A Study Comparing Denosumab vs. Zoledronic Acid for the Treatment of Bone Metastases in Breast Cancer Subjects.

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00321464
• Collaborator: Daiichi Sankyo, Inc. (Industry)
• Enrollment: 2,049
• Arms: 2
• Actual Duration (Months): 72.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone metastases in subjects with advanced breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Bone Metastases	Biological: Denosumab; Drug: Zoledronic Acid	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2049 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Supportive Care
• Official Title: A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid (Zometa®) in the Treatment of Bone Metastases in Subjects With Advanced Breast Cancer
• Actual Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Jul 20, 2009
• Actual Study Completion Date: Apr 4, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: zoledronic acid	Drug: Zoledronic Acid; Q4W 4 mg zoledronic acid IV over minimum 15 minutes and 120 mg denosumab placebo SC; Other Names: Zometa
Experimental: denosumab	Biological: Denosumab; Q4W 120 mg denosumab SC injection and 4 mg zoledronic acid (Zometa) placebo IV over a minimum of 15 minutes

Outcome Measures

Primary Outcome Measures

1. Time to First On-Study Skeletal Related Event (SRE) (Non-inferiority) [Up to 34 months]

   Time to first on-study skeletal-related event (SRE) using a non-inferiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented.

Secondary Outcome Measures

1. Time to First On-Study Skeletal-Related Event (Superiority) [Up to 34 months]

   Time to first on-study skeletal-related event (SRE) using a superiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented.

2. Time to First and Subsequent On-Study Skeletal-Related Event [Up to 34 months]

   Time to first and subsequent on-study skeletal-related event (SRE) using a multiple event analysis. To be considered a subsequent SRE, the event must occur at least 21 days after the previous SRE. This outcome measure utilizes multiple event times, was analyzed based on a proportional mean model, and is therefore more appropriately summarized by the cumulative number of events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults with histologically or cytologically confirmed breast adenocarcinoma

• radiographic evidence of at least one bone mets

• Easter Cooperative Oncology Group status of 0, 1 or 2;

• adequate organ function

Exclusion Criteria:

• Current or prior IV bisphosphonate administration

• current or prior oral bisphosphonates for bone mets

• life expectancy of less than 6 months

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen
• Daiichi Sankyo, Inc.

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Notice regarding posted summaries of trial results
• AmgenTrials clinical trials website

Publications

• Cleeland CS, Body JJ, Stopeck A, von Moos R, Fallowfield L, Mathias SD, Patrick DL, Clemons M, Tonkin K, Masuda N, Lipton A, de Boer R, Salvagni S, Oliveira CT, Qian Y, Jiang Q, Dansey R, Braun A, Chung K. Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double-blind study of denosumab and zoledronic acid. Cancer. 2013 Feb 15;119(4):832-8. doi: 10.1002/cncr.27789. Epub 2012 Sep 5.
• Martin M, Bell R, Bourgeois H, Brufsky A, Diel I, Eniu A, Fallowfield L, Fujiwara Y, Jassem J, Paterson AH, Ritchie D, Steger GG, Stopeck A, Vogel C, Fan M, Jiang Q, Chung K, Dansey R, Braun A. Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res. 2012 Sep 1;18(17):4841-9. Epub 2012 Aug 14.
• Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010 Dec 10;28(35):5132-9. doi: 10.1200/JCO.2010.29.7101. Epub 2010 Nov 8.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00321464
• Other Study ID Numbers: 20050136
• First Posted: May 3, 2006
• Last Update Posted: Oct 17, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Amgen: Fractures; Compressions; Bisphosphonates; Bone metastases; Breast cancer; Skeletal; Radiation; Surgery to Bone
• Additional relevant MeSH terms: Neoplasm Metastasis; Neoplasms, Second Primary; Bone Neoplasms; Bone Marrow Diseases; Zoledronic Acid; Denosumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from 27 April 2006 through 31 December 2007
Pre-assignment Detail	2049 patients were enrolled in the study, but 3 patients were excluded from all analyses because properly documented informed consent was not obtained.

Arm/Group Title	Zoledronic Acid	Denosumab
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with subcutaneous denosumab placebo once every 4 weeks	Denomsumab 120 mg subcutaneously with intravenous zoledronic acid placebo once every 4 weeks
Period Title: Overall Study
STARTED	1020	1026
Received Investigational Product	1014	1019
COMPLETED	461	468
NOT COMPLETED	559	558

Baseline Characteristics

Arm/Group Title	Zoledronic Acid	Denosumab	Total
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with subcutaneous denosumab placebo once every 4 weeks	Denomsumab 120 mg subcutaneously with intravenous zoledronic acid placebo once every 4 weeks	Total of all reporting groups
Overall Participants	1020	1026	2046
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.6 (11.6)	56.8 (11.5)	56.7 (11.5)
Sex: Female, Male (Count of Participants)
Female	1011 99.1%	1018 99.2%	2029 99.2%
Male	9 0.9%	8 0.8%	17 0.8%
Race/Ethnicity, Customized (Number) [Number]
White or Caucasian	813 79.7%	822 80.1%	1635 79.9%
Black or African American	25 2.5%	26 2.5%	51 2.5%
Hispanic or Latino	59 5.8%	59 5.8%	118 5.8%
Asian	37 3.6%	32 3.1%	69 3.4%
Japanese	69 6.8%	70 6.8%	139 6.8%
Native Hawaiian or Other Pacific Islander	1 0.1%	1 0.1%	2 0.1%
Other	16 1.6%	16 1.6%	32 1.6%
Previous Skeletal-Related Event Stratification Factor (Number) [Number]
Yes	373 36.6%	378 36.8%	751 36.7%
No	647 63.4%	648 63.2%	1295 63.3%
Prior Oral Bisphosphonate Use Stratification Factor (Number) [Number]
Yes	38 3.7%	42 4.1%	80 3.9%
No	982 96.3%	984 95.9%	1966 96.1%
Current Chemotherapy Stratification Factor (Number) [Number]
Yes	408 40%	410 40%	818 40%
No	612 60%	616 60%	1228 60%
Japan Stratification Factor (Number) [Number]
Yes	67 6.6%	69 6.7%	136 6.6%
No	953 93.4%	957 93.3%	1910 93.4%

Outcome Measures

1. Primary Outcome

Title	Time to First On-Study Skeletal Related Event (SRE) (Non-inferiority)
Description	Time to first on-study skeletal-related event (SRE) using a non-inferiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented.
Time Frame	Up to 34 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set, composed of all randomized participants.

Arm/Group Title	Zoledronic Acid	Denosumab
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with subcutaneous denosumab placebo once every 4 weeks	Denomsumab 120 mg subcutaneously with intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	1020	1026
Number [Participants]	372 36.5%	315 30.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Denosumab
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A synthesis method was used for the non-inferiority test for the hypothesis that denosumab preserves at least 50% of the effect of zoledronic acid vs. placebo.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	() 95%; 0.71 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by the randomization stratification factors (previous skeletal-related event, prior oral bisphosphonate use, current chemotherapy, and location in Japan).

