Study to Determine Treatment Effects of Denosumab in Patients With Breast Cancer Receiving Aromatase Inhibitor Therapy

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00556374
• Collaborator: Austrian Breast and Colorectal Cancer Study Group (Other)
• Enrollment: 3,420
• Locations: 47
• Arms: 4
• Actual Duration (Months): 187.2
• Patients Per Site: 72.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether denosumab compared to placebo, will reduce the rate of first clinical fracture in women with non-metastatic breast cancer receiving (non-steroidal) aromatase inhibitor therapy.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Placebo; Biological: Denosumab; Drug: Non-steroidal aromatase inhibitor therapy; Drug: Zoledronic Acid; Other: Standard of Care	Phase 3

Detailed Description

Participants will remain on treatment until the required number of events (where an event is defined as first clinical fracture) is reached and all participants have had the opportunity to receive a minimum of at least 2 doses of study drug, whichever occurs later. The primary analysis data cut-off date (PADCD) is defined as the time at which the required number of events is reached and all participants have had the opportunity to receive at least 2 doses of study drug. When the PADCD is reached, all participants will discontinue study drug.

Following the study PADCD, participants will be followed every 12 months starting from their last study visit until a maximum of 66 months after PADCD.

After approval of Amendment 4, willing and eligible participants randomized to placebo during the double-blind phase may participate in an open-label phase (OLP) and receive denosumab 60 mg Q6M for up to 36 months (maximum of 7 doses).

After approval of Amendment 6 in 2019 a zoledronic acid (ZA) substudy was added to the protocol. Willing and eligible participants who participated in the OLP of the study and completed open-label denosumab may opt in to this ZA substudy and either receive a single dose of ZA (Therapy Arm), or be managed according to the current standard of care for this patient population (Control Arm).

Study Design

• Study Type: Interventional
• Actual Enrollment: 3420 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Randomised, Double-Blind, Placebo-Controlled, Multi-Centre Phase 3 Study to Determine the Treatment Effect of Denosumab in Subjects With Non-Metastatic Breast Cancer Receiving Aromatase Inhibitor Therapy.
• Actual Study Start Date: Dec 18, 2006
• Actual Primary Completion Date: Oct 7, 2014
• Actual Study Completion Date: Jul 26, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Denosumab Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Biological: Denosumab; Administered as a subcutaneous injection; Other Names: Prolia® ; Drug: Non-steroidal aromatase inhibitor therapy; An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting
Placebo Comparator: Placebo Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Drug: Placebo; Other Names: Administered as a subcutaneous injection ; Drug: Non-steroidal aromatase inhibitor therapy; An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting
Experimental: SubStudy: Zoledronic Acid Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive a single 5 mg intravenous dose of zoledronic acid 8 months after the last open-label dose of denosumab.	Drug: Zoledronic Acid; 5 mg zoledronic acid administered at a constant infusion rate; Other Names: Reclast Zometa
Other: Substudy: Standard of Care Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive standard of care 8 months after the last open-label dose of denosumab.	Other: Standard of Care; Standard of care (SoC) as recommended by the treating physician, depending on individual factors such as bone density, lifestyle recommendations by the Investigator such as diet, physical activities and sun exposure, as well as local treatment standards.

Outcome Measures

Primary Outcome Measures

1. Time to First Clinical Fracture [From randomization until the primary analysis cut-off date of 26 March 2014; maximum time on study was 87 months.]

   The time to first on-study clinical fracture defined as the number of days from randomization to the date of the x-ray confirming the clinical fracture. A clinical fracture is any clinically evident fracture with associated symptoms and confirmed by x-ray. Participants who died or withdrew without experiencing a clinical fracture were censored at the date of last contact or study termination whichever was earlier.

Secondary Outcome Measures

1. Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites [Baseline and Month 36]

   Bone mineral density was assessed by dual x-ray absorptiometry.

2. Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites [Baseline and Month 36]

   Bone mineral density was assessed by dual x-ray absorptiometry.

3. Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites [Baseline and Month 36]

   Bone mineral density was assessed by dual x-ray absorptiometry.

4. Number of Participants With New Vertebral Fractures [36 months]

   Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture is defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays.

5. Number of Participants With New or Worsening Vertebral Fractures [36 months]

   Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture is defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays. Worsening of pre-existing fractures is defined as an increase in fracture severity of at least 1 grade on the semiquantitative scale.

6. Disease-free Survival [From randomization until the DFS data cut-off date of 15 September 2015; maximum time on study was 102 months.]

   Disease-free survival (DFS) is defined as the time interval from the randomization date to the date of first evidence of local or distant metastases, contra-lateral breast cancer, secondary carcinoma, or death from any cause (whichever occurred first). Participants last known to be alive, who did not experience recurrence of disease, were censored at their last contact date or at the data cut-off date whichever came first. DFS was initially specified to be analyzed after completion of the long-term follow-up period, however after analysis of the primary results was completed the data monitoring committee recommended that the analysis be conducted 18 months after the primary analysis data cut-off date.

7. Bone Metastases-free Survival [Participants will be followed for bone metastasis-free survival once every 12 months for 66 months after primary completion date.]

   Bone metastasis-free survival (BMFS) determined by the time from randomization to the first observation of bone metastasis or death from any cause. BMFS will be analyzed after long-term follow-up is complete.

8. Overall Survival [Participants will be followed for overall survival once every 12 months for 66 months after primary completion date.]

   Overall survival (OS) determined by the time from randomization to death from any cause. OS will be analyzed after long-term follow-up is complete.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 100 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria for Double Blinded Phase:

• Histologically or cytologically confirmed adenocarcinoma of the breast;

• Female subjects with non-metastatic disease who are estrogen receptor (ER) and/or progesterone receptor (PR) positive, and who have completed their treatment pathway;

• Subjects who are currently on, or will initiate an approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting;

• Postmenopausal woman, defined as a woman fulfilling any one of the following criteria:

• Having undergone a bilateral oophorectomy;

• Age ≥ 60 years;

• Aged < 60 years meeting the following requirements:

• Follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range;

• A negative pregnancy test within 7 days prior to randomization. Subjects who have undergone a hysterectomy do not require a pregnancy test.

• More criteria may apply.

Exclusion Criteria for Double Blinded Phase:

• Aromatase inhibitor therapy for more than 24 months;

• Prior or concurrent treatment with Selective Estrogen Receptor Modulators (eg, tamoxifen);

• Evidence of metastatic disease;

• Current or prior intravenous (IV) bisphosphonate administration;

• Oral bisphosphonate treatment greater than or equal to 3 years continuously OR greater than 3 months but less than 3 years unless there was a washout period of at least 1 year prior to randomization OR any use during the 3-month period prior to randomization;

• Prior administration of denosumab;

• Known liver or renal deficiency;

• Recurrence of the primary malignancy (e.g., during the allowed interval of pretreatment with aromatase inhibitor);

• Diagnosis of any second non-breast malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or for in situ carcinoma of the cervix uteri;

• Any kind of disorder that compromises the ability to give written informed consent and/or comply with study procedures.

Inclusion Criteria to Receive Open-label Phase Denosumab:

• Obtain signed and dated written informed consent prior to performing any study-specific procedure;

• Subjects currently taking an approved non-steroidal AIT (eg, anastrazole) or who have completed or discontinued AIT within 12 months prior to participation in the OLP;

• Randomized to placebo arm during the double-blind phase (as determined by unblinding procedures);

Exclusion Criteria to Receive Open-label Phase Denosumab:

• Current or prior IV bisphosphonate administration;

• Subjects meeting the following criteria for oral bisphosphonate treatment:

• Greater than or equal to 3 years continuously,

• Greater than 3 months but less than 3 years unless subject has had a washout period of at least 1 year prior to participation in the OLP,

• Any use during the 3-month period prior to participation in the OLP;

• Prior or concurrent treatment with SERMs (eg, tamoxifen);

• Subjects who ended treatment with investigational product (IP) prematurely in the double-blind phase; Treatment with commercial denosumab (Prolia or Xgeva) prior to participation in the OLP.

Eligibility for ZA substudy Inclusion Criteria

• Obtain signed and dated written informed consent prior to performing any substudy-specific procedure

• Subjects that received OLP denosumab and completed OLP treatment

• Last OLP denosumab administration no longer than 9 months ago Exclusion Criteria

• Current or prior ZA administration.

• Subjects who ended treatment with investigational product (IP) prematurely in the double-blind phase and OL phase

• Known sensitivity or intolerance to any of the products to be administered during the substudy (eg, ZA, calcium or vitamin D)

• Known history of any of the following conditions either by subject self report or chart review

• Paget's disease (bone), Cushing's disease, hyperprolactinemia or other active metabolic bone disease

• Known history of hypocalcemia

• Major surgery, or significant traumatic injury occurring within 4 weeks prior to randomization

• Parathyroid glands in neck surgically removed.

