%)		2/2343 (0.1%)
Cerebral artery embolism	1/2206 (0%)		0/2343 (0%)
Cerebral atrophy	0/2206 (0%)		1/2343 (0%)
Cerebral haemorrhage	5/2206 (0.2%)		2/2343 (0.1%)
Cerebral infarction	5/2206 (0.2%)		17/2343 (0.7%)
Cerebral ischaemia	6/2206 (0.3%)		6/2343 (0.3%)
Cerebral microangiopathy	1/2206 (0%)		0/2343 (0%)
Cerebral thrombosis	8/2206 (0.4%)		8/2343 (0.3%)
Cerebrovascular accident	22/2206 (1%)		29/2343 (1.2%)
Cerebrovascular disorder	1/2206 (0%)		1/2343 (0%)
Cerebrovascular insufficiency	1/2206 (0%)		1/2343 (0%)
Cervicogenic headache	0/2206 (0%)		1/2343 (0%)
Cognitive disorder	3/2206 (0.1%)		1/2343 (0%)
Coma	0/2206 (0%)		2/2343 (0.1%)
Cubital tunnel syndrome	0/2206 (0%)		2/2343 (0.1%)
Dementia	2/2206 (0.1%)		2/2343 (0.1%)
Dementia Alzheimer's type	2/2206 (0.1%)		5/2343 (0.2%)
Diabetic hyperosmolar coma	0/2206 (0%)		1/2343 (0%)
Diabetic neuropathy	0/2206 (0%)		1/2343 (0%)
Dizziness	5/2206 (0.2%)		5/2343 (0.2%)
Dysaesthesia	1/2206 (0%)		0/2343 (0%)
Embolic stroke	1/2206 (0%)		0/2343 (0%)
Encephalopathy	1/2206 (0%)		0/2343 (0%)
Epilepsy	2/2206 (0.1%)		2/2343 (0.1%)
Extrapyramidal disorder	0/2206 (0%)		2/2343 (0.1%)
Facial paresis	1/2206 (0%)		0/2343 (0%)
Haemorrhage intracranial	0/2206 (0%)		2/2343 (0.1%)
Haemorrhagic stroke	3/2206 (0.1%)		3/2343 (0.1%)
Headache	4/2206 (0.2%)		2/2343 (0.1%)
Hemiparesis	1/2206 (0%)		2/2343 (0.1%)
Hypertensive encephalopathy	0/2206 (0%)		1/2343 (0%)
Hypoaesthesia	1/2206 (0%)		0/2343 (0%)
Hypotonia	1/2206 (0%)		0/2343 (0%)
Hypoxic-ischaemic encephalopathy	0/2206 (0%)		1/2343 (0%)
Intercostal neuralgia	1/2206 (0%)		0/2343 (0%)
Intracranial aneurysm	1/2206 (0%)		0/2343 (0%)
Ischaemic cerebral infarction	1/2206 (0%)		0/2343 (0%)
Ischaemic stroke	11/2206 (0.5%)		9/2343 (0.4%)
Lacunar infarction	2/2206 (0.1%)		1/2343 (0%)
Loss of consciousness	2/2206 (0.1%)		3/2343 (0.1%)
Lumbar radiculopathy	2/2206 (0.1%)		2/2343 (0.1%)
Mental impairment	1/2206 (0%)		0/2343 (0%)
Mononeuropathy multiplex	1/2206 (0%)		0/2343 (0%)
Motor dysfunction	1/2206 (0%)		1/2343 (0%)
Motor neurone disease	1/2206 (0%)		0/2343 (0%)
Myasthenia gravis	2/2206 (0.1%)		1/2343 (0%)
Nervous system disorder	1/2206 (0%)		1/2343 (0%)
Optic neuritis	1/2206 (0%)		0/2343 (0%)
Paraesthesia	2/2206 (0.1%)		0/2343 (0%)
Parkinson's disease	0/2206 (0%)		1/2343 (0%)
Parkinsonism	0/2206 (0%)		1/2343 (0%)
Partial seizures	1/2206 (0%)		0/2343 (0%)
Polyneuropathy	0/2206 (0%)		1/2343 (0%)
Presyncope	2/2206 (0.1%)		1/2343 (0%)
Pseudoradicular syndrome	0/2206 (0%)		1/2343 (0%)
Pyramidal tract syndrome	0/2206 (0%)		1/2343 (0%)
Radicular syndrome	1/2206 (0%)		2/2343 (0.1%)
