Trial Outcomes & Findings for A Study to Evaluate the Safety and Efficacy of Zoledronic Acid in the Prevention or Delaying of Bone Metastasis in Patients With Stage IIIA and IIIB Non-small Cell Lung Cancer (NSCLC) (NCT NCT00172042)

NCT ID: NCT00172042

Last Updated: 2015-05-04

Results Overview

Progression-free survival is defined as the time from randomization to the date of the first documented progression or recurrence of disease or death from any cause. Time to disease progression (TTP) was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines with evaluations every 3 months.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

437 participants

Primary outcome timeframe

Up to 24 months

Results posted on

2015-05-04

Participant Flow

Participant milestones

Participant milestones
Measure	Zoledronic Acid Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Overall Study STARTED	226	211
Overall Study COMPLETED	68	86
Overall Study NOT COMPLETED	158	125

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Overall Study Adverse Event	27	13
Overall Study Abnormal laboratory value(s)	5	1
Overall Study Abnormal test procedure(s)	0	3
Overall Study Unsatisfactory therapeutic effect	13	11
Overall Study Patient no longer requires study drug	10	8
Overall Study Protocol Violation	8	7
Overall Study Withdrawal by Subject	37	25
Overall Study Lost to Follow-up	3	5
Overall Study Administrative problems	13	10
Overall Study Death	42	42

Baseline Characteristics

A Study to Evaluate the Safety and Efficacy of Zoledronic Acid in the Prevention or Delaying of Bone Metastasis in Patients With Stage IIIA and IIIB Non-small Cell Lung Cancer (NSCLC)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.	Total n=437 Participants Total of all reporting groups
Age, Continuous	59.2 years STANDARD_DEVIATION 9.19 • n=5 Participants	60.0 years STANDARD_DEVIATION 9.27 • n=7 Participants	59.6 years STANDARD_DEVIATION 9.23 • n=5 Participants
Sex: Female, Male Female	65 Participants n=5 Participants	65 Participants n=7 Participants	130 Participants n=5 Participants
Sex: Female, Male Male	161 Participants n=5 Participants	146 Participants n=7 Participants	307 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 24 months

Population: Intent-to-Treat Population consisting of all randomized participants.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Progression-Free Survival	9.0 Months Interval 6.8 to 12.4	11.3 Months Interval 7.7 to 15.8

PRIMARY outcome

Timeframe: Months 6, 12, 18, and 24

Population: Intent-to-Treat Population consisting of all randomized participants.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Kaplan-Meier Estimates for Progression-free Survival 6 months	63.0 Percentage of participants Interval 56.2 to 69.0	67.9 Percentage of participants Interval 61.0 to 73.9
Kaplan-Meier Estimates for Progression-free Survival 12 months	44.4 Percentage of participants Interval 37.6 to 51.0	48.8 Percentage of participants Interval 41.6 to 55.5
Kaplan-Meier Estimates for Progression-free Survival 18 months	30.7 Percentage of participants Interval 24.4 to 37.2	40.6 Percentage of participants Interval 33.7 to 47.5
Kaplan-Meier Estimates for Progression-free Survival 24 months	25.7 Percentage of participants Interval 19.8 to 32.0	36.0 Percentage of participants Interval 29.2 to 42.8

PRIMARY outcome

Timeframe: Up to 24 months

Population: Intent-to-Treat Population consisting of all randomized participants.

Percentage of Participants with the Progression-free survival events: disease progression and death. Time to disease progression (TTP) was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines with evaluations every 3 months.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Percentage of Participants With Progression-Free Survival Events Disease Progression	60.2 Percentage of participants	55.5 Percentage of participants
Percentage of Participants With Progression-Free Survival Events Death	8.4 Percentage of participants	5.7 Percentage of participants

SECONDARY outcome

Timeframe: Months 6, 12, 18 and 24

Population: Intent-to-Treat Population consisting of all randomized participants.

Percentage of participants developing at least 1 bone metastasis, whether or not symptomatic. Bone scans were scheduled at screening and at 6-monthly intervals after study entry, or when symptoms suggested the presence of bone metastases. Positive bone scans required confirmation by x-ray, magnetic resonance imaging (MRI), or computed tomography (CT).

