Safety and Efficacy Study to Evaluate Denosumab Compared With Zoledronic Acid in Postmenopausal Women With Osteoporosis

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01732770
• Collaborator: (none)
• Enrollment: 643
• Locations: 45
• Arms: 2
• Actual Duration (Months): 26
• Patients Per Site: 14.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study will compare the effectiveness of denosumab treatment every 6 months with once yearly zoledronic acid treatment on bone mineral density (BMD) at various skeletal sites.

Condition or Disease	Intervention/Treatment	Phase
Post Menopausal Osteoporosis	Biological: Denosumab; Drug: Zoledronic Acid; Drug: Placebo to Denosumab; Drug: Placebo to Zoledronic Acid	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 643 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-blind Study to Evaluate the Safety and Efficacy of Denosumab Compared With Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates
• Actual Study Start Date: Nov 7, 2012
• Actual Primary Completion Date: Jan 7, 2015
• Actual Study Completion Date: Jan 7, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Denosumab 60 mg Participants received denosumab 60 mg subcutaneous injection once every 6 months for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.	Biological: Denosumab; Denosumab 60 mg administered by subcutaneous injection once every 6 months.; Other Names: Prolia® AMG 162 ; Drug: Placebo to Zoledronic Acid; Administered by intravenous infusion once a year
Active Comparator: Zoledronic Acid 5 mg Participants received zoledronic acid 5 mg by intravenous infusion on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.	Drug: Zoledronic Acid; Zoledronic acid 5 mg administered by intravenous infusion once a year; Other Names: Reclast Aclasta ; Drug: Placebo to Denosumab; Administered by subcutaneous injection once every 6 months

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 - Non-inferiority Analysis [Baseline and Month 12]

   Bone mineral density (BMD) of the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging facility.

Secondary Outcome Measures

1. Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis [Baseline and Month 12]

   BMD of the hip was measured by DXA. DXA scans were analyzed by a central imaging facility.

2. Percent Change From Baseline in Lumbar Spine BMD at Month 12 - Superiority Analysis [Baseline and Month 12]

3. Percent Change From Baseline in Total Hip BMD at Month 12 - Superiority Analysis [Baseline and Month 12]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ambulatory postmenopausal women.

• Age 55 years or older

• Subject has provided informed consent prior to any study specific procedures

• Received oral bisphosphonate therapy for osteoporosis at least 2 years prior to screening visit

• Screening BMD (g/cm²) values at the lumbar spine, total hip or femoral neck values of equal to or less than those listed in the protocol.

• At least 2 lumbar vertebrae and one hip must be evaluable by dual energy x-ray absorptiometry (DXA) at the screening visit

Exclusion Criteria:

• Received other osteoporosis treatment or bone active treatment

• Evidence of history of any of the following:

• hyperthyroidism (stable on antithyroid therapy is allowed)

• hypothyroidism (stable on thyroid replacement therapy is allowed)

• hypo- or hyperparathyroidism

• hypo- or hypercalcemia based on the central laboratory reference ranges

• Recent tooth extraction (within 6 months of screening visit)

• Paget disease of bone (subject report or chart review)

• other bone diseases which affect bone metabolism (eg, osteopetrosis, osteogenesis imperfecta) (chart review)

• Abnormalities of the following per central laboratory reference ranges:

• vitamin D deficiency (25[OH] vitamin D level < 20 ng/mL), repletion will be allowed and subjects may be re-screened

• hypercalcemia

• elevated transaminases ≥ 2.0 x upper limits of normal (ULN)

• History of any solid organ or bone marrow transplant

• Malignancy (except nonmelanoma skin cancers, cervical or breast ductal carcinoma in situ) within the last 5 years

• Known intolerance to calcium or vitamin D supplements

• Self-reported alcohol or drug abuse within 12 months prior to screening

• Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s)