2. Secondary Outcome

Title	Time to First On-Study Skeletal-Related Event (Superiority)
Description	Time to first on-study skeletal-related event (SRE) using a superiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented.
Time Frame	Up to 34 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set, composed of all randomized participants.

Arm/Group Title	Zoledronic Acid	Denosumab
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with subcutaneous denosumab placebo once every 4 weeks	Denomsumab 120 mg subcutaneously with intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	1020	1026
Number [Participants]	372 36.5%	315 30.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	P-value was adjusted for multiplicity according to a hierarchical testing strategy and Hochberg procedure
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	() 95%; 0.71 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by the randomization stratification factors (previous skeletal-related event, prior oral bisphosphonate use, current chemotherapy, and location in Japan).

3. Secondary Outcome

Title	Time to First and Subsequent On-Study Skeletal-Related Event
Description	Time to first and subsequent on-study skeletal-related event (SRE) using a multiple event analysis. To be considered a subsequent SRE, the event must occur at least 21 days after the previous SRE. This outcome measure utilizes multiple event times, was analyzed based on a proportional mean model, and is therefore more appropriately summarized by the cumulative number of events.
Time Frame	Up to 34 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set, composed of all randomized participants

Arm/Group Title	Zoledronic Acid	Denosumab
Arm/Group Description	Zoledronic acid 4 mg by intravenous injection with subcutaneous denosumab placebo once every 4 weeks	Denomsumab 120 mg subcutaneously with intravenous zoledronic acid placebo once every 4 weeks
Measure Participants	1020	1026
Number [Events]	608	474

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	P-value was adjusted for multiplicity according to a hierarchical testing strategy and Hochberg procedure
	Method	Anderson-Gill model
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.77
	Confidence Interval	() 95%; 0.66 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by the randomization stratification factors (previous skeletal-related event, prior oral bisphosphonate use, current chemotherapy, and location in Japan).