• Any sections of intestine removed.

• Known human immunodeficiency virus infection

• Active infection with hepatitis B or hepatitis C virus

• Known liver or renal disease as determined by the investigator and indicated by the following criteria:

• Aspartate aminotransferase ≥ 2.5 x ULN

• Alanine transaminase ≥ 2.5 x ULN

• Serum creatinine ≥ 2 x ULN

• Creatine clearance < 35ml/min Subjects that are pregnant or breastfeeding

• All subjects with reproductive potential must have a negative pregnancy test within 7 days before randomization

• Subjects who are osteoporotic in baseline BMD

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Baden		Austria	2500
2	Research Site	Braunau		Austria	5280
3	Research Site	Dornbirn		Austria	6850
4	Research Site	Feldkirch		Austria	6807
5	Research Site	Gmunden		Austria	4810
6	Research Site	Graz		Austria	8020
7	Research Site	Graz		Austria	8036
8	Research Site	Güssing		Austria	7540
9	Research Site	Hall in Tirol		Austria	6060
10	Research Site	Innsbruck		Austria	6020
11	Research Site	Klagenfurt		Austria	9026
12	Research Site	Krems		Austria	3500
13	Research Site	Kufstein		Austria	6330
14	Research Site	Leoben		Austria	8700
15	Research Site	Lienz		Austria	9900
16	Research Site	Linz		Austria	4010
17	Research Site	Linz		Austria	4020
18	Research Site	Oberpullendorf		Austria	7350
19	Research Site	Ried		Austria	4910
20	Research Site	Rottenmann		Austria	8786
21	Research Site	Salzburg		Austria	5020
22	Research Site	Schärding		Austria	4780
23	Research Site	St Poelten		Austria	3100
24	Research Site	St Veit an der Glan		Austria	9300
25	Research Site	St. Poelten		Austria	3100
26	Research Site	Steyr		Austria	4400
27	Research Site	Villach		Austria	9500
28	Research Site	Villach		Austria	9504
29	Research Site	Voecklabruck		Austria	4840
30	Research Site	Weiz		Austria	8160
31	Research Site	Wels		Austria	4600
32	Research Site	Wiener Neustadt		Austria	2700
33	Research Site	Wien		Austria	1010
34	Research Site	Wien		Austria	1020
35	Research Site	Wien		Austria	1050
36	Research Site	Wien		Austria	1090
37	Research Site	Wien		Austria	1130
38	Research Site	Wien		Austria	1140
39	Research Site	Wien		Austria	1160
40	Research Site	Wien		Austria	1180
41	Research Site	Wien		Austria	1220
42	Research Site	Wolfsberg		Austria	9400
43	Research Site	Gävle		Sweden	801 87
44	Research Site	Göteborg		Sweden
45	Research Site	Stockholm		Sweden	112 81
46	Research Site	Stockholm		Sweden	171 76
47	Research Site	Uppsala		Sweden	751 85

Sponsors and Collaborators

• Amgen
• Austrian Breast and Colorectal Cancer Study Group

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Aug 1;386(9992):433-43. doi: 10.1016/S0140-6736(15)60995-3. Epub 2015 May 31.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00556374
• Other Study ID Numbers: 20050209; ABCSG-18; 2005-005275-15
• First Posted: Nov 12, 2007
• Last Update Posted: Aug 9, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Amgen: confirmed adenocarcinoma; non-metastatic breast cancer; estrogen receptor positive; progesterone receptor positive; non-steroidal aromatase; aromatase inhibitor therapy; postmenopausal woman; adjuvant chemotherapy; neoadjuvant chemotherapy
• Additional relevant MeSH terms: Breast Neoplasms; Zoledronic Acid; Denosumab; Aromatase Inhibitors

Study Results

Participant Flow

Recruitment Details	The first patient was enrolled on 18 December 2006 and the last patient was enrolled on 22 July 2013. Five patients randomized withdrew full consent and are not included in any analyses. Results data are reported as of 06 October 2014 (the date of the last end of treatment visit).
Pre-assignment Detail	Randomization was stratified by type of hospital (major academic centers or other centers), prior aromatase inhibitor usage (Yes/No) and total lumbar spine bone mineral density (BMD) score at baseline (T-score < -1.0 or ≥ -1.0).

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Period Title: Overall Study
STARTED	1709	1711
Received Study Drug	1699	1700
COMPLETED	1462	1491
NOT COMPLETED	247	220

Baseline Characteristics

Arm/Group Title	Placebo	Denosumab	Total
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Total of all reporting groups
Overall Participants	1709	1711	3420
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.6 (8.0)	64.0 (7.9)	64.3 (8.0)
Sex: Female, Male (Count of Participants)
Female	1709 100%	1711 100%	3420 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	1700 99.5%	1702 99.5%	3402 99.5%
Asian	7 0.4%	5 0.3%	12 0.4%
Hispanic/Latino	1 0.1%	3 0.2%	4 0.1%
Black/Afro-Caribbean	0 0%	1 0.1%	1 0%
Missing	1 0.1%	0 0%	1 0%
Stratification Factor: Type of Hospital (particpants) [Number]
Major Academic Center	632	633	1265
Other Center	1077	1078	2155
Stratification Factor: Prior Aromatase inhibitor Use (Count of Participants)
No	269 15.7%	270 15.8%	539 15.8%
Yes	1440 84.3%	1441 84.2%	2881 84.2%
Stratification Factor: Total Lumbar Spine Bone Mineral Density T-score (Count of Participants)
T-score < -1.0	775 45.3%	773 45.2%	1548 45.3%
T-score ≥ -1.0	934 54.7%	938 54.8%	1872 54.7%

Outcome Measures

1. Primary Outcome

Title	Time to First Clinical Fracture
Description	The time to first on-study clinical fracture defined as the number of days from randomization to the date of the x-ray confirming the clinical fracture. A clinical fracture is any clinically evident fracture with associated symptoms and confirmed by x-ray. Participants who died or withdrew without experiencing a clinical fracture were censored at the date of last contact or study termination whichever was earlier.
Time Frame	From randomization until the primary analysis cut-off date of 26 March 2014; maximum time on study was 87 months.

Outcome Measure Data

Analysis Population Description

Full analysis set (all randomized participants)

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Measure Participants	1709	1711
Median (95% Confidence Interval) [days]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	The efficacy clinical hypothesis is that denosumab, when administered subcutaneously at a dose of 60 mg every 6 months, will be considered efficacious in patients with non-metastatic breast cancer receiving AIT if the rate of first clinical fracture in denosumab-treated patients is lower than that in placebo-treated patients. It is anticipated that denosumab will reduce the rate by 30% compared with placebo (ie, the true hazard ratio of denosumab compared with placebo is 0.70).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cox Proportional Hazard Model
	Comments	Stratification factors are hospital type, prior use of aromatase inhibitor, and baseline lumbar spine BMD.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.504
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	From the Cox proportional hazard model with treatment as the independent variable and stratified by randomization strata. A hazard ratio < 1.0 indicates a lower average event rate and a longer fracture-free time for denosumab relative to placebo.

2. Secondary Outcome

Title	Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites
Description	Bone mineral density was assessed by dual x-ray absorptiometry.
Time Frame	Baseline and Month 36

Outcome Measure Data

Analysis Population Description

BMD analysis set - total lumbar spine at Month 36 (participants with evaluable BMD values at Baseline and Month 36 for total lumbar spine)

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Measure Participants	245	230
Least Squares Mean (95% Confidence Interval) [percent change]	-2.75	7.27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The Hochberg procedure was used to control for multiplicity.
	Method	ANCOVA
	Comments	Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors.
Method of Estimation	Estimation Parameter	Difference from Placebo
	Estimated Value	10.02
	Confidence Interval	(2-Sided) 95%; 9.04 to 11.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites
Description	Bone mineral density was assessed by dual x-ray absorptiometry.
Time Frame	Baseline and Month 36

Outcome Measure Data

Analysis Population Description

BMD analysis set - total hip at Month 36 (participants with evaluable BMD values at Baseline and Month 36 for total hip)

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Measure Participants	237	231
Least Squares Mean (95% Confidence Interval) [percent change]	-3.32	4.60

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The Hochberg procedure was used to control for multiplicity.
	Method	ANCOVA
	Comments	Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors.
Method of Estimation	Estimation Parameter	Difference from Placebo
	Estimated Value	7.92
	Confidence Interval	(2-Sided) 95%; 6.87 to 8.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites
Description	Bone mineral density was assessed by dual x-ray absorptiometry.
Time Frame	Baseline and Month 36

Outcome Measure Data

Analysis Population Description

BMD analysis set - femoral neck at Month 36 (participants with evaluable BMD values at Baseline and Month 36 for femoral neck)

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Measure Participants	238	231
Least Squares Mean (95% Confidence Interval) [percent change]	-3.10	3.41

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The Hochberg procedure was used to control for multiplicity.
	Method	ANCOVA
	Comments	Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors.
Method of Estimation	Estimation Parameter	Difference from Placebo
	Estimated Value	6.51
	Confidence Interval	(2-Sided) 95%; 5.62 to 7.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With New Vertebral Fractures
Description	Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture is defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Vertebral Fracture Analysis Set with a Baseline and at least one post-baseline vertebral x-ray prior to or at Month 36.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Measure Participants	809	835
Number [participants]	49 2.9%	27 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0088
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression model includes treatment groups as the independent variable and stratified by the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; 0.33 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < 1 for odds ratio favor denosumab.