• History or evidence of any other clinically significant disorder, condition or disease that in the opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Santa Monica	California	United States	90404
2	Research Site	Lakewood	Colorado	United States	80227
3	Research Site	Longmont	Colorado	United States	80501
4	Research Site	Washington	District of Columbia	United States	20007
5	Research Site	Bethesda	Maryland	United States	20817
6	Research Site	Hagerstown	Maryland	United States	21740
7	Research Site	Detroit	Michigan	United States	48236
8	Research Site	West Haverstraw	New York	United States	10993
9	Research Site	Houston	Texas	United States	77074
10	Research Site	Maroubra	New South Wales	Australia	2035
11	Research Site	Penrith	New South Wales	Australia	2750
12	Research Site	St Leonards	New South Wales	Australia	2065
13	Research Site	Box Hill	Victoria	Australia	3128
14	Research Site	Geelong	Victoria	Australia	3220
15	Research Site	Parkville	Victoria	Australia	3050
16	Research Site	Brussels		Belgium	1050
17	Research Site	Brussel		Belgium	1090
18	Research Site	Bruxelles		Belgium	1000
19	Research Site	Bruxelles		Belgium	1020
20	Research Site	Genk		Belgium	3600
21	Research Site	Leuven		Belgium	3000
22	Research Site	Liège		Belgium	4020
23	Research Site	Merksem		Belgium	2170
24	Research Site	Tessenderlo		Belgium	3980
25	Research Site	Wilrijk		Belgium	2610
26	Research Site	Yvoir		Belgium	5530
27	Research Site	Calgary	Alberta	Canada	T2N 4Z6
28	Research Site	Vancouver	British Columbia	Canada	V5Z 4E1
29	Research Site	Halifax	Nova Scotia	Canada	B3H 2Y9
30	Research Site	Toronto	Ontario	Canada	M5C 2T2
31	Research Site	Toronto	Ontario	Canada	M5G 2C4
32	Research Site	Toronto	Ontario	Canada	M9W 4L6
33	Research Site	Quebec		Canada	G1V 3M7
34	Research Site	Aalborg		Denmark	9000
35	Research Site	Ballerup		Denmark	2750
36	Research Site	Vejle		Denmark	7100
37	Research Site	Bialystok		Poland	15-879
38	Research Site	Kraków		Poland	31-501
39	Research Site	Torun		Poland	87-100
40	Research Site	Warszawa		Poland	01-192
41	Research Site	Granada	Andalucía	Spain	18012
42	Research Site	Barcelona	Cataluña	Spain	08036
43	Research Site	Barcelona	Cataluña	Spain	08041
44	Research Site	Madrid		Spain	28009
45	Research Site	Madrid		Spain	28040

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Chotiyarnwong P, McCloskey E, Eastell R, McClung MR, Gielen E, Gostage J, McDermott M, Chines A, Huang S, Cummings SR. A Pooled Analysis of Fall Incidence From Placebo-Controlled Trials of Denosumab. J Bone Miner Res. 2020 Jun;35(6):1014-1021. doi: 10.1002/jbmr.3972. Epub 2020 Apr 2.
• Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, Malouf J, Bone HG, Reginster JY, Singer A, Wang C, Wagman RB, Cummings SR. Denosumab or Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates. J Clin Endocrinol Metab. 2016 Aug;101(8):3163-70. doi: 10.1210/jc.2016-1801. Epub 2016 Jun 6.
• Miller PD, Pannacciulli N, Malouf-Sierra J, Singer A, Czerwiński E, Bone HG, Wang C, Huang S, Chines A, Lems W, Brown JP. Efficacy and safety of denosumab vs. bisphosphonates in postmenopausal women previously treated with oral bisphosphonates. Osteoporos Int. 2020 Jan;31(1):181-191. doi: 10.1007/s00198-019-05233-x. Epub 2019 Nov 28.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01732770
• Other Study ID Numbers: 20110153; 2012-001821-28
• First Posted: Nov 26, 2012
• Last Update Posted: Mar 10, 2020
• Last Verified: Mar 1, 2020

• Additional relevant MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal; Zoledronic Acid; Denosumab

Study Results

Participant Flow

Recruitment Details	This study was conducted at 37 centers in Belgium, Denmark, Poland, Spain, Canada, United States of America, and Australia. The first participant enrolled on 07 November 2012 and the last participant enrolled on 15 January 2014.
Pre-assignment Detail	Participants were randomized in a 1:1 allocation ratio to receive either denosumab or zoledronic acid. Randomization was stratified by screening serum type I collagen C-telopeptide (sCTX) values (< 0.3 ng/mL, 0.3 to 0.5 ng/mL).

Arm/Group Title	Zoledronic Acid 5 mg Q12M	Denosumab 60 mg Q6M
Arm/Group Description	Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.	Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Period Title: Overall Study
STARTED	322	321
Received Study Treatment	320	320
COMPLETED	312	313
NOT COMPLETED	10	8