Radiculitis	0/2206 (0%)		1/2343 (0%)
Radiculopathy	0/2206 (0%)		1/2343 (0%)
Sciatica	6/2206 (0.3%)		12/2343 (0.5%)
Seizure	2/2206 (0.1%)		0/2343 (0%)
Senile dementia	2/2206 (0.1%)		0/2343 (0%)
Sensory disturbance	1/2206 (0%)		0/2343 (0%)
Spinal cord compression	0/2206 (0%)		2/2343 (0.1%)
Subarachnoid haemorrhage	2/2206 (0.1%)		1/2343 (0%)
Syncope	18/2206 (0.8%)		20/2343 (0.9%)
Tarsal tunnel syndrome	1/2206 (0%)		0/2343 (0%)
Thrombotic cerebral infarction	1/2206 (0%)		0/2343 (0%)
Transient global amnesia	2/2206 (0.1%)		1/2343 (0%)
Transient ischaemic attack	21/2206 (1%)		19/2343 (0.8%)
Trigeminal neuralgia	1/2206 (0%)		0/2343 (0%)
VIIth nerve paralysis	3/2206 (0.1%)		1/2343 (0%)
Vascular dementia	1/2206 (0%)		1/2343 (0%)
Vascular headache	1/2206 (0%)		0/2343 (0%)
Vertebrobasilar insufficiency	1/2206 (0%)		3/2343 (0.1%)
Psychiatric disorders
Aggression	0/2206 (0%)		1/2343 (0%)
Anxiety	1/2206 (0%)		0/2343 (0%)
Anxiety disorder	0/2206 (0%)		1/2343 (0%)
Completed suicide	0/2206 (0%)		2/2343 (0.1%)
Confusional state	6/2206 (0.3%)		2/2343 (0.1%)
Depression	11/2206 (0.5%)		9/2343 (0.4%)
Emotional distress	1/2206 (0%)		0/2343 (0%)
Hallucination	0/2206 (0%)		2/2343 (0.1%)
Mental disorder	0/2206 (0%)		1/2343 (0%)
Psychotic disorder	1/2206 (0%)		1/2343 (0%)
Schizophrenia, paranoid type	1/2206 (0%)		0/2343 (0%)
Suicide attempt	0/2206 (0%)		1/2343 (0%)
Renal and urinary disorders
Acute kidney injury	1/2206 (0%)		6/2343 (0.3%)
Bladder disorder	0/2206 (0%)		2/2343 (0.1%)
Bladder irritation	0/2206 (0%)		1/2343 (0%)
Bladder prolapse	0/2206 (0%)		6/2343 (0.3%)
Calculus bladder	1/2206 (0%)		0/2343 (0%)
Calculus ureteric	2/2206 (0.1%)		2/2343 (0.1%)
Calculus urethral	1/2206 (0%)		0/2343 (0%)
Chronic kidney disease	3/2206 (0.1%)		1/2343 (0%)
Cystitis interstitial	0/2206 (0%)		1/2343 (0%)
Diabetic nephropathy	1/2206 (0%)		0/2343 (0%)
Haematuria	1/2206 (0%)		0/2343 (0%)
Hydronephrosis	2/2206 (0.1%)		0/2343 (0%)
Incontinence	0/2206 (0%)		1/2343 (0%)
Mixed incontinence	1/2206 (0%)		0/2343 (0%)
Nephrolithiasis	0/2206 (0%)		3/2343 (0.1%)
Nephropathy	0/2206 (0%)		1/2343 (0%)
Renal colic	1/2206 (0%)		0/2343 (0%)
Renal failure	3/2206 (0.1%)		5/2343 (0.2%)
Stress urinary incontinence	2/2206 (0.1%)		1/2343 (0%)
Tubulointerstitial nephritis	1/2206 (0%)		0/2343 (0%)
Ureteric stenosis	2/2206 (0.1%)		0/2343 (0%)
Urethral disorder	0/2206 (0%)		1/2343 (0%)
Urethral stenosis	1/2206 (0%)		0/2343 (0%)
Urge incontinence	1/2206 (0%)		0/2343 (0%)
Urinary bladder polyp	0/2206 (0%)		2/2343 (0.1%)
Urinary incontinence	4/2206 (0.2%)		5/2343 (0.2%)