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Percentage of Participants With Bone Metastases at 6, 12, 18, and 24 Months 18 months	6.2 Percentage of participants Interval 5.4 to 16.8	8.1 Percentage of participants Interval 6.9 to 18.3
Percentage of Participants With Bone Metastases at 6, 12, 18, and 24 Months 6 months	2.2 Percentage of participants Interval 0.4 to 5.1	4.3 Percentage of participants Interval 0.0 to 4.0
Percentage of Participants With Bone Metastases at 6, 12, 18, and 24 Months 12 months	4.0 Percentage of participants Interval 1.1 to 7.3	7.1 Percentage of participants Interval 4.3 to 13.7
Percentage of Participants With Bone Metastases at 6, 12, 18, and 24 Months 24 months	6.6 Percentage of participants Interval 6.2 to 18.5	9.0 Percentage of participants Interval 7.7 to 19.7

SECONDARY outcome

Timeframe: Months 6, 12, 18, and 24

Population: Intent-to-Treat Population consisting of all randomized participants. Any participant without documented bone metastases at the date of analysis was to be censored at the date of the last bone scan.

Time to occurrence of bone metastases was defined as the time from randomization to the date of the first documented bone metastases which could be asymptomatic or symptomatic at the time of detection. Bone scans were scheduled at screening and at 6-monthly intervals after study entry, or when symptoms suggested the presence of bone metastases. Positive bone scans required confirmation by x-ray, magnetic resonance imaging (MRI), or computed tomography (CT).

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Kaplan-Meier Estimate of the Time to Occurrence of Bone Metastases 6 months	2.7 Percentage of participants Interval 0.4 to 5.1	1.9 Percentage of participants Interval 0.0 to 4.0
Kaplan-Meier Estimate of the Time to Occurrence of Bone Metastases 12 months	4.2 Percentage of participants Interval 1.1 to 7.3	9.0 Percentage of participants Interval 4.3 to 13.7
Kaplan-Meier Estimate of the Time to Occurrence of Bone Metastases 18 months	11.1 Percentage of participants Interval 5.4 to 16.8	12.6 Percentage of participants Interval 6.9 to 18.3
Kaplan-Meier Estimate of the Time to Occurrence of Bone Metastases 24 months	12.4 Percentage of participants Interval 6.2 to 18.5	13.7 Percentage of participants Interval 7.7 to 19.7

SECONDARY outcome

Timeframe: Months 12 and 24

Population: Intent-to-Treat Population consisting of all randomized participants.

Skeletal Related Events were defined as radiation therapy or surgery to bone, spinal cord compression event or a pathologic bone fracture event.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Percentage of Participants With Skeletal Related Events (SREs) at 12 and 24 Months From Study Entry 12 months	2.2 Percentage of participants	1.4 Percentage of participants
Percentage of Participants With Skeletal Related Events (SREs) at 12 and 24 Months From Study Entry 24 months	2.2 Percentage of participants	1.4 Percentage of participants

SECONDARY outcome

Timeframe: Months 6,12, 18, and 24

Population: Intent-to-Treat Population consisting of all randomized participants. Any participant in whom no SRE had been observed during the study was to be censored at the date of the last visit or the date of death whichever was the earlier.

Time to the first skeletal related event defined as the time from randomization to the date of occurrence of the first SRE. Skeletal Related Events were defined as radiation therapy or surgery to bone, spinal cord compression event or a pathologic bone fracture event

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Kaplan-Meier Estimates of the Time to the First Skeletal Related Event (SRE) 6 month	1.0 Percentage of participants Interval 0.0 to 2.3	0.0 Percentage of participants Interval 0.0 to 0.0
Kaplan-Meier Estimates of the Time to the First Skeletal Related Event (SRE) 12 month	2.7 Percentage of participants Interval 0.4 to 5.0	1.8 Percentage of participants Interval 0.0 to 3.9
Kaplan-Meier Estimates of the Time to the First Skeletal Related Event (SRE) 18 month	2.7 Percentage of participants Interval 0.4 to 5.0	1.8 Percentage of participants Interval 0.0 to 3.9
Kaplan-Meier Estimates of the Time to the First Skeletal Related Event (SRE) 24 month	2.7 Percentage of participants Interval 0.4 to 5.0	1.8 Percentage of participants Interval 0.0 to 3.9