6. Secondary Outcome

Title	Number of Participants With New or Worsening Vertebral Fractures
Description	Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture is defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays. Worsening of pre-existing fractures is defined as an increase in fracture severity of at least 1 grade on the semiquantitative scale.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Vertebral Fracture Analysis Set with a Baseline and at least one post-baseline vertebral x-ray prior to or at Month 36.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Measure Participants	809	835
Number [participants]	55 3.2%	31 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0070
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression model includes treatment groups as the independent variable and stratified by the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < 1 for odds ratio favor denosumab.

7. Secondary Outcome

Title	Disease-free Survival
Description	Disease-free survival (DFS) is defined as the time interval from the randomization date to the date of first evidence of local or distant metastases, contra-lateral breast cancer, secondary carcinoma, or death from any cause (whichever occurred first). Participants last known to be alive, who did not experience recurrence of disease, were censored at their last contact date or at the data cut-off date whichever came first. DFS was initially specified to be analyzed after completion of the long-term follow-up period, however after analysis of the primary results was completed the data monitoring committee recommended that the analysis be conducted 18 months after the primary analysis data cut-off date.
Time Frame	From randomization until the DFS data cut-off date of 15 September 2015; maximum time on study was 102 months.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Measure Participants	1709	1711
Median (95% Confidence Interval) [days]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0515
	Comments
	Method	Cox Proportional Hazard Model
	Comments	Stratified by randomization strata (hospital type, use of aromatase inhibitor, baseline lumbar spine BMD).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.816
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	From the Cox Proportional hazard model with treatment fitted as a covariate and stratified by randomization strata. A hazard ratio < 1.0 indicates a lower average event rate and a longer disease-free time for denosumab relative to placebo.