Adverse Events

Time Frame	up to 2 years 10 months
Adverse Event Reporting Description	The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events. One subject who was randomized to zoledronic acid and received denosumab as the 1st investigational product was analyzed on the denosumab arm for safety analyses.
Arm/Group Title	Zoledronic Acid 4 mg Q4W		Denosumab 120 mg Q4W
Arm/Group Description
All Cause Mortality
	Zoledronic Acid 4 mg Q4W		Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zoledronic Acid 4 mg Q4W		Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	471/1013 (46.5%)		453/1020 (44.4%)
Blood and lymphatic system disorders
Anaemia	32/1013 (3.2%)		27/1020 (2.6%)
Bone marrow failure	0/1013 (0%)		1/1020 (0.1%)
Coagulopathy	0/1013 (0%)		4/1020 (0.4%)
Disseminated intravascular coagulation	2/1013 (0.2%)		0/1020 (0%)
Febrile neutropenia	22/1013 (2.2%)		17/1020 (1.7%)
Haemolytic anaemia	1/1013 (0.1%)		0/1020 (0%)
Heparin-induced thrombocytopenia	1/1013 (0.1%)		0/1020 (0%)
Leukopenia	6/1013 (0.6%)		6/1020 (0.6%)
Lymphadenitis	0/1013 (0%)		1/1020 (0.1%)
Lymphadenopathy	1/1013 (0.1%)		0/1020 (0%)
Neutropenia	14/1013 (1.4%)		16/1020 (1.6%)
Pancytopenia	2/1013 (0.2%)		5/1020 (0.5%)
Platelet disorder	1/1013 (0.1%)		0/1020 (0%)
Thrombocytopenia	11/1013 (1.1%)		12/1020 (1.2%)
Cardiac disorders
Acute coronary syndrome	1/1013 (0.1%)		0/1020 (0%)
Acute myocardial infarction	2/1013 (0.2%)		2/1020 (0.2%)
Angina unstable	1/1013 (0.1%)		0/1020 (0%)
Arrhythmia	2/1013 (0.2%)		0/1020 (0%)
Arrhythmia supraventricular	0/1013 (0%)		1/1020 (0.1%)
Arteriospasm coronary	1/1013 (0.1%)		0/1020 (0%)
Atrial fibrillation	5/1013 (0.5%)		3/1020 (0.3%)
Atrioventricular block second degree	0/1013 (0%)		1/1020 (0.1%)
Cardiac arrest	4/1013 (0.4%)		1/1020 (0.1%)
Cardiac failure	7/1013 (0.7%)		6/1020 (0.6%)
Cardiac failure acute	0/1013 (0%)		3/1020 (0.3%)
Cardiac failure congestive	5/1013 (0.5%)		2/1020 (0.2%)
Cardiac tamponade	0/1013 (0%)		2/1020 (0.2%)
Cardio-respiratory arrest	4/1013 (0.4%)		6/1020 (0.6%)
Cardiogenic shock	0/1013 (0%)		1/1020 (0.1%)
Cardiomyopathy	2/1013 (0.2%)		1/1020 (0.1%)
Cardiopulmonary failure	4/1013 (0.4%)		2/1020 (0.2%)
Cardiovascular disorder	1/1013 (0.1%)		0/1020 (0%)
Cytotoxic cardiomyopathy	0/1013 (0%)		2/1020 (0.2%)
Left ventricular failure	2/1013 (0.2%)		0/1020 (0%)
Myocardial infarction	2/1013 (0.2%)		0/1020 (0%)
Palpitations	0/1013 (0%)		2/1020 (0.2%)
Pericardial effusion	2/1013 (0.2%)		3/1020 (0.3%)
Pericarditis	1/1013 (0.1%)		1/1020 (0.1%)
Sinus bradycardia	0/1013 (0%)		1/1020 (0.1%)
Sinus tachycardia	1/1013 (0.1%)		0/1020 (0%)
Supraventricular tachycardia	1/1013 (0.1%)		0/1020 (0%)
Tachycardia	2/1013 (0.2%)		1/1020 (0.1%)
Ear and labyrinth disorders
Deafness neurosensory	0/1013 (0%)		1/1020 (0.1%)
Meniere's disease	1/1013 (0.1%)		0/1020 (0%)
Vertigo	4/1013 (0.4%)		3/1020 (0.3%)
Endocrine disorders
Endocrine disorder	1/1013 (0.1%)		0/1020 (0%)
Eye disorders
Amaurosis	3/1013 (0.3%)		1/1020 (0.1%)
Cataract	0/1013 (0%)		1/1020 (0.1%)
Diplopia	0/1013 (0%)		1/1020 (0.1%)
Exophthalmos	1/1013 (0.1%)		0/1020 (0%)
Keratitis	0/1013 (0%)		1/1020 (0.1%)
Macular oedema	1/1013 (0.1%)		0/1020 (0%)
Optic ischaemic neuropathy	0/1013 (0%)		1/1020 (0.1%)
Photophobia	1/1013 (0.1%)		0/1020 (0%)
Ulcerative keratitis	0/1013 (0%)		1/1020 (0.1%)
Vision blurred	0/1013 (0%)		2/1020 (0.2%)
Visual acuity reduced	0/1013 (0%)		1/1020 (0.1%)
Visual impairment	0/1013 (0%)		1/1020 (0.1%)
Gastrointestinal disorders
Abdominal discomfort	1/1013 (0.1%)		0/1020 (0%)
Abdominal distension	2/1013 (0.2%)		1/1020 (0.1%)
Abdominal pain	14/1013 (1.4%)		15/1020 (1.5%)
Abdominal pain upper	3/1013 (0.3%)		3/1020 (0.3%)
Ascites	5/1013 (0.5%)		10/1020 (1%)
Caecitis	0/1013 (0%)		1/1020 (0.1%)
Colitis	1/1013 (0.1%)		2/1020 (0.2%)
Constipation	5/1013 (0.5%)		3/1020 (0.3%)
Crohn's disease	0/1013 (0%)		1/1020 (0.1%)
Diarrhoea	16/1013 (1.6%)		19/1020 (1.9%)
Diarrhoea haemorrhagic	0/1013 (0%)		1/1020 (0.1%)
Diverticular perforation	1/1013 (0.1%)		2/1020 (0.2%)
Duodenal ulcer	0/1013 (0%)		1/1020 (0.1%)
Dyspepsia	1/1013 (0.1%)		0/1020 (0%)
Dysphagia	4/1013 (0.4%)		3/1020 (0.3%)
Enteritis	1/1013 (0.1%)		0/1020 (0%)
Enterocele	0/1013 (0%)		1/1020 (0.1%)
Epigastric discomfort	1/1013 (0.1%)		0/1020 (0%)
Faeces discoloured	1/1013 (0.1%)		0/1020 (0%)
Femoral hernia	0/1013 (0%)		1/1020 (0.1%)
Gastric disorder	1/1013 (0.1%)		0/1020 (0%)
Gastric perforation	1/1013 (0.1%)		0/1020 (0%)
Gastric ulcer haemorrhage	0/1013 (0%)		1/1020 (0.1%)
Gastritis	2/1013 (0.2%)		2/1020 (0.2%)
Gastritis erosive	0/1013 (0%)		1/1020 (0.1%)
Gastrointestinal haemorrhage	2/1013 (0.2%)		3/1020 (0.3%)
Gastrointestinal inflammation	0/1013 (0%)		1/1020 (0.1%)
Gastrointestinal obstruction	0/1013 (0%)		1/1020 (0.1%)
Haematemesis	2/1013 (0.2%)		2/1020 (0.2%)
Haemorrhoids	1/1013 (0.1%)		0/1020 (0%)
Ileus	2/1013 (0.2%)		3/1020 (0.3%)