Urinary retention	1/2206 (0%)		3/2343 (0.1%)
Urinary tract obstruction	1/2206 (0%)		0/2343 (0%)
Reproductive system and breast disorders
Breast mass	1/2206 (0%)		0/2343 (0%)
Colpocele	2/2206 (0.1%)		3/2343 (0.1%)
Cystocele	11/2206 (0.5%)		5/2343 (0.2%)
Endometrial atrophy	1/2206 (0%)		0/2343 (0%)
Endometrial metaplasia	1/2206 (0%)		0/2343 (0%)
Female genital tract fistula	0/2206 (0%)		1/2343 (0%)
Fibrocystic breast disease	1/2206 (0%)		0/2343 (0%)
Genital prolapse	1/2206 (0%)		0/2343 (0%)
Mammary duct ectasia	0/2206 (0%)		1/2343 (0%)
Metrorrhagia	1/2206 (0%)		0/2343 (0%)
Ovarian cyst	4/2206 (0.2%)		3/2343 (0.1%)
Rectocele	4/2206 (0.2%)		5/2343 (0.2%)
Uterine cyst	0/2206 (0%)		1/2343 (0%)
Uterine haemorrhage	1/2206 (0%)		1/2343 (0%)
Uterine polyp	4/2206 (0.2%)		4/2343 (0.2%)
Uterine prolapse	9/2206 (0.4%)		9/2343 (0.4%)
Vaginal cyst	1/2206 (0%)		0/2343 (0%)
Vaginal prolapse	5/2206 (0.2%)		3/2343 (0.1%)
Vulval leukoplakia	0/2206 (0%)		1/2343 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/2206 (0%)		1/2343 (0%)
Acute respiratory distress syndrome	0/2206 (0%)		1/2343 (0%)
Acute respiratory failure	4/2206 (0.2%)		1/2343 (0%)
Aspiration	0/2206 (0%)		1/2343 (0%)
Asthma	4/2206 (0.2%)		1/2343 (0%)
Atelectasis	1/2206 (0%)		3/2343 (0.1%)
Bronchial hyperreactivity	1/2206 (0%)		0/2343 (0%)
Bronchiectasis	0/2206 (0%)		1/2343 (0%)
Bronchitis chronic	0/2206 (0%)		2/2343 (0.1%)
Bronchomalacia	0/2206 (0%)		1/2343 (0%)
Chronic obstructive pulmonary disease	14/2206 (0.6%)		6/2343 (0.3%)
Dysphonia	1/2206 (0%)		0/2343 (0%)
Dyspnoea	6/2206 (0.3%)		7/2343 (0.3%)
Dyspnoea exertional	0/2206 (0%)		1/2343 (0%)
Emphysema	1/2206 (0%)		0/2343 (0%)
Epistaxis	2/2206 (0.1%)		4/2343 (0.2%)
Haemoptysis	2/2206 (0.1%)		1/2343 (0%)
Hydrothorax	1/2206 (0%)		0/2343 (0%)
Interstitial lung disease	1/2206 (0%)		0/2343 (0%)
Laryngeal cyst	0/2206 (0%)		1/2343 (0%)
Lung disorder	0/2206 (0%)		2/2343 (0.1%)
Lung infiltration	0/2206 (0%)		1/2343 (0%)
Mediastinal cyst	0/2206 (0%)		1/2343 (0%)
Nasal ulcer	0/2206 (0%)		1/2343 (0%)
Painful respiration	1/2206 (0%)		0/2343 (0%)
Pleural effusion	1/2206 (0%)		5/2343 (0.2%)
Pleurisy	0/2206 (0%)		1/2343 (0%)
Pneumonia aspiration	1/2206 (0%)		1/2343 (0%)
Pneumonitis	0/2206 (0%)		1/2343 (0%)
Pneumothorax	2/2206 (0.1%)		3/2343 (0.1%)
Pulmonary congestion	0/2206 (0%)		1/2343 (0%)
Pulmonary embolism	19/2206 (0.9%)		13/2343 (0.6%)
Pulmonary fibrosis	0/2206 (0%)		1/2343 (0%)
Pulmonary mass	0/2206 (0%)		1/2343 (0%)
Pulmonary oedema	6/2206 (0.3%)		5/2343 (0.2%)
Respiratory arrest	1/2206 (0%)		0/2343 (0%)
Respiratory failure	3/2206 (0.1%)		4/2343 (0.2%)
