Trial Outcomes & Findings for Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Men With Hormone-refractory Prostate Cancer (NCT NCT00321620)

Last Updated: 2018-08-29

Results Overview

Time to the first on-study skeletal-related event (SRE) analyzed for non-inferiority. Kaplan-Meier estimates of the median and its dispersion are reported.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1904 participants

Primary outcome timeframe

Up to 40.5 months

Results posted on

2018-08-29

Participant Flow

Participants were enrolled from 12 May 2006 through 18 December 2008.

1904 participants were enrolled, however 3 were excluded from all analyses as Institutional Review Board review activities and oversight were not ensured.

Participant milestones

Participant milestones
Measure	Zoledronic Acid Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Overall Study STARTED	951	950
Overall Study Received Investigational Product	946	942
Overall Study COMPLETED	208	228
Overall Study NOT COMPLETED	743	722

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Overall Study Death	269	294
Overall Study Withdrawal by Subject	164	147
Overall Study Disease progression	113	117
Overall Study Adverse Event	43	56
Overall Study Lost to Follow-up	13	9
Overall Study Physician Decision	4	1
Overall Study Noncompliance	14	7
Overall Study Protocol deviation	4	3
Overall Study Ineligibility determined	2	3
Overall Study Participant request	75	52
Overall Study Other	42	33

Baseline Characteristics

Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Men With Hormone-refractory Prostate Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid n=951 Participants Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab n=950 Participants Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks	Total n=1901 Participants Total of all reporting groups
Age, Continuous	71.0 Years STANDARD_DEVIATION 8.4 • n=5 Participants	70.5 Years STANDARD_DEVIATION 8.7 • n=7 Participants	70.8 Years STANDARD_DEVIATION 8.6 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	951 Participants n=5 Participants	950 Participants n=7 Participants	1901 Participants n=5 Participants
Race/Ethnicity, Customized White or Caucasian	810 Participants n=5 Participants	829 Participants n=7 Participants	1639 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	35 Participants n=5 Participants	38 Participants n=7 Participants	73 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	57 Participants n=5 Participants	45 Participants n=7 Participants	102 Participants n=5 Participants
Race/Ethnicity, Customized Asian	26 Participants n=5 Participants	22 Participants n=7 Participants	48 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Other	22 Participants n=5 Participants	15 Participants n=7 Participants	37 Participants n=5 Participants
Prostate-Specific Antigen (PSA) Stratification Factor PSA level < 10 ng/mL	145 Participants n=5 Participants	145 Participants n=7 Participants	290 Participants n=5 Participants
Prostate-Specific Antigen (PSA) Stratification Factor PSA level ≥ 10 ng/mL	806 Participants n=5 Participants	805 Participants n=7 Participants	1611 Participants n=5 Participants
Previous Skeletal-Related Event (SRE) Stratification Factor Yes	231 Participants n=5 Participants	232 Participants n=7 Participants	463 Participants n=5 Participants
Previous Skeletal-Related Event (SRE) Stratification Factor No	720 Participants n=5 Participants	718 Participants n=7 Participants	1438 Participants n=5 Participants
Current Prostate Cancer Chemotherapy Stratification Factor Yes	132 Participants n=5 Participants	132 Participants n=7 Participants	264 Participants n=5 Participants
Current Prostate Cancer Chemotherapy Stratification Factor No	819 Participants n=5 Participants	818 Participants n=7 Participants	1637 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 40.5 months

Population: Full Analysis Set, composed of all randomized participants

Time to the first on-study skeletal-related event (SRE) analyzed for non-inferiority. Kaplan-Meier estimates of the median and its dispersion are reported.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=951 Participants Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab n=950 Participants Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Time to the First On-Study SRE (Non-inferiority)	521.0 Days Interval 456.0 to 592.0	629.0 Days Interval 573.0 to 757.0

SECONDARY outcome

Timeframe: Up to 40.5 months

Population: Full Analysis Set, composed of all randomized participants

Time to the first on-study skeletal-related event (SRE), analyzed for superiority of denosumab. Kaplan-Meier estimates of the median and its dispersion are reported.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=951 Participants Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab n=950 Participants Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Time to the First On-Study SRE (Superiority)	521.0 Days Interval 456.0 to 592.0	629.0 Days Interval 573.0 to 757.0

SECONDARY outcome

Timeframe: Up to 40.5 months

Population: Full Analysis Set, composed of all randomized participants

Time to the first-and-subsequent on-study skeletal-related event (SRE), analyzed for superiority of denosumab using multiple event analysis, 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 mean number of events.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=951 Participants Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab n=950 Participants Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks
Time to the First-And-Subsequent On-Study SRE	584 Events	494 Events