Intestinal obstruction	3/1013 (0.3%)		1/1020 (0.1%)
Intestinal perforation	1/1013 (0.1%)		0/1020 (0%)
Large intestinal haemorrhage	0/1013 (0%)		1/1020 (0.1%)
Large intestine perforation	2/1013 (0.2%)		0/1020 (0%)
Melaena	1/1013 (0.1%)		2/1020 (0.2%)
Nausea	23/1013 (2.3%)		21/1020 (2.1%)
Neutropenic colitis	1/1013 (0.1%)		0/1020 (0%)
Odynophagia	0/1013 (0%)		1/1020 (0.1%)
Oesophagitis	1/1013 (0.1%)		0/1020 (0%)
Pancreatitis	1/1013 (0.1%)		1/1020 (0.1%)
Peritonitis	1/1013 (0.1%)		0/1020 (0%)
Rectal haemorrhage	2/1013 (0.2%)		1/1020 (0.1%)
Small intestinal obstruction	1/1013 (0.1%)		0/1020 (0%)
Stomatitis	1/1013 (0.1%)		1/1020 (0.1%)
Subileus	1/1013 (0.1%)		1/1020 (0.1%)
Vomiting	31/1013 (3.1%)		31/1020 (3%)
General disorders
Adverse drug reaction	0/1013 (0%)		1/1020 (0.1%)
Asthenia	14/1013 (1.4%)		12/1020 (1.2%)
Catheter site pain	1/1013 (0.1%)		0/1020 (0%)
Chest discomfort	1/1013 (0.1%)		2/1020 (0.2%)
Chest pain	9/1013 (0.9%)		5/1020 (0.5%)
Chills	2/1013 (0.2%)		3/1020 (0.3%)
Condition aggravated	1/1013 (0.1%)		0/1020 (0%)
Crepitations	1/1013 (0.1%)		0/1020 (0%)
Death	1/1013 (0.1%)		2/1020 (0.2%)
Disease progression	12/1013 (1.2%)		11/1020 (1.1%)
Drowning	1/1013 (0.1%)		0/1020 (0%)
Face oedema	0/1013 (0%)		1/1020 (0.1%)
Fatigue	5/1013 (0.5%)		15/1020 (1.5%)
Gait disturbance	1/1013 (0.1%)		0/1020 (0%)
General physical health deterioration	15/1013 (1.5%)		20/1020 (2%)
Generalised oedema	1/1013 (0.1%)		1/1020 (0.1%)
Impaired healing	2/1013 (0.2%)		0/1020 (0%)
Implant expulsion	0/1013 (0%)		1/1020 (0.1%)
Localised oedema	0/1013 (0%)		1/1020 (0.1%)
Malaise	1/1013 (0.1%)		0/1020 (0%)
Mucosal inflammation	2/1013 (0.2%)		3/1020 (0.3%)
Multi-organ failure	9/1013 (0.9%)		9/1020 (0.9%)
Oedema	1/1013 (0.1%)		1/1020 (0.1%)
Oedema peripheral	5/1013 (0.5%)		4/1020 (0.4%)
Organ failure	1/1013 (0.1%)		0/1020 (0%)
Pain	8/1013 (0.8%)		4/1020 (0.4%)
Performance status decreased	2/1013 (0.2%)		0/1020 (0%)
Pyrexia	26/1013 (2.6%)		21/1020 (2.1%)
Sudden death	0/1013 (0%)		1/1020 (0.1%)
Systemic inflammatory response syndrome	1/1013 (0.1%)		0/1020 (0%)
Hepatobiliary disorders
Acute hepatic failure	2/1013 (0.2%)		2/1020 (0.2%)
Bile duct obstruction	0/1013 (0%)		1/1020 (0.1%)
Cholangitis	0/1013 (0%)		1/1020 (0.1%)
Cholecystitis	2/1013 (0.2%)		0/1020 (0%)
Cholecystitis acute	0/1013 (0%)		1/1020 (0.1%)
Cholestasis	1/1013 (0.1%)		0/1020 (0%)
Hepatic congestion	1/1013 (0.1%)		0/1020 (0%)
Hepatic cyst	1/1013 (0.1%)		0/1020 (0%)
Hepatic failure	16/1013 (1.6%)		24/1020 (2.4%)
Hepatic function abnormal	7/1013 (0.7%)		10/1020 (1%)
Hepatic haemorrhage	1/1013 (0.1%)		0/1020 (0%)
Hepatitis acute	1/1013 (0.1%)		0/1020 (0%)
Hepatitis toxic	0/1013 (0%)		1/1020 (0.1%)
Hepatorenal failure	0/1013 (0%)		1/1020 (0.1%)
Hepatotoxicity	0/1013 (0%)		1/1020 (0.1%)
Hyperbilirubinaemia	3/1013 (0.3%)		2/1020 (0.2%)
Jaundice	0/1013 (0%)		5/1020 (0.5%)
Liver disorder	3/1013 (0.3%)		0/1020 (0%)
Immune system disorders
Anaphylactic reaction	0/1013 (0%)		1/1020 (0.1%)
Anaphylactic shock	1/1013 (0.1%)		0/1020 (0%)
Drug hypersensitivity	1/1013 (0.1%)		0/1020 (0%)
Infections and infestations
Abdominal abscess	1/1013 (0.1%)		0/1020 (0%)
Abdominal infection	1/1013 (0.1%)		0/1020 (0%)
Abdominal wall abscess	0/1013 (0%)		1/1020 (0.1%)
Abdominal wall infection	1/1013 (0.1%)		0/1020 (0%)
Abscess jaw	0/1013 (0%)		1/1020 (0.1%)
Abscess limb	0/1013 (0%)		1/1020 (0.1%)
Abscess neck	1/1013 (0.1%)		0/1020 (0%)
Anal abscess	1/1013 (0.1%)		1/1020 (0.1%)
Bacteraemia	1/1013 (0.1%)		0/1020 (0%)
Bacterial sepsis	1/1013 (0.1%)		1/1020 (0.1%)
Breast cellulitis	0/1013 (0%)		1/1020 (0.1%)
Bronchitis	2/1013 (0.2%)		2/1020 (0.2%)
Candida sepsis	1/1013 (0.1%)		0/1020 (0%)
Catheter related infection	3/1013 (0.3%)		3/1020 (0.3%)
Catheter sepsis	0/1013 (0%)		1/1020 (0.1%)
Cellulitis	3/1013 (0.3%)		7/1020 (0.7%)
Clostridial infection	0/1013 (0%)		1/1020 (0.1%)
Cystitis	2/1013 (0.2%)		0/1020 (0%)
Diabetic foot infection	0/1013 (0%)		1/1020 (0.1%)
Diverticulitis	0/1013 (0%)		2/1020 (0.2%)
Ear infection	1/1013 (0.1%)		0/1020 (0%)
Endocarditis	1/1013 (0.1%)		0/1020 (0%)
Erysipelas	1/1013 (0.1%)		3/1020 (0.3%)
Escherichia bacteraemia	3/1013 (0.3%)		0/1020 (0%)
Escherichia sepsis	0/1013 (0%)		1/1020 (0.1%)
Gastroenteritis	0/1013 (0%)		1/1020 (0.1%)
Gastrointestinal infection	1/1013 (0.1%)		0/1020 (0%)
Herpes zoster	3/1013 (0.3%)		0/1020 (0%)
Infection	2/1013 (0.2%)		2/1020 (0.2%)
Klebsiella sepsis	1/1013 (0.1%)		0/1020 (0%)
Lobar pneumonia	1/1013 (0.1%)		1/1020 (0.1%)
Localised infection	1/1013 (0.1%)		0/1020 (0%)
Lower respiratory tract infection bacterial	0/1013 (0%)		1/1020 (0.1%)
Lung infection	1/1013 (0.1%)		1/1020 (0.1%)
Mastitis	1/1013 (0.1%)		0/1020 (0%)
Meningitis	0/1013 (0%)		1/1020 (0.1%)
Nasopharyngitis	0/1013 (0%)		1/1020 (0.1%)
Neutropenic infection	1/1013 (0.1%)		0/1020 (0%)
Neutropenic sepsis	3/1013 (0.3%)		0/1020 (0%)