8. Secondary Outcome

Title	Bone Metastases-free Survival
Description	Bone metastasis-free survival (BMFS) determined by the time from randomization to the first observation of bone metastasis or death from any cause. BMFS will be analyzed after long-term follow-up is complete.
Time Frame	Participants will be followed for bone metastasis-free survival once every 12 months for 66 months after primary completion date.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) determined by the time from randomization to death from any cause. OS will be analyzed after long-term follow-up is complete.
Time Frame	Participants will be followed for overall survival once every 12 months for 66 months after primary completion date.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From the first dose of study drug until 30 days after the last dose; 0.1 - 7.5 years with median of 3.0 years in Placebo arm, and 0.1 - 7.1 years with median of 3.0 years in Denosumab arm
Adverse Event Reporting Description	Nine participants in the placebo arm received denosumab in error and are counted in this arm for safety analyses. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo Q6M		Denosumab 60mg Q6M
Arm/Group Description	Participants received placebo subcutaneous injection once every 6 months (Q6M). All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.		Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy
All Cause Mortality
	Placebo Q6M		Denosumab 60mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Q6M		Denosumab 60mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	515/1690 (30.5%)		521/1709 (30.5%)
Blood and lymphatic system disorders
Agranulocytosis	0/1690 (0%)		1/1709 (0.1%)
Anaemia	2/1690 (0.1%)		3/1709 (0.2%)
Iron deficiency anaemia	3/1690 (0.2%)		3/1709 (0.2%)
Leukopenia	0/1690 (0%)		1/1709 (0.1%)
Lymphadenitis	1/1690 (0.1%)		0/1709 (0%)
Lymphadenopathy	0/1690 (0%)		1/1709 (0.1%)
Pancytopenia	1/1690 (0.1%)		1/1709 (0.1%)
Cardiac disorders
Acute coronary syndrome	1/1690 (0.1%)		0/1709 (0%)
Acute left ventricular failure	1/1690 (0.1%)		0/1709 (0%)
Acute myocardial infarction	1/1690 (0.1%)		1/1709 (0.1%)
Angina pectoris	4/1690 (0.2%)		5/1709 (0.3%)
Aortic valve incompetence	0/1690 (0%)		2/1709 (0.1%)
Aortic valve stenosis	2/1690 (0.1%)		4/1709 (0.2%)
Arrhythmia	1/1690 (0.1%)		0/1709 (0%)
Arteriosclerosis coronary artery	1/1690 (0.1%)		0/1709 (0%)
Atrial fibrillation	11/1690 (0.7%)		14/1709 (0.8%)
Atrial flutter	2/1690 (0.1%)		0/1709 (0%)
Atrial tachycardia	1/1690 (0.1%)		1/1709 (0.1%)
Atrioventricular block second degree	1/1690 (0.1%)		0/1709 (0%)
Bradycardia	2/1690 (0.1%)		3/1709 (0.2%)
Cardiac arrest	0/1690 (0%)		1/1709 (0.1%)
Cardiac failure	1/1690 (0.1%)		8/1709 (0.5%)
Cardio-respiratory arrest	1/1690 (0.1%)		0/1709 (0%)
Cardiomyopathy	2/1690 (0.1%)		1/1709 (0.1%)
Congestive cardiomyopathy	1/1690 (0.1%)		2/1709 (0.1%)
Coronary artery disease	11/1690 (0.7%)		10/1709 (0.6%)
Coronary artery stenosis	0/1690 (0%)		1/1709 (0.1%)
Ischaemic cardiomyopathy	1/1690 (0.1%)		0/1709 (0%)
Mitral valve incompetence	1/1690 (0.1%)		2/1709 (0.1%)
Myocardial infarction	5/1690 (0.3%)		1/1709 (0.1%)
Palpitations	1/1690 (0.1%)		0/1709 (0%)
Sick sinus syndrome	0/1690 (0%)		1/1709 (0.1%)
Sinus tachycardia	2/1690 (0.1%)		0/1709 (0%)
Stress cardiomyopathy	1/1690 (0.1%)		0/1709 (0%)
Supraventricular extrasystoles	0/1690 (0%)		1/1709 (0.1%)
Supraventricular tachycardia	1/1690 (0.1%)		0/1709 (0%)
Tachycardia	1/1690 (0.1%)		1/1709 (0.1%)
Congenital, familial and genetic disorders
Developmental hip dysplasia	1/1690 (0.1%)		0/1709 (0%)
Gene mutation	0/1690 (0%)		1/1709 (0.1%)
Ear and labyrinth disorders
Deafness	0/1690 (0%)		1/1709 (0.1%)
Deafness unilateral	0/1690 (0%)		1/1709 (0.1%)
Ear canal stenosis	1/1690 (0.1%)		0/1709 (0%)
Meniere's disease	0/1690 (0%)		1/1709 (0.1%)
Sudden hearing loss	0/1690 (0%)		1/1709 (0.1%)
Tinnitus	0/1690 (0%)		1/1709 (0.1%)
Vertigo	10/1690 (0.6%)		9/1709 (0.5%)
Vertigo positional	0/1690 (0%)		4/1709 (0.2%)
Vestibular disorder	1/1690 (0.1%)		1/1709 (0.1%)
Endocrine disorders
Basedow's disease	1/1690 (0.1%)		0/1709 (0%)
Goitre	12/1690 (0.7%)		21/1709 (1.2%)
Hyperparathyroidism	0/1690 (0%)		2/1709 (0.1%)
Hyperthyroidism	0/1690 (0%)		1/1709 (0.1%)
Eye disorders
Blepharochalasis	0/1690 (0%)		1/1709 (0.1%)
Cataract	28/1690 (1.7%)		16/1709 (0.9%)
Cataract cortical	1/1690 (0.1%)		1/1709 (0.1%)
Cataract nuclear	1/1690 (0.1%)		3/1709 (0.2%)
Diabetic retinopathy	0/1690 (0%)		1/1709 (0.1%)
Exfoliation glaucoma	1/1690 (0.1%)		0/1709 (0%)
Macular degeneration	1/1690 (0.1%)		0/1709 (0%)
Macular fibrosis	1/1690 (0.1%)		0/1709 (0%)
Open angle glaucoma	0/1690 (0%)		1/1709 (0.1%)
Retinal degeneration	1/1690 (0.1%)		0/1709 (0%)
Retinal detachment	0/1690 (0%)		2/1709 (0.1%)
Retinal tear	0/1690 (0%)		2/1709 (0.1%)
Vitreous haemorrhage	1/1690 (0.1%)		0/1709 (0%)
Vitreous opacities	1/1690 (0.1%)		0/1709 (0%)
Gastrointestinal disorders
Abdominal adhesions	0/1690 (0%)		1/1709 (0.1%)
Abdominal discomfort	0/1690 (0%)		1/1709 (0.1%)
Abdominal hernia	1/1690 (0.1%)		0/1709 (0%)
Abdominal pain	2/1690 (0.1%)		2/1709 (0.1%)
Abdominal pain upper	2/1690 (0.1%)		0/1709 (0%)
Abdominal wall haematoma	0/1690 (0%)		1/1709 (0.1%)
Abnormal faeces	0/1690 (0%)		2/1709 (0.1%)
Anal fissure	0/1690 (0%)		1/1709 (0.1%)
Chronic gastritis	1/1690 (0.1%)		0/1709 (0%)
Colitis	3/1690 (0.2%)		1/1709 (0.1%)
Colitis ischaemic	0/1690 (0%)		2/1709 (0.1%)
Colon dysplasia	0/1690 (0%)		1/1709 (0.1%)
Constipation	0/1690 (0%)		2/1709 (0.1%)
Crohn's disease	0/1690 (0%)		1/1709 (0.1%)
Dental caries	1/1690 (0.1%)		0/1709 (0%)
Diaphragmatic hernia	0/1690 (0%)		1/1709 (0.1%)
Diarrhoea	4/1690 (0.2%)		2/1709 (0.1%)
Diverticular perforation	1/1690 (0.1%)		1/1709 (0.1%)
Diverticulum	0/1690 (0%)		2/1709 (0.1%)
Diverticulum intestinal	2/1690 (0.1%)		1/1709 (0.1%)
Duodenitis	0/1690 (0%)		1/1709 (0.1%)
Dysphagia	1/1690 (0.1%)		1/1709 (0.1%)
Enteritis	3/1690 (0.2%)		2/1709 (0.1%)
Gastric antral vascular ectasia	0/1690 (0%)		1/1709 (0.1%)
Gastric haemorrhage	1/1690 (0.1%)		0/1709 (0%)
Gastritis	6/1690 (0.4%)		7/1709 (0.4%)
Gastritis erosive	0/1690 (0%)		2/1709 (0.1%)
Gastritis haemorrhagic	1/1690 (0.1%)		0/1709 (0%)
Gastrointestinal angiodysplasia	0/1690 (0%)		1/1709 (0.1%)