Adverse Events

Zoledronic Acid 4 mg Q4W

Serious events: 568 serious events

Other events: 853 other events

Deaths: 0 deaths

Denosumab 120 mg Q4W

Serious events: 594 serious events

Other events: 844 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Zoledronic Acid 4 mg Q4W n=945 participants at risk	Denosumab 120 mg Q4W n=943 participants at risk
Blood and lymphatic system disorders Anaemia	8.7% 82/945 • up to 3 years 5 months 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.	11.5% 108/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Anaemia of malignant disease	0.11% 1/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Coagulopathy	0.11% 1/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.21% 2/945 • up to 3 years 5 months 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.	0.32% 3/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.11% 1/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Febrile neutropenia	0.85% 8/945 • up to 3 years 5 months 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.	0.85% 8/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Haemorrhagic anaemia	0.00% 0/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Heparin-induced thrombocytopenia	0.00% 0/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Hypercoagulation	0.00% 0/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Leukopenia	0.11% 1/945 • up to 3 years 5 months 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.	0.32% 3/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/945 • up to 3 years 5 months 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.	0.32% 3/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Neutropenia	0.42% 4/945 • up to 3 years 5 months 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.	1.1% 10/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Normochromic normocytic anaemia	0.00% 0/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Pancytopenia	0.32% 3/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Splenic infarction	0.11% 1/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.
Blood and lymphatic system disorders Thrombocytopenia	0.53% 5/945 • up to 3 years 5 months 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.	1.1% 10/943 • up to 3 years 5 months 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.
Cardiac disorders Acute coronary syndrome	0.21% 2/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Cardiac disorders Acute myocardial infarction	0.74% 7/945 • up to 3 years 5 months 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.	0.53% 5/943 • up to 3 years 5 months 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.
Cardiac disorders Angina pectoris	0.53% 5/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Cardiac disorders Angina unstable	0.11% 1/945 • up to 3 years 5 months 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.	0.21% 2/943 • up to 3 years 5 months 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.
Cardiac disorders Arrhythmia	0.21% 2/945 • up to 3 years 5 months 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.	0.64% 6/943 • up to 3 years 5 months 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.
Cardiac disorders Arteriosclerosis coronary artery	0.11% 1/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.
Cardiac disorders Atrial fibrillation	0.85% 8/945 • up to 3 years 5 months 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.	1.1% 10/943 • up to 3 years 5 months 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.
Cardiac disorders Atrial flutter	0.32% 3/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.
Cardiac disorders Atrial tachycardia	0.00% 0/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Cardiac disorders Atrioventricular block complete	0.00% 0/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Cardiac disorders Bundle branch block right	0.00% 0/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiac arrest	0.42% 4/945 • up to 3 years 5 months 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.	0.53% 5/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiac asthma	0.00% 0/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiac failure	2.4% 23/945 • up to 3 years 5 months 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.	2.2% 21/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiac failure acute	0.11% 1/945 • up to 3 years 5 months 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.	0.21% 2/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiac failure congestive	0.74% 7/945 • up to 3 years 5 months 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.	0.85% 8/943 • up to 3 years 5 months 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.
Cardiac disorders Cardio-respiratory arrest	1.3% 12/945 • up to 3 years 5 months 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.	0.74% 7/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiogenic shock	0.00% 0/945 • up to 3 years 5 months 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.	0.21% 2/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiomegaly	0.11% 1/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiopulmonary failure	0.63% 6/945 • up to 3 years 5 months 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.	0.21% 2/943 • up to 3 years 5 months 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.
Cardiac disorders Cardiovascular insufficiency	0.32% 3/945 • up to 3 years 5 months 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.	0.11% 1/943 • up to 3 years 5 months 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.
Cardiac disorders Coronary artery disease	0.00% 0/945 • up to 3 years 5 months 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.	0.21% 2/943 • up to 3 years 5 months 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.
Cardiac disorders Coronary artery stenosis	0.11% 1/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.
Cardiac disorders Ischaemic cardiomyopathy	0.11% 1/945 • up to 3 years 5 months 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.	0.00% 0/943 • up to 3 years 5 months 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.