Oral fungal infection	1/1013 (0.1%)		0/1020 (0%)
Osteomyelitis	2/1013 (0.2%)		0/1020 (0%)
Periodontal infection	1/1013 (0.1%)		0/1020 (0%)
Peritoneal abscess	1/1013 (0.1%)		0/1020 (0%)
Pharyngitis	0/1013 (0%)		1/1020 (0.1%)
Pneumonia	25/1013 (2.5%)		20/1020 (2%)
Pneumonia primary atypical	0/1013 (0%)		1/1020 (0.1%)
Postoperative wound infection	1/1013 (0.1%)		0/1020 (0%)
Pseudomonal bacteraemia	1/1013 (0.1%)		0/1020 (0%)
Pseudomonal sepsis	1/1013 (0.1%)		0/1020 (0%)
Pyelonephritis	2/1013 (0.2%)		1/1020 (0.1%)
Pyelonephritis chronic	0/1013 (0%)		1/1020 (0.1%)
Respiratory tract infection	1/1013 (0.1%)		3/1020 (0.3%)
Salmonellosis	1/1013 (0.1%)		0/1020 (0%)
Sepsis	4/1013 (0.4%)		2/1020 (0.2%)
Septic shock	2/1013 (0.2%)		1/1020 (0.1%)
Sinusitis	0/1013 (0%)		1/1020 (0.1%)
Staphylococcal bacteraemia	0/1013 (0%)		1/1020 (0.1%)
Staphylococcal sepsis	0/1013 (0%)		1/1020 (0.1%)
Stenotrophomonas sepsis	2/1013 (0.2%)		0/1020 (0%)
Streptococcal bacteraemia	1/1013 (0.1%)		0/1020 (0%)
Streptococcal sepsis	1/1013 (0.1%)		0/1020 (0%)
Subcutaneous abscess	1/1013 (0.1%)		0/1020 (0%)
Tonsillitis	1/1013 (0.1%)		0/1020 (0%)
Upper respiratory tract infection	0/1013 (0%)		1/1020 (0.1%)
Urinary tract infection	9/1013 (0.9%)		7/1020 (0.7%)
Urinary tract infection bacterial	0/1013 (0%)		1/1020 (0.1%)
Viral infection	1/1013 (0.1%)		0/1020 (0%)
Wound infection	0/1013 (0%)		1/1020 (0.1%)
Injury, poisoning and procedural complications
Arthropod bite	0/1013 (0%)		1/1020 (0.1%)
Concussion	0/1013 (0%)		1/1020 (0.1%)
Drug toxicity	1/1013 (0.1%)		1/1020 (0.1%)
Fall	0/1013 (0%)		1/1020 (0.1%)
Femur fracture	12/1013 (1.2%)		11/1020 (1.1%)
Fibula fracture	0/1013 (0%)		2/1020 (0.2%)
Fracture	4/1013 (0.4%)		1/1020 (0.1%)
Gastroenteritis radiation	2/1013 (0.2%)		2/1020 (0.2%)
Head injury	1/1013 (0.1%)		1/1020 (0.1%)
Humerus fracture	1/1013 (0.1%)		1/1020 (0.1%)
Incorrect route of drug administration	1/1013 (0.1%)		0/1020 (0%)
Injury	1/1013 (0.1%)		0/1020 (0%)
Ligament rupture	0/1013 (0%)		1/1020 (0.1%)
Lumbar vertebral fracture	2/1013 (0.2%)		0/1020 (0%)
Medical device complication	0/1013 (0%)		1/1020 (0.1%)
Medication error	1/1013 (0.1%)		0/1020 (0%)
Patella fracture	1/1013 (0.1%)		0/1020 (0%)
Poisoning	1/1013 (0.1%)		0/1020 (0%)
Post-traumatic pain	1/1013 (0.1%)		0/1020 (0%)
Radiation injury	0/1013 (0%)		1/1020 (0.1%)
Radiation myelopathy	0/1013 (0%)		1/1020 (0.1%)
Radius fracture	2/1013 (0.2%)		0/1020 (0%)
Recall phenomenon	1/1013 (0.1%)		0/1020 (0%)
Rib fracture	0/1013 (0%)		1/1020 (0.1%)
Skin laceration	1/1013 (0.1%)		0/1020 (0%)
Subdural haematoma	0/1013 (0%)		3/1020 (0.3%)
Subdural haemorrhage	0/1013 (0%)		1/1020 (0.1%)
Tendon rupture	1/1013 (0.1%)		0/1020 (0%)
Thermal burn	1/1013 (0.1%)		0/1020 (0%)
Thoracic vertebral fracture	2/1013 (0.2%)		1/1020 (0.1%)
Tibia fracture	1/1013 (0.1%)		2/1020 (0.2%)
Tracheal obstruction	1/1013 (0.1%)		1/1020 (0.1%)
Ulna fracture	1/1013 (0.1%)		0/1020 (0%)
Wound dehiscence	0/1013 (0%)		2/1020 (0.2%)
Investigations
Alanine aminotransferase increased	1/1013 (0.1%)		1/1020 (0.1%)
Aspartate aminotransferase increased	1/1013 (0.1%)		1/1020 (0.1%)
Aspiration bronchial	0/1013 (0%)		1/1020 (0.1%)
Blood alkaline phosphatase increased	1/1013 (0.1%)		0/1020 (0%)
Blood bilirubin increased	1/1013 (0.1%)		1/1020 (0.1%)
Blood culture positive	1/1013 (0.1%)		0/1020 (0%)
Blood glucose increased	1/1013 (0.1%)		0/1020 (0%)
Blood lactate dehydrogenase increased	1/1013 (0.1%)		0/1020 (0%)
Blood pressure increased	0/1013 (0%)		1/1020 (0.1%)
Blood urea increased	1/1013 (0.1%)		0/1020 (0%)
C-reactive protein increased	2/1013 (0.2%)		1/1020 (0.1%)
Electrocardiogram QT prolonged	0/1013 (0%)		1/1020 (0.1%)
Gamma-glutamyltransferase increased	1/1013 (0.1%)		0/1020 (0%)
Haemoglobin decreased	2/1013 (0.2%)		3/1020 (0.3%)
Hepatic enzyme increased	1/1013 (0.1%)		2/1020 (0.2%)
International normalised ratio increased	0/1013 (0%)		1/1020 (0.1%)
Liver function test abnormal	1/1013 (0.1%)		1/1020 (0.1%)
Platelet count decreased	0/1013 (0%)		2/1020 (0.2%)
Renal function test abnormal	0/1013 (0%)		1/1020 (0.1%)
Weight decreased	2/1013 (0.2%)		1/1020 (0.1%)
White blood cell count abnormal	0/1013 (0%)		1/1020 (0.1%)
Metabolism and nutrition disorders
Acidosis	0/1013 (0%)		1/1020 (0.1%)
Anorexia	7/1013 (0.7%)		10/1020 (1%)
Cachexia	7/1013 (0.7%)		6/1020 (0.6%)
Decreased appetite	1/1013 (0.1%)		0/1020 (0%)
Dehydration	24/1013 (2.4%)		13/1020 (1.3%)
Diabetes mellitus	0/1013 (0%)		1/1020 (0.1%)
Diabetes mellitus inadequate control	0/1013 (0%)		1/1020 (0.1%)
Diabetic foot	0/1013 (0%)		1/1020 (0.1%)
Electrolyte imbalance	1/1013 (0.1%)		1/1020 (0.1%)
Failure to thrive	1/1013 (0.1%)		0/1020 (0%)
Fluid overload	1/1013 (0.1%)		0/1020 (0%)
Hypercalcaemia	10/1013 (1%)		2/1020 (0.2%)
Hyperglycaemia	2/1013 (0.2%)		0/1020 (0%)
Hyperkalaemia	2/1013 (0.2%)		0/1020 (0%)
Hypocalcaemia	2/1013 (0.2%)		5/1020 (0.5%)