Gastrointestinal haemorrhage	1/1690 (0.1%)		1/1709 (0.1%)
Gastrointestinal motility disorder	0/1690 (0%)		1/1709 (0.1%)
Gastrointestinal necrosis	0/1690 (0%)		1/1709 (0.1%)
Gastrooesophageal reflux disease	2/1690 (0.1%)		1/1709 (0.1%)
Haematochezia	1/1690 (0.1%)		0/1709 (0%)
Haemorrhoids	1/1690 (0.1%)		4/1709 (0.2%)
Hiatus hernia	4/1690 (0.2%)		0/1709 (0%)
Ileus	1/1690 (0.1%)		2/1709 (0.1%)
Incarcerated umbilical hernia	0/1690 (0%)		1/1709 (0.1%)
Inguinal hernia	2/1690 (0.1%)		2/1709 (0.1%)
Intestinal obstruction	0/1690 (0%)		1/1709 (0.1%)
Intestinal perforation	0/1690 (0%)		1/1709 (0.1%)
Intestinal polyp	1/1690 (0.1%)		0/1709 (0%)
Large intestinal stenosis	0/1690 (0%)		1/1709 (0.1%)
Large intestine perforation	1/1690 (0.1%)		0/1709 (0%)
Large intestine polyp	4/1690 (0.2%)		8/1709 (0.5%)
Mallory-Weiss syndrome	0/1690 (0%)		1/1709 (0.1%)
Nausea	0/1690 (0%)		2/1709 (0.1%)
Oesophageal motility disorder	1/1690 (0.1%)		0/1709 (0%)
Painful defaecation	0/1690 (0%)		1/1709 (0.1%)
Pancreatic pseudocyst	1/1690 (0.1%)		0/1709 (0%)
Pancreatitis	0/1690 (0%)		3/1709 (0.2%)
Pancreatitis acute	1/1690 (0.1%)		1/1709 (0.1%)
Peritoneal necrosis	1/1690 (0.1%)		0/1709 (0%)
Rectal polyp	0/1690 (0%)		1/1709 (0.1%)
Subileus	0/1690 (0%)		1/1709 (0.1%)
Swollen tongue	0/1690 (0%)		1/1709 (0.1%)
Umbilical hernia	2/1690 (0.1%)		4/1709 (0.2%)
Vomiting	2/1690 (0.1%)		0/1709 (0%)
General disorders
Chest discomfort	0/1690 (0%)		2/1709 (0.1%)
Chest pain	7/1690 (0.4%)		4/1709 (0.2%)
Cyst	1/1690 (0.1%)		1/1709 (0.1%)
Device connection issue	0/1690 (0%)		1/1709 (0.1%)
Device dislocation	4/1690 (0.2%)		3/1709 (0.2%)
Face oedema	1/1690 (0.1%)		0/1709 (0%)
Fat necrosis	1/1690 (0.1%)		2/1709 (0.1%)
Fibrosis	0/1690 (0%)		1/1709 (0.1%)
General physical health deterioration	1/1690 (0.1%)		3/1709 (0.2%)
Granuloma	0/1690 (0%)		1/1709 (0.1%)
Hyperplasia	0/1690 (0%)		1/1709 (0.1%)
Impaired healing	0/1690 (0%)		4/1709 (0.2%)
Incarcerated hernia	0/1690 (0%)		1/1709 (0.1%)
Local swelling	1/1690 (0.1%)		0/1709 (0%)
Medical device complication	1/1690 (0.1%)		1/1709 (0.1%)
Multi-organ failure	1/1690 (0.1%)		0/1709 (0%)
Non-cardiac chest pain	2/1690 (0.1%)		1/1709 (0.1%)
Oedema peripheral	2/1690 (0.1%)		3/1709 (0.2%)
Pain	2/1690 (0.1%)		2/1709 (0.1%)
Pyrexia	1/1690 (0.1%)		0/1709 (0%)
Hepatobiliary disorders
Bile duct stone	1/1690 (0.1%)		1/1709 (0.1%)
Biliary cirrhosis primary	1/1690 (0.1%)		0/1709 (0%)
Biliary colic	1/1690 (0.1%)		1/1709 (0.1%)
Cholangitis	0/1690 (0%)		1/1709 (0.1%)
Cholecystitis	2/1690 (0.1%)		8/1709 (0.5%)
Cholecystitis acute	1/1690 (0.1%)		0/1709 (0%)
Cholecystitis chronic	3/1690 (0.2%)		2/1709 (0.1%)
Cholelithiasis	9/1690 (0.5%)		14/1709 (0.8%)
Drug-induced liver injury	1/1690 (0.1%)		0/1709 (0%)
Gallbladder polyp	2/1690 (0.1%)		0/1709 (0%)
Hepatic cirrhosis	1/1690 (0.1%)		0/1709 (0%)
Jaundice	0/1690 (0%)		1/1709 (0.1%)
Immune system disorders
Allergy to arthropod sting	1/1690 (0.1%)		0/1709 (0%)
Anaphylactic reaction	0/1690 (0%)		1/1709 (0.1%)
Drug hypersensitivity	1/1690 (0.1%)		0/1709 (0%)
Hypersensitivity	2/1690 (0.1%)		2/1709 (0.1%)
Sarcoidosis	1/1690 (0.1%)		0/1709 (0%)
Infections and infestations
Abscess	0/1690 (0%)		1/1709 (0.1%)
Abscess jaw	0/1690 (0%)		1/1709 (0.1%)
Abscess limb	0/1690 (0%)		1/1709 (0.1%)
Anal abscess	0/1690 (0%)		1/1709 (0.1%)
Appendicitis	2/1690 (0.1%)		5/1709 (0.3%)
Arthritis infective	1/1690 (0.1%)		0/1709 (0%)
Bacterial infection	1/1690 (0.1%)		0/1709 (0%)
Borrelia infection	2/1690 (0.1%)		0/1709 (0%)
Breast abscess	1/1690 (0.1%)		2/1709 (0.1%)
Bronchitis	1/1690 (0.1%)		6/1709 (0.4%)
Bronchopneumonia	1/1690 (0.1%)		2/1709 (0.1%)
Campylobacter gastroenteritis	0/1690 (0%)		1/1709 (0.1%)
Cellulitis	2/1690 (0.1%)		0/1709 (0%)
Cholecystitis infective	1/1690 (0.1%)		0/1709 (0%)
Chronic sinusitis	0/1690 (0%)		1/1709 (0.1%)
Clostridium difficile colitis	1/1690 (0.1%)		0/1709 (0%)
Cystitis	2/1690 (0.1%)		0/1709 (0%)
Device related infection	3/1690 (0.2%)		2/1709 (0.1%)
Diverticulitis	9/1690 (0.5%)		9/1709 (0.5%)
Encephalitis	0/1690 (0%)		1/1709 (0.1%)
Erysipelas	10/1690 (0.6%)		15/1709 (0.9%)
Escherichia sepsis	1/1690 (0.1%)		1/1709 (0.1%)
Escherichia urinary tract infection	1/1690 (0.1%)		0/1709 (0%)
Eye infection bacterial	0/1690 (0%)		1/1709 (0.1%)
Febrile infection	2/1690 (0.1%)		1/1709 (0.1%)
Gastroenteritis	1/1690 (0.1%)		6/1709 (0.4%)
Gastrointestinal infection	1/1690 (0.1%)		0/1709 (0%)
Haematoma infection	2/1690 (0.1%)		0/1709 (0%)
Helicobacter gastritis	1/1690 (0.1%)		1/1709 (0.1%)
Herpes zoster	3/1690 (0.2%)		2/1709 (0.1%)
Implant site infection	0/1690 (0%)		1/1709 (0.1%)
Incision site abscess	0/1690 (0%)		1/1709 (0.1%)
Infected seroma	0/1690 (0%)		1/1709 (0.1%)
Infection	2/1690 (0.1%)		0/1709 (0%)
Infective exacerbation of chronic obstructive airways disease	1/1690 (0.1%)		1/1709 (0.1%)
Influenza	1/1690 (0.1%)		0/1709 (0%)
Joint abscess	1/1690 (0.1%)		0/1709 (0%)
Localised infection	0/1690 (0%)		1/1709 (0.1%)
Mastitis	1/1690 (0.1%)		2/1709 (0.1%)
Nasopharyngitis	1/1690 (0.1%)		1/1709 (0.1%)
Oesophageal candidiasis	0/1690 (0%)		1/1709 (0.1%)
Ophthalmic herpes zoster	0/1690 (0%)		1/1709 (0.1%)
Otitis media	1/1690 (0.1%)		0/1709 (0%)
Paronychia	1/1690 (0.1%)		0/1709 (0%)
Peritoneal abscess	1/1690 (0.1%)		0/1709 (0%)
Pharyngitis	0/1690 (0%)		3/1709 (0.2%)
Pneumonia	7/1690 (0.4%)		9/1709 (0.5%)
Pneumonia bacterial	1/1690 (0.1%)		0/1709 (0%)
Post procedural infection	0/1690 (0%)		2/1709 (0.1%)
Postoperative wound infection	2/1690 (0.1%)		0/1709 (0%)
Psoas abscess	0/1690 (0%)		1/1709 (0.1%)
Pyelonephritis	2/1690 (0.1%)		3/1709 (0.2%)
Respiratory tract infection	1/1690 (0.1%)		4/1709 (0.2%)
Rhinitis	1/1690 (0.1%)		0/1709 (0%)
Salpingitis	1/1690 (0.1%)		1/1709 (0.1%)
Sepsis	0/1690 (0%)		1/1709 (0.1%)
Sinusitis	1/1690 (0.1%)		4/1709 (0.2%)
Skin infection	1/1690 (0.1%)		0/1709 (0%)
Soft tissue infection	1/1690 (0.1%)		0/1709 (0%)
Subcutaneous abscess	3/1690 (0.2%)		6/1709 (0.4%)
Tonsillitis	0/1690 (0%)		1/1709 (0.1%)
Tracheobronchitis	0/1690 (0%)		1/1709 (0.1%)
Urinary tract infection	9/1690 (0.5%)		7/1709 (0.4%)
Vestibular neuronitis	0/1690 (0%)		1/1709 (0.1%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/1690 (0.1%)		1/1709 (0.1%)