Tonsillar cyst	1/2206 (0%)		0/2343 (0%)
Tracheomalacia	0/2206 (0%)		1/2343 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/2206 (0%)		0/2343 (0%)
Decubitus ulcer	0/2206 (0%)		2/2343 (0.1%)
Dermatitis	0/2206 (0%)		1/2343 (0%)
Dermatitis allergic	1/2206 (0%)		1/2343 (0%)
Diabetic foot	1/2206 (0%)		0/2343 (0%)
Drug eruption	0/2206 (0%)		1/2343 (0%)
Lichen sclerosus	1/2206 (0%)		0/2343 (0%)
Lichenoid keratosis	0/2206 (0%)		1/2343 (0%)
Pemphigoid	0/2206 (0%)		1/2343 (0%)
Pruritus	1/2206 (0%)		1/2343 (0%)
Psoriasis	0/2206 (0%)		1/2343 (0%)
Rash pruritic	0/2206 (0%)		1/2343 (0%)
Skin ulcer	3/2206 (0.1%)		5/2343 (0.2%)
Urticaria	1/2206 (0%)		1/2343 (0%)
Social circumstances
Activities of daily living impaired	1/2206 (0%)		0/2343 (0%)
Physical assault	0/2206 (0%)		1/2343 (0%)
Surgical and medical procedures
Anticoagulant therapy	0/2206 (0%)		1/2343 (0%)
Arthrodesis	0/2206 (0%)		1/2343 (0%)
Benign tumour excision	1/2206 (0%)		0/2343 (0%)
Cardiac pacemaker replacement	0/2206 (0%)		1/2343 (0%)
Chemotherapy	0/2206 (0%)		1/2343 (0%)
Hip arthroplasty	0/2206 (0%)		2/2343 (0.1%)
Hospitalisation	0/2206 (0%)		1/2343 (0%)
Hysterectomy	0/2206 (0%)		1/2343 (0%)
Joint arthroplasty	1/2206 (0%)		2/2343 (0.1%)
Knee arthroplasty	1/2206 (0%)		0/2343 (0%)
Rehabilitation therapy	0/2206 (0%)		1/2343 (0%)
Spinal decompression	1/2206 (0%)		0/2343 (0%)
Tooth extraction	0/2206 (0%)		1/2343 (0%)
Urethral operation	0/2206 (0%)		1/2343 (0%)
Vascular disorders
Accelerated hypertension	0/2206 (0%)		1/2343 (0%)
Aortic aneurysm	1/2206 (0%)		5/2343 (0.2%)
Aortic dissection	2/2206 (0.1%)		0/2343 (0%)
Aortic stenosis	5/2206 (0.2%)		8/2343 (0.3%)
Arterial disorder	0/2206 (0%)		2/2343 (0.1%)
Arterial haemorrhage	1/2206 (0%)		0/2343 (0%)
Arterial occlusive disease	0/2206 (0%)		1/2343 (0%)
Arteriosclerosis	5/2206 (0.2%)		5/2343 (0.2%)
Circulatory collapse	3/2206 (0.1%)		1/2343 (0%)
Deep vein thrombosis	8/2206 (0.4%)		8/2343 (0.3%)
Embolism venous	1/2206 (0%)		0/2343 (0%)
Essential hypertension	1/2206 (0%)		0/2343 (0%)
Femoral artery aneurysm	0/2206 (0%)		1/2343 (0%)
Femoral artery occlusion	1/2206 (0%)		0/2343 (0%)
Haematoma	2/2206 (0.1%)		3/2343 (0.1%)
Haemorrhage	1/2206 (0%)		0/2343 (0%)
Hypertension	18/2206 (0.8%)		21/2343 (0.9%)
Hypertensive crisis	7/2206 (0.3%)		3/2343 (0.1%)
Hypotension	0/2206 (0%)		3/2343 (0.1%)
Hypovolaemic shock	1/2206 (0%)		0/2343 (0%)
Intermittent claudication	0/2206 (0%)		3/2343 (0.1%)
Ischaemia	0/2206 (0%)		1/2343 (0%)
Orthostatic hypotension	1/2206 (0%)		3/2343 (0.1%)
Peripheral arterial occlusive disease	4/2206 (0.2%)		2/2343 (0.1%)