Other adverse events
Measure	Zoledronic Acid 4 mg Q4W n=945 participants at risk	Denosumab 120 mg Q4W n=943 participants at risk
Blood and lymphatic system disorders Anaemia	33.1% 313/945 • up to 3 years 5 months 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.	31.8% 300/943 • up to 3 years 5 months 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.
Gastrointestinal disorders Abdominal pain	6.0% 57/945 • up to 3 years 5 months 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.	7.1% 67/943 • up to 3 years 5 months 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.
Gastrointestinal disorders Constipation	26.1% 247/945 • up to 3 years 5 months 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.	24.7% 233/943 • up to 3 years 5 months 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.
Gastrointestinal disorders Diarrhoea	15.1% 143/945 • up to 3 years 5 months 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.	18.5% 174/943 • up to 3 years 5 months 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.
Gastrointestinal disorders Nausea	25.6% 242/945 • up to 3 years 5 months 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.	28.7% 271/943 • up to 3 years 5 months 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.
Gastrointestinal disorders Vomiting	14.6% 138/945 • up to 3 years 5 months 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.	16.4% 155/943 • up to 3 years 5 months 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.
General disorders Asthenia	23.9% 226/945 • up to 3 years 5 months 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.	23.2% 219/943 • up to 3 years 5 months 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.
General disorders Chest pain	6.6% 62/945 • up to 3 years 5 months 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.	7.1% 67/943 • up to 3 years 5 months 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.
General disorders Fatigue	23.0% 217/945 • up to 3 years 5 months 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.	26.2% 247/943 • up to 3 years 5 months 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.
General disorders Oedema peripheral	18.1% 171/945 • up to 3 years 5 months 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.	19.8% 187/943 • up to 3 years 5 months 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.
General disorders Pain	9.0% 85/945 • up to 3 years 5 months 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.	8.3% 78/943 • up to 3 years 5 months 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.
General disorders Pyrexia	12.8% 121/945 • up to 3 years 5 months 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.	9.2% 87/943 • up to 3 years 5 months 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.
Infections and infestations Urinary tract infection	11.1% 105/945 • up to 3 years 5 months 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.	9.3% 88/943 • up to 3 years 5 months 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.
Investigations Blood creatinine increased	5.3% 50/945 • up to 3 years 5 months 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.	4.3% 41/943 • up to 3 years 5 months 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.
Investigations Weight decreased	13.9% 131/945 • up to 3 years 5 months 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.	15.9% 150/943 • up to 3 years 5 months 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.
Metabolism and nutrition disorders Decreased appetite	27.8% 263/945 • up to 3 years 5 months 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.	28.0% 264/943 • up to 3 years 5 months 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.
Metabolism and nutrition disorders Hypocalcaemia	4.8% 45/945 • up to 3 years 5 months 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.	11.1% 105/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Arthralgia	20.8% 197/945 • up to 3 years 5 months 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.	19.9% 188/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Back pain	28.7% 271/945 • up to 3 years 5 months 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.	30.8% 290/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Bone pain	24.3% 230/945 • up to 3 years 5 months 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.	23.4% 221/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Muscle spasms	2.9% 27/945 • up to 3 years 5 months 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.	5.4% 51/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Muscular weakness	6.1% 58/945 • up to 3 years 5 months 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.	5.5% 52/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	5.7% 54/945 • up to 3 years 5 months 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.	5.0% 47/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	14.1% 133/945 • up to 3 years 5 months 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.	11.8% 111/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Myalgia	6.0% 57/945 • up to 3 years 5 months 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.	3.8% 36/943 • up to 3 years 5 months 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.
Musculoskeletal and connective tissue disorders Pain in extremity	19.5% 184/945 • up to 3 years 5 months 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.	20.4% 192/943 • up to 3 years 5 months 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.
Nervous system disorders Dizziness	6.7% 63/945 • up to 3 years 5 months 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.	5.7% 54/943 • up to 3 years 5 months 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.
Nervous system disorders Headache	7.5% 71/945 • up to 3 years 5 months 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.	6.5% 61/943 • up to 3 years 5 months 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.
Nervous system disorders Paraesthesia	7.3% 69/945 • up to 3 years 5 months 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.	5.6% 53/943 • up to 3 years 5 months 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.
Psychiatric disorders Anxiety	5.5% 52/945 • up to 3 years 5 months 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.	4.8% 45/943 • up to 3 years 5 months 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.
Psychiatric disorders Depression	4.1% 39/945 • up to 3 years 5 months 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.	5.3% 50/943 • up to 3 years 5 months 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.
Psychiatric disorders Insomnia	9.9% 94/945 • up to 3 years 5 months 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.	9.4% 89/943 • up to 3 years 5 months 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.
Renal and urinary disorders Dysuria	5.5% 52/945 • up to 3 years 5 months 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.	6.6% 62/943 • up to 3 years 5 months 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.
Renal and urinary disorders Haematuria	8.0% 76/945 • up to 3 years 5 months 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.	8.1% 76/943 • up to 3 years 5 months 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.
Renal and urinary disorders Urinary retention	5.0% 47/945 • up to 3 years 5 months 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.	6.6% 62/943 • up to 3 years 5 months 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.
Respiratory, thoracic and mediastinal disorders Cough	8.7% 82/945 • up to 3 years 5 months 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.	9.7% 91/943 • up to 3 years 5 months 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.1% 95/945 • up to 3 years 5 months 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.	12.4% 117/943 • up to 3 years 5 months 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.
Skin and subcutaneous tissue disorders Alopecia	6.6% 62/945 • up to 3 years 5 months 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.	6.2% 58/943 • up to 3 years 5 months 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.