Anastomotic stenosis	0/1690 (0%)		1/1709 (0.1%)
Animal bite	1/1690 (0.1%)		0/1709 (0%)
Bone contusion	2/1690 (0.1%)		0/1709 (0%)
Brain contusion	0/1690 (0%)		1/1709 (0.1%)
Bursa injury	0/1690 (0%)		1/1709 (0.1%)
Concussion	5/1690 (0.3%)		1/1709 (0.1%)
Contusion	6/1690 (0.4%)		4/1709 (0.2%)
Extradural haematoma	1/1690 (0.1%)		0/1709 (0%)
Fall	1/1690 (0.1%)		0/1709 (0%)
Haemodilution	0/1690 (0%)		1/1709 (0.1%)
Head injury	1/1690 (0.1%)		0/1709 (0%)
Incisional hernia	3/1690 (0.2%)		3/1709 (0.2%)
Joint dislocation	3/1690 (0.2%)		2/1709 (0.1%)
Joint injury	1/1690 (0.1%)		0/1709 (0%)
Ligament rupture	3/1690 (0.2%)		0/1709 (0%)
Ligament sprain	2/1690 (0.1%)		0/1709 (0%)
Meniscus injury	24/1690 (1.4%)		23/1709 (1.3%)
Post procedural bile leak	0/1690 (0%)		1/1709 (0.1%)
Post procedural complication	2/1690 (0.1%)		1/1709 (0.1%)
Post procedural haematoma	1/1690 (0.1%)		2/1709 (0.1%)
Post procedural inflammation	1/1690 (0.1%)		0/1709 (0%)
Post-traumatic neck syndrome	0/1690 (0%)		1/1709 (0.1%)
Postoperative hernia	0/1690 (0%)		1/1709 (0.1%)
Postoperative thrombosis	1/1690 (0.1%)		0/1709 (0%)
Procedural intestinal perforation	0/1690 (0%)		1/1709 (0.1%)
Procedural pain	0/1690 (0%)		2/1709 (0.1%)
Radiation alveolitis	1/1690 (0.1%)		0/1709 (0%)
Radiation pneumonitis	1/1690 (0.1%)		1/1709 (0.1%)
Radiation skin injury	1/1690 (0.1%)		4/1709 (0.2%)
Road traffic accident	0/1690 (0%)		1/1709 (0.1%)
Scar	5/1690 (0.3%)		2/1709 (0.1%)
Seroma	2/1690 (0.1%)		2/1709 (0.1%)
Skin abrasion	0/1690 (0%)		1/1709 (0.1%)
Spinal column injury	1/1690 (0.1%)		0/1709 (0%)
Splenic haematoma	0/1690 (0%)		1/1709 (0.1%)
Subdural haematoma	4/1690 (0.2%)		0/1709 (0%)
Suture rupture	1/1690 (0.1%)		0/1709 (0%)
Tendon rupture	1/1690 (0.1%)		1/1709 (0.1%)
Toxicity to various agents	1/1690 (0.1%)		1/1709 (0.1%)
Traumatic arthrosis	0/1690 (0%)		1/1709 (0.1%)
Vascular bypass dysfunction	0/1690 (0%)		1/1709 (0.1%)
Wound	1/1690 (0.1%)		0/1709 (0%)
Wound dehiscence	1/1690 (0.1%)		1/1709 (0.1%)
Investigations
Blood creatinine increased	0/1690 (0%)		1/1709 (0.1%)
Blood pressure abnormal	0/1690 (0%)		1/1709 (0.1%)
Colonoscopy	0/1690 (0%)		1/1709 (0.1%)
Glycosylated haemoglobin increased	0/1690 (0%)		1/1709 (0.1%)
Mammogram abnormal	0/1690 (0%)		1/1709 (0.1%)
Pulmonary arterial pressure increased	1/1690 (0.1%)		0/1709 (0%)
Smear cervix abnormal	1/1690 (0.1%)		0/1709 (0%)
Weight decreased	0/1690 (0%)		1/1709 (0.1%)
Metabolism and nutrition disorders
Dehydration	0/1690 (0%)		1/1709 (0.1%)
Diabetes mellitus	0/1690 (0%)		1/1709 (0.1%)
Electrolyte imbalance	0/1690 (0%)		2/1709 (0.1%)
Hyperglycaemia	1/1690 (0.1%)		0/1709 (0%)
Hypocalcaemia	1/1690 (0.1%)		2/1709 (0.1%)
Hyponatraemia	1/1690 (0.1%)		0/1709 (0%)
Insulin resistance	1/1690 (0.1%)		0/1709 (0%)
Obesity	1/1690 (0.1%)		0/1709 (0%)
Type 2 diabetes mellitus	1/1690 (0.1%)		3/1709 (0.2%)
Musculoskeletal and connective tissue disorders
Acquired claw toe	1/1690 (0.1%)		0/1709 (0%)
Arthralgia	2/1690 (0.1%)		6/1709 (0.4%)
Arthritis	4/1690 (0.2%)		0/1709 (0%)
Back pain	8/1690 (0.5%)		10/1709 (0.6%)
Bone cyst	0/1690 (0%)		1/1709 (0.1%)
Bone pain	0/1690 (0%)		1/1709 (0.1%)
Bursitis	1/1690 (0.1%)		1/1709 (0.1%)
Cervical spinal stenosis	1/1690 (0.1%)		0/1709 (0%)
Chondromalacia	2/1690 (0.1%)		0/1709 (0%)
Chondropathy	1/1690 (0.1%)		6/1709 (0.4%)
Dupuytren's contracture	2/1690 (0.1%)		0/1709 (0%)
Exostosis	1/1690 (0.1%)		0/1709 (0%)
Fistula	2/1690 (0.1%)		0/1709 (0%)
Foot deformity	12/1690 (0.7%)		13/1709 (0.8%)
Haemarthrosis	0/1690 (0%)		1/1709 (0.1%)
Intervertebral disc degeneration	0/1690 (0%)		1/1709 (0.1%)
Intervertebral disc disorder	1/1690 (0.1%)		0/1709 (0%)
Intervertebral disc protrusion	15/1690 (0.9%)		14/1709 (0.8%)
Joint effusion	1/1690 (0.1%)		0/1709 (0%)
Joint instability	0/1690 (0%)		1/1709 (0.1%)
Ligament disorder	1/1690 (0.1%)		1/1709 (0.1%)
Lumbar spinal stenosis	6/1690 (0.4%)		8/1709 (0.5%)
Meniscal degeneration	2/1690 (0.1%)		0/1709 (0%)
Mobility decreased	0/1690 (0%)		1/1709 (0.1%)
Musculoskeletal chest pain	1/1690 (0.1%)		1/1709 (0.1%)
Musculoskeletal pain	1/1690 (0.1%)		1/1709 (0.1%)
Osteoarthritis	58/1690 (3.4%)		62/1709 (3.6%)
Osteochondrosis	1/1690 (0.1%)		2/1709 (0.1%)
Osteonecrosis	3/1690 (0.2%)		1/1709 (0.1%)
Pain in extremity	0/1690 (0%)		2/1709 (0.1%)
Polyarthritis	1/1690 (0.1%)		4/1709 (0.2%)
Polymyalgia rheumatica	1/1690 (0.1%)		0/1709 (0%)
Pseudarthrosis	0/1690 (0%)		1/1709 (0.1%)
Rheumatoid arthritis	0/1690 (0%)		1/1709 (0.1%)
Rotator cuff syndrome	1/1690 (0.1%)		3/1709 (0.2%)
Scoliosis	1/1690 (0.1%)		1/1709 (0.1%)
Spinal column stenosis	1/1690 (0.1%)		3/1709 (0.2%)
Spinal osteoarthritis	0/1690 (0%)		1/1709 (0.1%)
Spinal pain	3/1690 (0.2%)		2/1709 (0.1%)
Spondyloarthropathy	0/1690 (0%)		1/1709 (0.1%)
Spondylolisthesis	2/1690 (0.1%)		1/1709 (0.1%)
Synovitis	0/1690 (0%)		1/1709 (0.1%)
Tendon disorder	0/1690 (0%)		3/1709 (0.2%)
Tenosynovitis	1/1690 (0.1%)		1/1709 (0.1%)
Tenosynovitis stenosans	4/1690 (0.2%)		9/1709 (0.5%)
Torticollis	0/1690 (0%)		1/1709 (0.1%)
Trigger finger	6/1690 (0.4%)		2/1709 (0.1%)
Vertebral foraminal stenosis	1/1690 (0.1%)		4/1709 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/1690 (0%)		1/1709 (0.1%)
Basal cell carcinoma	5/1690 (0.3%)		4/1709 (0.2%)
Benign breast neoplasm	0/1690 (0%)		2/1709 (0.1%)
Benign lymph node neoplasm	0/1690 (0%)		1/1709 (0.1%)
Benign salivary gland neoplasm	1/1690 (0.1%)		1/1709 (0.1%)
Bladder papilloma	1/1690 (0.1%)		0/1709 (0%)
Bladder transitional cell carcinoma recurrent	1/1690 (0.1%)		0/1709 (0%)
Bowen's disease	0/1690 (0%)		1/1709 (0.1%)
Breast adenoma	1/1690 (0.1%)		1/1709 (0.1%)
Breast cancer	0/1690 (0%)		1/1709 (0.1%)
Breast cancer metastatic	1/1690 (0.1%)		0/1709 (0%)
Breast cancer recurrent	4/1690 (0.2%)		3/1709 (0.2%)
Breast cancer stage III	0/1690 (0%)		1/1709 (0.1%)
Bronchial carcinoma	1/1690 (0.1%)		3/1709 (0.2%)
Cervix carcinoma	0/1690 (0%)		1/1709 (0.1%)
Chronic lymphocytic leukaemia	1/1690 (0.1%)		0/1709 (0%)
Colon adenoma	1/1690 (0.1%)		3/1709 (0.2%)
Colon cancer	1/1690 (0.1%)		2/1709 (0.1%)
Colon neoplasm	2/1690 (0.1%)		0/1709 (0%)
Contralateral breast cancer	1/1690 (0.1%)		4/1709 (0.2%)
Endometrial adenocarcinoma	1/1690 (0.1%)		1/1709 (0.1%)
Fibroadenoma of breast	1/1690 (0.1%)		1/1709 (0.1%)