Hypoglycaemia	5/1013 (0.5%)		2/1020 (0.2%)
Hypokalaemia	6/1013 (0.6%)		0/1020 (0%)
Hyponatraemia	1/1013 (0.1%)		1/1020 (0.1%)
Hypophagia	0/1013 (0%)		1/1020 (0.1%)
Hypophosphataemia	0/1013 (0%)		1/1020 (0.1%)
Hypovolaemia	0/1013 (0%)		1/1020 (0.1%)
Ketoacidosis	1/1013 (0.1%)		0/1020 (0%)
Metabolic acidosis	1/1013 (0.1%)		1/1020 (0.1%)
Metabolic disorder	1/1013 (0.1%)		0/1020 (0%)
Type 2 diabetes mellitus	1/1013 (0.1%)		0/1020 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/1013 (0.7%)		4/1020 (0.4%)
Arthritis	2/1013 (0.2%)		0/1020 (0%)
Back pain	14/1013 (1.4%)		8/1020 (0.8%)
Bone pain	13/1013 (1.3%)		10/1020 (1%)
Fistula	0/1013 (0%)		1/1020 (0.1%)
Intervertebral disc protrusion	0/1013 (0%)		2/1020 (0.2%)
Jaw cyst	1/1013 (0.1%)		0/1020 (0%)
Lumbar spinal stenosis	1/1013 (0.1%)		0/1020 (0%)
Muscle spasms	0/1013 (0%)		1/1020 (0.1%)
Muscular weakness	4/1013 (0.4%)		2/1020 (0.2%)
Musculoskeletal chest pain	4/1013 (0.4%)		1/1020 (0.1%)
Musculoskeletal pain	1/1013 (0.1%)		3/1020 (0.3%)
Myalgia	1/1013 (0.1%)		1/1020 (0.1%)
Myopathy	0/1013 (0%)		1/1020 (0.1%)
Neck pain	1/1013 (0.1%)		3/1020 (0.3%)
Osteoarthritis	0/1013 (0%)		1/1020 (0.1%)
Osteolysis	1/1013 (0.1%)		0/1020 (0%)
Osteonecrosis	11/1013 (1.1%)		18/1020 (1.8%)
Pain in extremity	3/1013 (0.3%)		8/1020 (0.8%)
Pain in jaw	1/1013 (0.1%)		2/1020 (0.2%)
Pathological fracture	1/1013 (0.1%)		0/1020 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	0/1013 (0%)		1/1020 (0.1%)
Breast cancer	17/1013 (1.7%)		17/1020 (1.7%)
Breast cancer metastatic	11/1013 (1.1%)		7/1020 (0.7%)
Cancer pain	3/1013 (0.3%)		1/1020 (0.1%)
Chronic myeloid leukaemia	1/1013 (0.1%)		0/1020 (0%)
Colon cancer	1/1013 (0.1%)		1/1020 (0.1%)
Contralateral breast cancer	0/1013 (0%)		1/1020 (0.1%)
Endometrial cancer	1/1013 (0.1%)		0/1020 (0%)
Gastric cancer	0/1013 (0%)		1/1020 (0.1%)
Lipoma	1/1013 (0.1%)		0/1020 (0%)
Lymphangiosis carcinomatosa	1/1013 (0.1%)		1/1020 (0.1%)
Malignant ascites	1/1013 (0.1%)		3/1020 (0.3%)
Malignant neoplasm progression	7/1013 (0.7%)		6/1020 (0.6%)
Malignant pleural effusion	6/1013 (0.6%)		8/1020 (0.8%)
Meningioma	0/1013 (0%)		2/1020 (0.2%)
Metastases to abdominal cavity	0/1013 (0%)		1/1020 (0.1%)
Metastases to biliary tract	1/1013 (0.1%)		0/1020 (0%)
Metastases to bladder	1/1013 (0.1%)		0/1020 (0%)
Metastases to bone	2/1013 (0.2%)		2/1020 (0.2%)
Metastases to bone marrow	2/1013 (0.2%)		3/1020 (0.3%)
Metastases to central nervous system	46/1013 (4.5%)		47/1020 (4.6%)
Metastases to eye	0/1013 (0%)		1/1020 (0.1%)
Metastases to gastrointestinal tract	0/1013 (0%)		2/1020 (0.2%)
Metastases to liver	28/1013 (2.8%)		20/1020 (2%)
Metastases to lung	7/1013 (0.7%)		6/1020 (0.6%)
Metastases to lymph nodes	2/1013 (0.2%)		2/1020 (0.2%)
Metastases to meninges	6/1013 (0.6%)		5/1020 (0.5%)
Metastases to ovary	1/1013 (0.1%)		2/1020 (0.2%)
Metastases to peritoneum	1/1013 (0.1%)		2/1020 (0.2%)
Metastases to pleura	2/1013 (0.2%)		1/1020 (0.1%)
Metastases to skin	0/1013 (0%)		1/1020 (0.1%)
Metastases to spine	0/1013 (0%)		1/1020 (0.1%)
Metastases to uterus	0/1013 (0%)		1/1020 (0.1%)
Metastasis	3/1013 (0.3%)		9/1020 (0.9%)
Metastatic malignant melanoma	0/1013 (0%)		1/1020 (0.1%)
Myelofibrosis	0/1013 (0%)		1/1020 (0.1%)
Neoplasm progression	2/1013 (0.2%)		0/1020 (0%)
Paraneoplastic dermatomyositis	1/1013 (0.1%)		0/1020 (0%)
Pericarditis malignant	1/1013 (0.1%)		0/1020 (0%)
Rectal cancer	0/1013 (0%)		1/1020 (0.1%)
Tumour associated fever	1/1013 (0.1%)		0/1020 (0%)
Tumour haemorrhage	1/1013 (0.1%)		0/1020 (0%)
Tumour pain	0/1013 (0%)		1/1020 (0.1%)
Nervous system disorders
Aphasia	2/1013 (0.2%)		0/1020 (0%)
Aphonia	1/1013 (0.1%)		0/1020 (0%)
Ataxia	2/1013 (0.2%)		0/1020 (0%)
Balance disorder	1/1013 (0.1%)		0/1020 (0%)
Brain compression	0/1013 (0%)		1/1020 (0.1%)
Brain oedema	5/1013 (0.5%)		1/1020 (0.1%)
Cerebral haemorrhage	1/1013 (0.1%)		0/1020 (0%)
Cerebral infarction	0/1013 (0%)		1/1020 (0.1%)
Cerebral ischaemia	1/1013 (0.1%)		0/1020 (0%)
Cerebrovascular accident	2/1013 (0.2%)		2/1020 (0.2%)
Cerebrovascular disorder	1/1013 (0.1%)		0/1020 (0%)
Cervical cord compression	1/1013 (0.1%)		0/1020 (0%)
Cognitive disorder	2/1013 (0.2%)		1/1020 (0.1%)
Coma	0/1013 (0%)		1/1020 (0.1%)
Convulsion	10/1013 (1%)		8/1020 (0.8%)
Cranial nerve paralysis	1/1013 (0.1%)		0/1020 (0%)
Dementia	0/1013 (0%)		1/1020 (0.1%)
Depressed level of consciousness	1/1013 (0.1%)		2/1020 (0.2%)
Diplegia	1/1013 (0.1%)		0/1020 (0%)
Dizziness	4/1013 (0.4%)		7/1020 (0.7%)
Dysarthria	1/1013 (0.1%)		0/1020 (0%)
Encephalopathy	0/1013 (0%)		1/1020 (0.1%)
Epilepsy	0/1013 (0%)		1/1020 (0.1%)
Facial palsy	0/1013 (0%)		2/1020 (0.2%)
Facial paresis	1/1013 (0.1%)		0/1020 (0%)
Haemorrhage intracranial	1/1013 (0.1%)		0/1020 (0%)
Haemorrhagic stroke	1/1013 (0.1%)		0/1020 (0%)
Headache	9/1013 (0.9%)		13/1020 (1.3%)
Hemiparesis	2/1013 (0.2%)		1/1020 (0.1%)
Hemiplegia	1/1013 (0.1%)		0/1020 (0%)