Baseline Characteristics

Arm/Group Title	Zoledronic Acid 5 mg Q12M	Denosumab 60 mg Q6M	Total
Arm/Group Description	Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.	Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.	Total of all reporting groups
Overall Participants	322	321	643
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.5 (7.7)	68.5 (7.1)	69.0 (7.4)
Sex: Female, Male (Count of Participants)
Female	322 100%	321 100%	643 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	314 97.5%	309 96.3%	623 96.9%
Asian	4 1.2%	5 1.6%	9 1.4%
Other	2 0.6%	4 1.2%	6 0.9%
Native Hawaiian or Other Pacific Islander	1 0.3%	2 0.6%	3 0.5%
Black or African American	0 0%	1 0.3%	1 0.2%
Multiple	1 0.3%	0 0%	1 0.2%
Screening serum CTX (participants) [Number]
< 0.3 ng/mL	242 75.2%	239 74.5%	481 74.8%
≥ 0.3 ng/mL	78 24.2%	82 25.5%	160 24.9%
Missing	2 0.6%	0 0%	2 0.3%
Lumbar Spine Bone Mineral Density (BMD) T-score (T-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T-score]	-2.64 (0.86)	-2.74 (0.83)	-2.69 (0.84)
Total Hip BMD T-score (T-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T-score]	-1.93 (0.80)	-1.93 (0.74)	-1.93 (0.77)
Femoral Neck BMD T-score (T-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T-score]	-2.17 (0.68)	-2.17 (0.66)	-2.17 (0.67)
Prior Oral Bisphosphonate Duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6.35 (3.68)	6.21 (3.84)	6.28 (3.76)
Historical Fractures (participants) [Number]
Any prior fracture	159 49.4%	169 52.6%	328 51%
Prior osteoporotic fracture	121 37.6%	120 37.4%	241 37.5%
Body Mass Index (BMI) (kg/m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m²]	24.31 (4.18)	24.27 (3.99)	24.29 (4.08)

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 - Non-inferiority Analysis
Description	Bone mineral density (BMD) of the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging facility.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

The primary efficacy analysis set includes all randomized participants who have a baseline BMD measurement and at least one postbaseline BMD measurement. Any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, last observation carried forward [LOCF]).

Arm/Group Title	Zoledronic Acid 5 mg Q12M	Denosumab 60 mg Q6M
Arm/Group Description	Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.	Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Measure Participants	312	314
Least Squares Mean (95% Confidence Interval) [percent change]	1.1	3.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid 5 mg Q12M, Denosumab 60 mg Q6M
	Comments	A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the non-inferiority analysis the 1-sided significance level was 2.5%.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	The lower bound of the 2-sided 95% confidence interval (CI) of (denosumab - zoledronic acid) was compared with the non-inferiority margin of -0.46% for assessing non-inferiority.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; 1.6 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference = denosumab - zoledronic acid

2. Secondary Outcome

Title	Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis
Description	BMD of the hip was measured by DXA. DXA scans were analyzed by a central imaging facility.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).

Arm/Group Title	Zoledronic Acid 5 mg Q12M	Denosumab 60 mg Q6M
Arm/Group Description	Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.	Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Measure Participants	309	311
Least Squares Mean (95% Confidence Interval) [percent change]	0.6	1.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid 5 mg Q12M, Denosumab 60 mg Q6M
	Comments	A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the non-inferiority analysis the 1-sided significance level was 2.5%.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	The lower bound of the 2-sided 95% CI) of (denosumab - zoledronic acid) was compared with the non-inferiority margin of -0.51% for assessing non-inferiority.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 1.0 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference = denosumab - zoledronic acid

3. Secondary Outcome

Title	Percent Change From Baseline in Lumbar Spine BMD at Month 12 - Superiority Analysis
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).

Arm/Group Title	Zoledronic Acid 5 mg Q12M	Denosumab 60 mg Q6M
Arm/Group Description	Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.	Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Measure Participants	312	314
Least Squares Mean (95% Confidence Interval) [percent change]	1.1	3.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid 5 mg Q12M, Denosumab 60 mg Q6M
	Comments	A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the superiority analysis the 2-sided significance level was 5%.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; 1.6 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference = denosumab - zoledronic acid

4. Secondary Outcome

Title	Percent Change From Baseline in Total Hip BMD at Month 12 - Superiority Analysis
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).

Arm/Group Title	Zoledronic Acid 5 mg Q12M	Denosumab 60 mg Q6M
Arm/Group Description	Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.	Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Measure Participants	309	311
Least Squares Mean (95% Confidence Interval) [percent change]	0.6	1.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid 5 mg Q12M, Denosumab 60 mg Q6M
	Comments	A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the superiority analysis the 2-sided significance level was 5%.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 1.0 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference = denosumab - zoledronic acid