Gastric cancer	1/1690 (0.1%)		0/1709 (0%)
Gastrointestinal tract adenoma	1/1690 (0.1%)		2/1709 (0.1%)
Haemangioma of liver	1/1690 (0.1%)		0/1709 (0%)
Hepatic neoplasm	0/1690 (0%)		1/1709 (0.1%)
Inflammatory myofibroblastic tumour	1/1690 (0.1%)		0/1709 (0%)
Intestinal adenocarcinoma	1/1690 (0.1%)		1/1709 (0.1%)
Intraductal papilloma of breast	1/1690 (0.1%)		0/1709 (0%)
Intraductal proliferative breast lesion	4/1690 (0.2%)		1/1709 (0.1%)
Invasive ductal breast carcinoma	0/1690 (0%)		2/1709 (0.1%)
Lentigo maligna	1/1690 (0.1%)		0/1709 (0%)
Lip and/or oral cavity cancer	1/1690 (0.1%)		0/1709 (0%)
Lipoma	1/1690 (0.1%)		0/1709 (0%)
Lobular breast carcinoma in situ	1/1690 (0.1%)		0/1709 (0%)
Lung adenocarcinoma	1/1690 (0.1%)		2/1709 (0.1%)
Lung neoplasm malignant	2/1690 (0.1%)		0/1709 (0%)
Malignant melanoma	1/1690 (0.1%)		1/1709 (0.1%)
Malignant melanoma in situ	1/1690 (0.1%)		0/1709 (0%)
Malignant pleural effusion	0/1690 (0%)		1/1709 (0.1%)
Mediastinum neoplasm	0/1690 (0%)		1/1709 (0.1%)
Melanocytic naevus	1/1690 (0.1%)		0/1709 (0%)
Meningioma	2/1690 (0.1%)		1/1709 (0.1%)
Meningioma benign	0/1690 (0%)		1/1709 (0.1%)
Metastases to bone	5/1690 (0.3%)		5/1709 (0.3%)
Metastases to liver	3/1690 (0.2%)		2/1709 (0.1%)
Metastases to lung	0/1690 (0%)		1/1709 (0.1%)
Metastases to lymph nodes	1/1690 (0.1%)		2/1709 (0.1%)
Metastases to peritoneum	1/1690 (0.1%)		1/1709 (0.1%)
Metastases to pleura	0/1690 (0%)		1/1709 (0.1%)
Metastases to skin	1/1690 (0.1%)		0/1709 (0%)
Neuroma	1/1690 (0.1%)		0/1709 (0%)
Oral fibroma	1/1690 (0.1%)		0/1709 (0%)
Ovarian adenoma	0/1690 (0%)		4/1709 (0.2%)
Ovarian epithelial cancer	1/1690 (0.1%)		0/1709 (0%)
Ovarian fibroma	1/1690 (0.1%)		0/1709 (0%)
Pancreatic carcinoma	1/1690 (0.1%)		0/1709 (0%)
Papillary thyroid cancer	1/1690 (0.1%)		1/1709 (0.1%)
Parathyroid tumour benign	2/1690 (0.1%)		0/1709 (0%)
Pituitary tumour benign	0/1690 (0%)		1/1709 (0.1%)
Rectal adenocarcinoma	1/1690 (0.1%)		0/1709 (0%)
Rectal adenoma	3/1690 (0.2%)		0/1709 (0%)
Rectal cancer	1/1690 (0.1%)		3/1709 (0.2%)
Renal cell carcinoma	1/1690 (0.1%)		1/1709 (0.1%)
Salivary gland adenoma	0/1690 (0%)		2/1709 (0.1%)
Schwannoma	0/1690 (0%)		1/1709 (0.1%)
Squamous cell carcinoma	3/1690 (0.2%)		0/1709 (0%)
Squamous cell carcinoma of lung	1/1690 (0.1%)		0/1709 (0%)
Thyroid adenoma	0/1690 (0%)		1/1709 (0.1%)
Thyroid cancer	1/1690 (0.1%)		1/1709 (0.1%)
Thyroid neoplasm	2/1690 (0.1%)		1/1709 (0.1%)
Transitional cell carcinoma	0/1690 (0%)		2/1709 (0.1%)
Transitional cell carcinoma urethra	1/1690 (0.1%)		0/1709 (0%)
Uterine leiomyoma	3/1690 (0.2%)		0/1709 (0%)
Uterine leiomyosarcoma	1/1690 (0.1%)		0/1709 (0%)
Nervous system disorders
Acoustic neuritis	0/1690 (0%)		1/1709 (0.1%)
Amnesia	1/1690 (0.1%)		1/1709 (0.1%)
Amnestic disorder	0/1690 (0%)		1/1709 (0.1%)
Carotid artery aneurysm	2/1690 (0.1%)		0/1709 (0%)
Carotid artery disease	0/1690 (0%)		1/1709 (0.1%)
Carotid artery stenosis	2/1690 (0.1%)		1/1709 (0.1%)
Carpal tunnel syndrome	13/1690 (0.8%)		14/1709 (0.8%)
Cerebellar haemorrhage	0/1690 (0%)		1/1709 (0.1%)
Cerebral infarction	1/1690 (0.1%)		1/1709 (0.1%)
Cerebral ischaemia	1/1690 (0.1%)		1/1709 (0.1%)
Cerebrovascular accident	9/1690 (0.5%)		6/1709 (0.4%)
Cerebrovascular disorder	1/1690 (0.1%)		0/1709 (0%)
Cervical myelopathy	1/1690 (0.1%)		0/1709 (0%)
Cervical radiculopathy	0/1690 (0%)		1/1709 (0.1%)
Cervicobrachial syndrome	2/1690 (0.1%)		3/1709 (0.2%)
Chronic inflammatory demyelinating polyradiculoneuropathy	0/1690 (0%)		1/1709 (0.1%)
Cognitive disorder	1/1690 (0.1%)		0/1709 (0%)
Dementia	1/1690 (0.1%)		0/1709 (0%)
Diabetic coma	1/1690 (0.1%)		0/1709 (0%)
Dizziness	2/1690 (0.1%)		0/1709 (0%)
Drop attacks	0/1690 (0%)		1/1709 (0.1%)
Epilepsy	0/1690 (0%)		1/1709 (0.1%)
Facial neuralgia	1/1690 (0.1%)		0/1709 (0%)
Facial paresis	0/1690 (0%)		1/1709 (0.1%)
Generalised tonic-clonic seizure	1/1690 (0.1%)		0/1709 (0%)
Guillain-Barre syndrome	1/1690 (0.1%)		0/1709 (0%)
Headache	0/1690 (0%)		2/1709 (0.1%)
Intercostal neuralgia	0/1690 (0%)		1/1709 (0.1%)
Intracranial aneurysm	1/1690 (0.1%)		0/1709 (0%)
Loss of consciousness	0/1690 (0%)		1/1709 (0.1%)
Lumbar radiculopathy	0/1690 (0%)		2/1709 (0.1%)
Medication overuse headache	0/1690 (0%)		1/1709 (0.1%)
Meralgia paraesthetica	1/1690 (0.1%)		0/1709 (0%)
Migraine	0/1690 (0%)		1/1709 (0.1%)
Monoplegia	0/1690 (0%)		1/1709 (0.1%)
Morton's neuralgia	1/1690 (0.1%)		1/1709 (0.1%)
Motor neurone disease	1/1690 (0.1%)		0/1709 (0%)
Nerve compression	0/1690 (0%)		1/1709 (0.1%)
Nervous system disorder	0/1690 (0%)		1/1709 (0.1%)
Neuralgia	0/1690 (0%)		1/1709 (0.1%)
Paraesthesia	0/1690 (0%)		2/1709 (0.1%)
Peroneal nerve palsy	1/1690 (0.1%)		0/1709 (0%)
Polyneuropathy	0/1690 (0%)		1/1709 (0.1%)
Radicular syndrome	1/1690 (0.1%)		2/1709 (0.1%)
Sciatica	4/1690 (0.2%)		7/1709 (0.4%)
Senile dementia	0/1690 (0%)		1/1709 (0.1%)
Small fibre neuropathy	1/1690 (0.1%)		0/1709 (0%)
Speech disorder	1/1690 (0.1%)		0/1709 (0%)
Spinal claudication	0/1690 (0%)		2/1709 (0.1%)
Syncope	4/1690 (0.2%)		6/1709 (0.4%)
Transient global amnesia	0/1690 (0%)		3/1709 (0.2%)
Transient ischaemic attack	1/1690 (0.1%)		1/1709 (0.1%)
VIIth nerve paralysis	0/1690 (0%)		1/1709 (0.1%)
Vascular encephalopathy	0/1690 (0%)		2/1709 (0.1%)
Psychiatric disorders
Alcohol withdrawal syndrome	0/1690 (0%)		2/1709 (0.1%)
Bipolar disorder	1/1690 (0.1%)		0/1709 (0%)
Burnout syndrome	0/1690 (0%)		1/1709 (0.1%)
Depressed mood	0/1690 (0%)		1/1709 (0.1%)
Depression	8/1690 (0.5%)		8/1709 (0.5%)
Mental disorder	1/1690 (0.1%)		1/1709 (0.1%)
Panic attack	2/1690 (0.1%)		0/1709 (0%)
Post-traumatic stress disorder	1/1690 (0.1%)		0/1709 (0%)
Psychosomatic disease	1/1690 (0.1%)		0/1709 (0%)
Stress	0/1690 (0%)		1/1709 (0.1%)
Suicide attempt	1/1690 (0.1%)		0/1709 (0%)
Renal and urinary disorders
Acute prerenal failure	0/1690 (0%)		1/1709 (0.1%)
Calculus ureteric	2/1690 (0.1%)		1/1709 (0.1%)
Cystitis haemorrhagic	1/1690 (0.1%)		1/1709 (0.1%)
Diabetic nephropathy	1/1690 (0.1%)		0/1709 (0%)
Hydronephrosis	1/1690 (0.1%)		1/1709 (0.1%)
Hypertonic bladder	1/1690 (0.1%)		0/1709 (0%)
Incontinence	2/1690 (0.1%)		1/1709 (0.1%)
Nephrolithiasis	2/1690 (0.1%)		0/1709 (0%)
Renal artery stenosis	0/1690 (0%)		1/1709 (0.1%)
Renal colic	2/1690 (0.1%)		0/1709 (0%)