Hepatic encephalopathy	6/1013 (0.6%)		1/1020 (0.1%)
Hydrocephalus	0/1013 (0%)		1/1020 (0.1%)
Hypoaesthesia	1/1013 (0.1%)		0/1020 (0%)
Intracranial pressure increased	2/1013 (0.2%)		2/1020 (0.2%)
Intraventricular haemorrhage	1/1013 (0.1%)		0/1020 (0%)
Ischaemic stroke	2/1013 (0.2%)		2/1020 (0.2%)
Lethargy	3/1013 (0.3%)		0/1020 (0%)
Leukoencephalopathy	1/1013 (0.1%)		0/1020 (0%)
Loss of consciousness	1/1013 (0.1%)		2/1020 (0.2%)
Meningism	0/1013 (0%)		1/1020 (0.1%)
Migraine	1/1013 (0.1%)		0/1020 (0%)
Monoparesis	4/1013 (0.4%)		0/1020 (0%)
Nervous system disorder	1/1013 (0.1%)		0/1020 (0%)
Neurological symptom	1/1013 (0.1%)		0/1020 (0%)
Paraesthesia	1/1013 (0.1%)		1/1020 (0.1%)
Partial seizures	1/1013 (0.1%)		1/1020 (0.1%)
Peripheral motor neuropathy	2/1013 (0.2%)		0/1020 (0%)
Phrenic nerve paralysis	0/1013 (0%)		1/1020 (0.1%)
Reversible posterior leukoencephalopathy syndrome	1/1013 (0.1%)		0/1020 (0%)
Sciatica	0/1013 (0%)		1/1020 (0.1%)
Sensory loss	0/1013 (0%)		1/1020 (0.1%)
Somnolence	3/1013 (0.3%)		0/1020 (0%)
Speech disorder	1/1013 (0.1%)		0/1020 (0%)
Spinal cord compression	8/1013 (0.8%)		6/1020 (0.6%)
Stupor	1/1013 (0.1%)		0/1020 (0%)
Syncope	3/1013 (0.3%)		6/1020 (0.6%)
Transient ischaemic attack	1/1013 (0.1%)		4/1020 (0.4%)
Tremor	1/1013 (0.1%)		0/1020 (0%)
Vascular encephalopathy	1/1013 (0.1%)		0/1020 (0%)
Psychiatric disorders
Abnormal behaviour	0/1013 (0%)		1/1020 (0.1%)
Adjustment disorder	0/1013 (0%)		1/1020 (0.1%)
Anxiety	1/1013 (0.1%)		1/1020 (0.1%)
Confusional state	6/1013 (0.6%)		3/1020 (0.3%)
Depression	1/1013 (0.1%)		1/1020 (0.1%)
Disorientation	1/1013 (0.1%)		0/1020 (0%)
Insomnia	1/1013 (0.1%)		1/1020 (0.1%)
Mental disorder	0/1013 (0%)		1/1020 (0.1%)
Mental status changes	2/1013 (0.2%)		2/1020 (0.2%)
Renal and urinary disorders
Anuria	1/1013 (0.1%)		0/1020 (0%)
Calculus urinary	0/1013 (0%)		1/1020 (0.1%)
Hydronephrosis	0/1013 (0%)		1/1020 (0.1%)
Nephrolithiasis	0/1013 (0%)		1/1020 (0.1%)
Renal colic	1/1013 (0.1%)		0/1020 (0%)
Renal failure	9/1013 (0.9%)		1/1020 (0.1%)
Renal failure acute	6/1013 (0.6%)		0/1020 (0%)
Renal pain	1/1013 (0.1%)		0/1020 (0%)
Urinary hesitation	0/1013 (0%)		1/1020 (0.1%)
Urinary retention	0/1013 (0%)		1/1020 (0.1%)
Reproductive system and breast disorders
Breast pain	0/1013 (0%)		1/1020 (0.1%)
Cystocele	0/1013 (0%)		1/1020 (0.1%)
Endometrial hyperplasia	1/1013 (0.1%)		0/1020 (0%)
Female genital tract fistula	0/1013 (0%)		1/1020 (0.1%)
Ovarian cyst	1/1013 (0.1%)		2/1020 (0.2%)
Ovarian mass	0/1013 (0%)		1/1020 (0.1%)
Pelvic pain	0/1013 (0%)		1/1020 (0.1%)
Rectocele	0/1013 (0%)		1/1020 (0.1%)
Urogenital prolapse	0/1013 (0%)		1/1020 (0.1%)
Vaginal prolapse	0/1013 (0%)		1/1020 (0.1%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/1013 (0.1%)		0/1020 (0%)
Acute respiratory distress syndrome	1/1013 (0.1%)		2/1020 (0.2%)
Acute respiratory failure	1/1013 (0.1%)		1/1020 (0.1%)
Aspiration	2/1013 (0.2%)		0/1020 (0%)
Asthma	1/1013 (0.1%)		0/1020 (0%)
Atelectasis	0/1013 (0%)		1/1020 (0.1%)
Bronchitis chronic	1/1013 (0.1%)		0/1020 (0%)
Bronchospasm	0/1013 (0%)		1/1020 (0.1%)
Chronic obstructive pulmonary disease	0/1013 (0%)		1/1020 (0.1%)
Cough	1/1013 (0.1%)		1/1020 (0.1%)
Dyspnoea	38/1013 (3.8%)		53/1020 (5.2%)
Emphysema	1/1013 (0.1%)		0/1020 (0%)
Epistaxis	0/1013 (0%)		1/1020 (0.1%)
Hydropneumothorax	0/1013 (0%)		1/1020 (0.1%)
Hydrothorax	4/1013 (0.4%)		2/1020 (0.2%)
Hypoxia	4/1013 (0.4%)		2/1020 (0.2%)
Interstitial lung disease	1/1013 (0.1%)		0/1020 (0%)
Lung disorder	2/1013 (0.2%)		0/1020 (0%)
Lung infiltration	1/1013 (0.1%)		1/1020 (0.1%)
Oropharyngeal pain	1/1013 (0.1%)		0/1020 (0%)
Orthopnoea	1/1013 (0.1%)		0/1020 (0%)
Pharyngeal inflammation	0/1013 (0%)		1/1020 (0.1%)
Pleural effusion	25/1013 (2.5%)		24/1020 (2.4%)
Pleurisy	1/1013 (0.1%)		1/1020 (0.1%)
Pleuritic pain	1/1013 (0.1%)		1/1020 (0.1%)
Pneumonitis	3/1013 (0.3%)		0/1020 (0%)
Pneumothorax	5/1013 (0.5%)		2/1020 (0.2%)
Pulmonary artery thrombosis	0/1013 (0%)		1/1020 (0.1%)
Pulmonary embolism	18/1013 (1.8%)		11/1020 (1.1%)
Pulmonary hilum mass	0/1013 (0%)		1/1020 (0.1%)
Pulmonary hypertension	1/1013 (0.1%)		0/1020 (0%)
Pulmonary oedema	2/1013 (0.2%)		1/1020 (0.1%)
Respiratory arrest	0/1013 (0%)		1/1020 (0.1%)
Respiratory depression	1/1013 (0.1%)		0/1020 (0%)
Respiratory distress	2/1013 (0.2%)		4/1020 (0.4%)
Respiratory failure	20/1013 (2%)		20/1020 (2%)
Tachypnoea	0/1013 (0%)		1/1020 (0.1%)
Skin and subcutaneous tissue disorders
Dermatomyositis	0/1013 (0%)		1/1020 (0.1%)
Drug eruption	0/1013 (0%)		1/1020 (0.1%)
Eczema	1/1013 (0.1%)		0/1020 (0%)
Exfoliative rash	1/1013 (0.1%)		0/1020 (0%)
Intertrigo	1/1013 (0.1%)		0/1020 (0%)
Pruritus	0/1013 (0%)		2/1020 (0.2%)
Rash	1/1013 (0.1%)		1/1020 (0.1%)
Rash erythematous	0/1013 (0%)		2/1020 (0.2%)
Skin lesion	0/1013 (0%)		1/1020 (0.1%)
Skin ulcer	1/1013 (0.1%)		1/1020 (0.1%)
Surgical and medical procedures