Adverse Events

Time Frame	12 months
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Zoledronic Acid 5 mg Q12M		Denosumab 60 mg Q6M
Arm/Group Description	Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.		Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
All Cause Mortality
	Zoledronic Acid 5 mg Q12M		Denosumab 60 mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zoledronic Acid 5 mg Q12M		Denosumab 60 mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/320 (9.1%)		25/320 (7.8%)
Blood and lymphatic system disorders
Febrile neutropenia	0/320 (0%)		1/320 (0.3%)
Cardiac disorders
Acute myocardial infarction	1/320 (0.3%)		0/320 (0%)
Atrial fibrillation	0/320 (0%)		1/320 (0.3%)
Atrial flutter	0/320 (0%)		1/320 (0.3%)
Coronary artery disease	0/320 (0%)		1/320 (0.3%)
Myocardial infarction	0/320 (0%)		1/320 (0.3%)
Endocrine disorders
Goitre	0/320 (0%)		1/320 (0.3%)
Gastrointestinal disorders
Diverticulum	0/320 (0%)		1/320 (0.3%)
Dysphagia	0/320 (0%)		1/320 (0.3%)
Gastrointestinal obstruction	1/320 (0.3%)		0/320 (0%)
Inguinal hernia	1/320 (0.3%)		0/320 (0%)
General disorders
Drug interaction	1/320 (0.3%)		0/320 (0%)
Hepatobiliary disorders
Autoimmune hepatitis	1/320 (0.3%)		0/320 (0%)
Hepatic failure	1/320 (0.3%)		0/320 (0%)
Infections and infestations
Bronchitis	0/320 (0%)		1/320 (0.3%)
Cellulitis	0/320 (0%)		1/320 (0.3%)
Clostridium difficile infection	1/320 (0.3%)		0/320 (0%)
Diverticulitis	1/320 (0.3%)		0/320 (0%)
Herpes zoster	0/320 (0%)		1/320 (0.3%)
Laryngitis	1/320 (0.3%)		0/320 (0%)
Pneumonia	0/320 (0%)		1/320 (0.3%)
Sepsis	1/320 (0.3%)		0/320 (0%)
Urinary tract infection	2/320 (0.6%)		1/320 (0.3%)
Vulval abscess	0/320 (0%)		1/320 (0.3%)
Injury, poisoning and procedural complications
Concussion	1/320 (0.3%)		0/320 (0%)
Femoral neck fracture	1/320 (0.3%)		0/320 (0%)
Femur fracture	2/320 (0.6%)		2/320 (0.6%)
Radius fracture	0/320 (0%)		1/320 (0.3%)
Subdural haematoma	0/320 (0%)		1/320 (0.3%)
Tendon rupture	1/320 (0.3%)		0/320 (0%)
Metabolism and nutrition disorders
Hyponatraemia	0/320 (0%)		1/320 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/320 (0%)		1/320 (0.3%)
Intervertebral disc disorder	1/320 (0.3%)		0/320 (0%)
Osteoarthritis	1/320 (0.3%)		0/320 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/320 (0.3%)		0/320 (0%)
Breast cancer female	0/320 (0%)		1/320 (0.3%)
Colon cancer	0/320 (0%)		1/320 (0.3%)
Lung adenocarcinoma stage I	0/320 (0%)		1/320 (0.3%)
Lung neoplasm malignant	1/320 (0.3%)		0/320 (0%)
Malignant melanoma	1/320 (0.3%)		0/320 (0%)
Non-small cell lung cancer	1/320 (0.3%)		0/320 (0%)
Pituitary tumour benign	1/320 (0.3%)		0/320 (0%)
Pleomorphic adenoma	0/320 (0%)		1/320 (0.3%)
Uterine leiomyoma	1/320 (0.3%)		0/320 (0%)
Nervous system disorders
Cerebral thrombosis	1/320 (0.3%)		0/320 (0%)
Cerebrovascular accident	1/320 (0.3%)		2/320 (0.6%)
Ischaemic stroke	1/320 (0.3%)		0/320 (0%)
Transient ischaemic attack	1/320 (0.3%)		0/320 (0%)
Reproductive system and breast disorders
Cystocele	1/320 (0.3%)		0/320 (0%)
Rectocele	1/320 (0.3%)		0/320 (0%)
Uterine prolapse	1/320 (0.3%)		0/320 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/320 (0.3%)		0/320 (0%)
Dyspnoea	1/320 (0.3%)		0/320 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	1/320 (0.3%)		0/320 (0%)
Surgical and medical procedures
Knee operation	1/320 (0.3%)		0/320 (0%)
Tendon operation	0/320 (0%)		1/320 (0.3%)
Varicose vein operation	0/320 (0%)		1/320 (0.3%)
Vascular disorders
Hypertension	1/320 (0.3%)		0/320 (0%)
Peripheral artery thrombosis	1/320 (0.3%)		0/320 (0%)
Varicose vein	0/320 (0%)		1/320 (0.3%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid 5 mg Q12M		Denosumab 60 mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/320 (6.9%)		15/320 (4.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	22/320 (6.9%)		15/320 (4.7%)

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.