Renal failure acute	1/1690 (0.1%)		1/1709 (0.1%)
Stress urinary incontinence	1/1690 (0.1%)		4/1709 (0.2%)
Urethral disorder	1/1690 (0.1%)		0/1709 (0%)
Urge incontinence	2/1690 (0.1%)		1/1709 (0.1%)
Urinary incontinence	0/1690 (0%)		1/1709 (0.1%)
Reproductive system and breast disorders
Adenomyosis	1/1690 (0.1%)		0/1709 (0%)
Adnexa uteri cyst	0/1690 (0%)		2/1709 (0.1%)
Adnexa uteri mass	1/1690 (0.1%)		0/1709 (0%)
Breast calcifications	4/1690 (0.2%)		4/1709 (0.2%)
Breast cyst	1/1690 (0.1%)		1/1709 (0.1%)
Breast discharge	1/1690 (0.1%)		0/1709 (0%)
Breast disorder	6/1690 (0.4%)		1/1709 (0.1%)
Breast enlargement	1/1690 (0.1%)		0/1709 (0%)
Breast fibrosis	3/1690 (0.2%)		2/1709 (0.1%)
Breast haematoma	2/1690 (0.1%)		1/1709 (0.1%)
Breast necrosis	1/1690 (0.1%)		3/1709 (0.2%)
Breast pain	1/1690 (0.1%)		0/1709 (0%)
Cervical dysplasia	1/1690 (0.1%)		4/1709 (0.2%)
Cervical polyp	0/1690 (0%)		3/1709 (0.2%)
Cystocele	2/1690 (0.1%)		0/1709 (0%)
Dyspareunia	0/1690 (0%)		1/1709 (0.1%)
Endometrial hyperplasia	2/1690 (0.1%)		3/1709 (0.2%)
Fibrocystic breast disease	0/1690 (0%)		3/1709 (0.2%)
Ovarian cyst	1/1690 (0.1%)		7/1709 (0.4%)
Postmenopausal haemorrhage	1/1690 (0.1%)		3/1709 (0.2%)
Rectocele	2/1690 (0.1%)		0/1709 (0%)
Uterine adhesions	0/1690 (0%)		1/1709 (0.1%)
Uterine polyp	3/1690 (0.2%)		4/1709 (0.2%)
Uterine prolapse	2/1690 (0.1%)		1/1709 (0.1%)
Uterovaginal prolapse	2/1690 (0.1%)		2/1709 (0.1%)
Vaginal prolapse	0/1690 (0%)		1/1709 (0.1%)
Respiratory, thoracic and mediastinal disorders
Asthma	2/1690 (0.1%)		0/1709 (0%)
Atelectasis	0/1690 (0%)		2/1709 (0.1%)
Cheyne-Stokes respiration	0/1690 (0%)		1/1709 (0.1%)
Chronic obstructive pulmonary disease	0/1690 (0%)		3/1709 (0.2%)
Cough	1/1690 (0.1%)		1/1709 (0.1%)
Diaphragmatic paralysis	0/1690 (0%)		1/1709 (0.1%)
Dyspnoea	4/1690 (0.2%)		3/1709 (0.2%)
Dyspnoea exertional	0/1690 (0%)		4/1709 (0.2%)
Emphysema	0/1690 (0%)		1/1709 (0.1%)
Epistaxis	0/1690 (0%)		1/1709 (0.1%)
Hyperventilation	0/1690 (0%)		1/1709 (0.1%)
Lung disorder	0/1690 (0%)		1/1709 (0.1%)
Nasal polyps	0/1690 (0%)		1/1709 (0.1%)
Organising pneumonia	1/1690 (0.1%)		0/1709 (0%)
Oropharyngeal pain	0/1690 (0%)		1/1709 (0.1%)
Pharyngeal cyst	1/1690 (0.1%)		0/1709 (0%)
Pleural effusion	2/1690 (0.1%)		1/1709 (0.1%)
Pleurisy	0/1690 (0%)		2/1709 (0.1%)
Pneumonia aspiration	2/1690 (0.1%)		0/1709 (0%)
Pneumonitis	0/1690 (0%)		1/1709 (0.1%)
Pneumothorax	1/1690 (0.1%)		0/1709 (0%)
Pulmonary alveolar haemorrhage	1/1690 (0.1%)		0/1709 (0%)
Pulmonary embolism	11/1690 (0.7%)		12/1709 (0.7%)
Pulmonary fibrosis	1/1690 (0.1%)		0/1709 (0%)
Pulmonary hypertension	0/1690 (0%)		1/1709 (0.1%)
Pulmonary mass	2/1690 (0.1%)		0/1709 (0%)
Pulmonary oedema	1/1690 (0.1%)		0/1709 (0%)
Sinus polyp	0/1690 (0%)		1/1709 (0.1%)
Sleep apnoea syndrome	5/1690 (0.3%)		2/1709 (0.1%)
Vocal cord polyp	2/1690 (0.1%)		0/1709 (0%)
Skin and subcutaneous tissue disorders
Acquired epidermolysis bullosa	0/1690 (0%)		1/1709 (0.1%)
Angioedema	0/1690 (0%)		1/1709 (0.1%)
Dermal cyst	0/1690 (0%)		1/1709 (0.1%)
Dermatitis allergic	0/1690 (0%)		2/1709 (0.1%)
Diabetic foot	0/1690 (0%)		1/1709 (0.1%)
Drug eruption	2/1690 (0.1%)		0/1709 (0%)
Eczema	0/1690 (0%)		1/1709 (0.1%)
Erythema	0/1690 (0%)		1/1709 (0.1%)
Erythema nodosum	0/1690 (0%)		1/1709 (0.1%)
Hyperkeratosis	1/1690 (0.1%)		1/1709 (0.1%)
Keloid scar	0/1690 (0%)		2/1709 (0.1%)
Lichen sclerosus	0/1690 (0%)		1/1709 (0.1%)
Panniculitis	0/1690 (0%)		1/1709 (0.1%)
Rash	0/1690 (0%)		1/1709 (0.1%)
Rash maculo-papular	0/1690 (0%)		1/1709 (0.1%)
Scar pain	1/1690 (0.1%)		2/1709 (0.1%)
Skin necrosis	1/1690 (0.1%)		1/1709 (0.1%)
Skin ulcer	1/1690 (0.1%)		3/1709 (0.2%)
Stasis dermatitis	0/1690 (0%)		1/1709 (0.1%)
Urticaria	1/1690 (0.1%)		1/1709 (0.1%)
Surgical and medical procedures
Breast reconstruction	0/1690 (0%)		1/1709 (0.1%)
Hysterectomy	1/1690 (0.1%)		0/1709 (0%)
Hysterosalpingo-oophorectomy	0/1690 (0%)		1/1709 (0.1%)
Intraocular lens implant	0/1690 (0%)		1/1709 (0.1%)
Knee arthroplasty	1/1690 (0.1%)		0/1709 (0%)
Mastectomy	3/1690 (0.2%)		1/1709 (0.1%)
Oophorectomy	1/1690 (0.1%)		0/1709 (0%)
Prophylaxis	0/1690 (0%)		1/1709 (0.1%)
Vascular disorders
Aortic dissection	0/1690 (0%)		1/1709 (0.1%)
Arterial stenosis	2/1690 (0.1%)		0/1709 (0%)
Arteriovenous fistula	0/1690 (0%)		1/1709 (0.1%)
Bleeding varicose vein	1/1690 (0.1%)		1/1709 (0.1%)
Circulatory collapse	4/1690 (0.2%)		3/1709 (0.2%)
Deep vein thrombosis	3/1690 (0.2%)		2/1709 (0.1%)
Femoral artery occlusion	1/1690 (0.1%)		2/1709 (0.1%)
Haematoma	3/1690 (0.2%)		0/1709 (0%)
Hypertension	6/1690 (0.4%)		5/1709 (0.3%)
Hypertensive crisis	14/1690 (0.8%)		10/1709 (0.6%)
Hypotension	2/1690 (0.1%)		0/1709 (0%)
Iliac artery occlusion	0/1690 (0%)		1/1709 (0.1%)
Intermittent claudication	0/1690 (0%)		1/1709 (0.1%)
Lymphoedema	2/1690 (0.1%)		5/1709 (0.3%)
Peripheral arterial occlusive disease	4/1690 (0.2%)		3/1709 (0.2%)
Peripheral artery stenosis	1/1690 (0.1%)		3/1709 (0.2%)
Peripheral venous disease	4/1690 (0.2%)		0/1709 (0%)
Raynaud's phenomenon	1/1690 (0.1%)		0/1709 (0%)
Subclavian artery stenosis	1/1690 (0.1%)		0/1709 (0%)
Subclavian steal syndrome	1/1690 (0.1%)		0/1709 (0%)
Temporal arteritis	0/1690 (0%)		2/1709 (0.1%)
Thrombophlebitis	0/1690 (0%)		1/1709 (0.1%)
Thrombosis	1/1690 (0.1%)		1/1709 (0.1%)
Varicose vein	10/1690 (0.6%)		12/1709 (0.7%)
Vasculitis	1/1690 (0.1%)		0/1709 (0%)
Venous thrombosis	1/1690 (0.1%)		1/1709 (0.1%)
Venous thrombosis limb	0/1690 (0%)		1/1709 (0.1%)
Other (Not Including Serious) Adverse Events
	Placebo Q6M		Denosumab 60mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	838/1690 (49.6%)		882/1709 (51.6%)
General disorders
Fatigue	100/1690 (5.9%)		109/1709 (6.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	446/1690 (26.4%)		441/1709 (25.8%)
Back pain	146/1690 (8.6%)		151/1709 (8.8%)
Bone pain	111/1690 (6.6%)		139/1709 (8.1%)
Osteoarthritis	61/1690 (3.6%)		89/1709 (5.2%)
Pain in extremity	85/1690 (5%)		107/1709 (6.3%)
Spinal pain	73/1690 (4.3%)		89/1709 (5.2%)
Skin and subcutaneous tissue disorders
Scar pain	86/1690 (5.1%)		78/1709 (4.6%)
Vascular disorders
Hot flush	234/1690 (13.8%)		270/1709 (15.8%)
Hypertension	94/1690 (5.6%)		111/1709 (6.5%)

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.