Abdominal cavity drainage	1/1013 (0.1%)		0/1020 (0%)
Arterial bypass operation	0/1013 (0%)		1/1020 (0.1%)
Breast reconstruction	0/1013 (0%)		1/1020 (0.1%)
Colostomy closure	1/1013 (0.1%)		0/1020 (0%)
Mastectomy	1/1013 (0.1%)		4/1020 (0.4%)
Oophorectomy	0/1013 (0%)		1/1020 (0.1%)
Pleurodesis	0/1013 (0%)		1/1020 (0.1%)
Radical hysterectomy	0/1013 (0%)		1/1020 (0.1%)
Salpingo-oophorectomy bilateral	0/1013 (0%)		1/1020 (0.1%)
Simple mastectomy	1/1013 (0.1%)		0/1020 (0%)
Skin neoplasm excision	1/1013 (0.1%)		0/1020 (0%)
Vascular disorders
Cardiovascular insufficiency	1/1013 (0.1%)		0/1020 (0%)
Circulatory collapse	1/1013 (0.1%)		1/1020 (0.1%)
Deep vein thrombosis	8/1013 (0.8%)		4/1020 (0.4%)
Embolism	2/1013 (0.2%)		0/1020 (0%)
Endocrine hypertension	1/1013 (0.1%)		0/1020 (0%)
Flushing	1/1013 (0.1%)		0/1020 (0%)
Haemodynamic instability	1/1013 (0.1%)		0/1020 (0%)
Hypertension	3/1013 (0.3%)		3/1020 (0.3%)
Hypertensive crisis	1/1013 (0.1%)		0/1020 (0%)
Hypotension	8/1013 (0.8%)		5/1020 (0.5%)
Hypovolaemic shock	1/1013 (0.1%)		0/1020 (0%)
Iliac artery occlusion	0/1013 (0%)		1/1020 (0.1%)
Jugular vein thrombosis	1/1013 (0.1%)		0/1020 (0%)
Lymphangiopathy	1/1013 (0.1%)		0/1020 (0%)
Peripheral arterial occlusive disease	0/1013 (0%)		1/1020 (0.1%)
Peripheral ischaemia	0/1013 (0%)		1/1020 (0.1%)
Phlebitis	1/1013 (0.1%)		0/1020 (0%)
Subclavian vein thrombosis	0/1013 (0%)		1/1020 (0.1%)
Thrombophlebitis	2/1013 (0.2%)		2/1020 (0.2%)
Thrombosis	1/1013 (0.1%)		1/1020 (0.1%)
Venous thrombosis	0/1013 (0%)		1/1020 (0.1%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid 4 mg Q4W		Denosumab 120 mg Q4W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	941/1013 (92.9%)		924/1020 (90.6%)
Blood and lymphatic system disorders
Anaemia	217/1013 (21.4%)		183/1020 (17.9%)
Leukopenia	72/1013 (7.1%)		78/1020 (7.6%)
Neutropenia	118/1013 (11.6%)		114/1020 (11.2%)
Thrombocytopenia	53/1013 (5.2%)		62/1020 (6.1%)
Gastrointestinal disorders
Abdominal pain	113/1013 (11.2%)		114/1020 (11.2%)
Abdominal pain upper	80/1013 (7.9%)		68/1020 (6.7%)
Constipation	203/1013 (20%)		175/1020 (17.2%)
Diarrhoea	198/1013 (19.5%)		223/1020 (21.9%)
Dyspepsia	73/1013 (7.2%)		52/1020 (5.1%)
Nausea	377/1013 (37.2%)		350/1020 (34.3%)
Stomatitis	70/1013 (6.9%)		90/1020 (8.8%)
Toothache	37/1013 (3.7%)		57/1020 (5.6%)
Vomiting	225/1013 (22.2%)		199/1020 (19.5%)
General disorders
Asthenia	192/1013 (19%)		187/1020 (18.3%)
Chest pain	79/1013 (7.8%)		90/1020 (8.8%)
Chills	56/1013 (5.5%)		26/1020 (2.5%)
Fatigue	323/1013 (31.9%)		291/1020 (28.5%)
Mucosal inflammation	60/1013 (5.9%)		68/1020 (6.7%)
Oedema peripheral	146/1013 (14.4%)		172/1020 (16.9%)
Pain	91/1013 (9%)		68/1020 (6.7%)
Pyrexia	231/1013 (22.8%)		157/1020 (15.4%)
Infections and infestations
Influenza	54/1013 (5.3%)		57/1020 (5.6%)
Nasopharyngitis	94/1013 (9.3%)		83/1020 (8.1%)
Upper respiratory tract infection	58/1013 (5.7%)		55/1020 (5.4%)
Urinary tract infection	86/1013 (8.5%)		68/1020 (6.7%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture	54/1013 (5.3%)		35/1020 (3.4%)
Rib fracture	93/1013 (9.2%)		82/1020 (8%)
Thoracic vertebral fracture	76/1013 (7.5%)		63/1020 (6.2%)
Investigations
Aspartate aminotransferase increased	53/1013 (5.2%)		35/1020 (3.4%)
Weight decreased	92/1013 (9.1%)		78/1020 (7.6%)
Metabolism and nutrition disorders
Anorexia	171/1013 (16.9%)		176/1020 (17.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	289/1013 (28.5%)		246/1020 (24.1%)
Back pain	256/1013 (25.3%)		238/1020 (23.3%)
Bone pain	233/1013 (23%)		181/1020 (17.7%)
Musculoskeletal chest pain	77/1013 (7.6%)		81/1020 (7.9%)
Musculoskeletal pain	147/1013 (14.5%)		147/1020 (14.4%)
Myalgia	106/1013 (10.5%)		82/1020 (8%)
Neck pain	71/1013 (7%)		64/1020 (6.3%)
Pain in extremity	221/1013 (21.8%)		199/1020 (19.5%)
Nervous system disorders
Dizziness	110/1013 (10.9%)		102/1020 (10%)
Headache	210/1013 (20.7%)		193/1020 (18.9%)
Neuropathy peripheral	71/1013 (7%)		71/1020 (7%)
Paraesthesia	72/1013 (7.1%)		68/1020 (6.7%)
Peripheral sensory neuropathy	51/1013 (5%)		50/1020 (4.9%)
Psychiatric disorders
Anxiety	73/1013 (7.2%)		74/1020 (7.3%)
Depression	85/1013 (8.4%)		71/1020 (7%)
Insomnia	136/1013 (13.4%)		123/1020 (12.1%)
Respiratory, thoracic and mediastinal disorders
Cough	179/1013 (17.7%)		171/1020 (16.8%)
Dyspnoea	173/1013 (17.1%)		197/1020 (19.3%)
Skin and subcutaneous tissue disorders
Alopecia	142/1013 (14%)		159/1020 (15.6%)
Palmar-plantar erythrodysaesthesia syndrome	91/1013 (9%)		91/1020 (8.9%)
Pruritus	66/1013 (6.5%)		57/1020 (5.6%)
Rash	99/1013 (9.8%)		96/1020 (9.4%)
Vascular disorders
Hot flush	70/1013 (6.9%)		66/1020 (6.5%)
Hypertension	64/1013 (6.3%)		64/1020 (6.3%)

Limitations/Caveats

[Not Specified]

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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 aftercompletion. 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.