Peripheral artery stenosis	2/2206 (0.1%)		0/2343 (0%)
Peripheral embolism	2/2206 (0.1%)		0/2343 (0%)
Peripheral ischaemia	0/2206 (0%)		3/2343 (0.1%)
Peripheral vascular disorder	2/2206 (0.1%)		0/2343 (0%)
Peripheral venous disease	0/2206 (0%)		1/2343 (0%)
Phlebolith	0/2206 (0%)		1/2343 (0%)
Shock haemorrhagic	0/2206 (0%)		1/2343 (0%)
Subclavian artery occlusion	0/2206 (0%)		1/2343 (0%)
Temporal arteritis	2/2206 (0.1%)		3/2343 (0.1%)
Thrombophlebitis	1/2206 (0%)		2/2343 (0.1%)
Thrombophlebitis superficial	1/2206 (0%)		0/2343 (0%)
Thrombosis	4/2206 (0.2%)		3/2343 (0.1%)
Varicose vein	5/2206 (0.2%)		3/2343 (0.1%)
Vasculitis	2/2206 (0.1%)		1/2343 (0%)
Vasculitis necrotising	0/2206 (0%)		1/2343 (0%)
Venous thrombosis limb	1/2206 (0%)		0/2343 (0%)
Other (Not Including Serious) Adverse Events
	Placebo/ Denosumab 60 mg Q6M		Denosumab/ Denosumab 60 mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1809/2206 (82%)		1920/2343 (81.9%)
Blood and lymphatic system disorders
Anaemia	141/2206 (6.4%)		168/2343 (7.2%)
Ear and labyrinth disorders
Vertigo	138/2206 (6.3%)		140/2343 (6%)
Eye disorders
Cataract	319/2206 (14.5%)		317/2343 (13.5%)
Gastrointestinal disorders
Constipation	141/2206 (6.4%)		118/2343 (5%)
Diarrhoea	139/2206 (6.3%)		152/2343 (6.5%)
Infections and infestations
Bronchitis	206/2206 (9.3%)		226/2343 (9.6%)
Cystitis	194/2206 (8.8%)		212/2343 (9%)
Influenza	179/2206 (8.1%)		192/2343 (8.2%)
Nasopharyngitis	372/2206 (16.9%)		385/2343 (16.4%)
Pneumonia	137/2206 (6.2%)		167/2343 (7.1%)
Upper respiratory tract infection	139/2206 (6.3%)		128/2343 (5.5%)
Urinary tract infection	242/2206 (11%)		250/2343 (10.7%)
Injury, poisoning and procedural complications
Contusion	181/2206 (8.2%)		176/2343 (7.5%)
Fall	240/2206 (10.9%)		268/2343 (11.4%)
Metabolism and nutrition disorders
Hypercholesterolaemia	215/2206 (9.7%)		200/2343 (8.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	527/2206 (23.9%)		541/2343 (23.1%)
Back pain	501/2206 (22.7%)		493/2343 (21%)
Musculoskeletal pain	197/2206 (8.9%)		231/2343 (9.9%)
Osteoarthritis	332/2206 (15%)		355/2343 (15.2%)
Pain in extremity	264/2206 (12%)		293/2343 (12.5%)
Nervous system disorders
Dizziness	173/2206 (7.8%)		163/2343 (7%)
Headache	121/2206 (5.5%)		103/2343 (4.4%)
Sciatica	149/2206 (6.8%)		165/2343 (7%)
Psychiatric disorders
Depression	135/2206 (6.1%)		143/2343 (6.1%)
Respiratory, thoracic and mediastinal disorders
Cough	172/2206 (7.8%)		168/2343 (7.2%)
Vascular disorders
Hypertension	460/2206 (20.9%)		498/2343 (21.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.