SECONDARY outcome

Timeframe: Months 6, 12, 18, and 24

Population: Intent-to-Treat Population consisting of all randomized participants.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=226 Participants Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=211 Participants No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Kaplan-Meier Estimates for Overall Survival 6 months	92.8 Percentage of participants Interval 88.4 to 95.5	93.6 Percentage of participants Interval 89.3 to 96.3
Kaplan-Meier Estimates for Overall Survival 12 months	81.8 Percentage of participants Interval 76.0 to 86.4	81.8 Percentage of participants Interval 75.7 to 86.5
Kaplan-Meier Estimates for Overall Survival 18 months	72.4 Percentage of participants Interval 65.7 to 78.0	71.0 Percentage of participants Interval 64.0 to 76.9
Kaplan-Meier Estimates for Overall Survival 24 months	59.5 Percentage of participants Interval 51.9 to 66.2	63.6 Percentage of participants Interval 56.1 to 70.1

Adverse Events

Zoledronic Acid

Serious events: 71 serious events

Other events: 166 other events

Deaths: 0 deaths

Control

Serious events: 84 serious events

Other events: 139 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Zoledronic Acid n=224 participants at risk Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=213 participants at risk No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Blood and lymphatic system disorders Anaemia	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Blood and lymphatic system disorders Febrile neutropenia	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Blood and lymphatic system disorders Neutropenia	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Blood and lymphatic system disorders Pancytopenia	0.89% 2/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Blood and lymphatic system disorders Thrombocytopenia	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Acute myocardial infarction	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Angina pectoris	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Angina unstable	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Atrial fibrillation	0.89% 2/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Atrial flutter	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Bradycardia	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Cardiac failure	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	1.4% 3/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Cardiopulmonary failure	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Myocardial infarction	0.89% 2/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Palpitations	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Pericardial effusion	0.89% 2/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Cardiac disorders Sinus tachycardia	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Ear and labyrinth disorders Hypoacusis	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Ear and labyrinth disorders Vertigo	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Abdominal pain	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Abdominal pain upper	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Constipation	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Diarrhoea	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	1.4% 3/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Dysphagia	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Gastric haemorrhage	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Gastritis	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Gastropleural fistula	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Haematemesis	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Melaena	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Mesenteric artery thrombosis	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Nausea	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Oesophageal stenosis	0.89% 2/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Oesophagitis	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Subileus	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.00% 0/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Vomiting	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Chest discomfort	0.00% 0/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Chest pain	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	1.9% 4/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Disease progression	0.89% 2/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	1.9% 4/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Fatigue	0.45% 1/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.47% 1/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders General physical health deterioration	1.8% 4/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	0.94% 2/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.

Other adverse events
Measure	Zoledronic Acid n=224 participants at risk Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks for 24 months. Dosage was adjusted for participants with mild or moderate renal impairment.	Control n=213 participants at risk No investigational treatment. If a participant developed bone metastases, treatment was started with Zoledronic acid 4 mg intravenous infusion over at least 15 minutes every 3 to 4 weeks until 24 months from the date of study entry had elapsed.
Blood and lymphatic system disorders Anaemia	10.3% 23/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	10.8% 23/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Abdominal pain upper	5.4% 12/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	3.3% 7/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Constipation	14.3% 32/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	6.1% 13/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Diarrhoea	5.4% 12/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	6.1% 13/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Nausea	10.7% 24/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	10.8% 23/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Gastrointestinal disorders Vomiting	8.9% 20/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	4.2% 9/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Asthenia	4.9% 11/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	7.0% 15/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Chest pain	12.5% 28/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	8.9% 19/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Fatigue	17.0% 38/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	12.2% 26/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Influenza like illness	5.4% 12/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	1.4% 3/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
General disorders Pyrexia	20.5% 46/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	10.3% 22/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Infections and infestations Bronchitis	2.7% 6/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.2% 11/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Infections and infestations Nasopharyngitis	7.6% 17/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	8.9% 19/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Infections and infestations Respiratory tract infection	6.7% 15/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.6% 12/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Infections and infestations Upper respiratory tract infection	3.1% 7/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	7.5% 16/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Investigations Weight decreased	4.9% 11/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.6% 12/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Metabolism and nutrition disorders Decreased appetite	13.8% 31/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	13.6% 29/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Metabolism and nutrition disorders Hyperglycaemia	1.8% 4/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.6% 12/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Musculoskeletal and connective tissue disorders Arthralgia	7.6% 17/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.6% 12/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Musculoskeletal and connective tissue disorders Back pain	7.6% 17/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	6.6% 14/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.5% 10/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	6.1% 13/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Musculoskeletal and connective tissue disorders Myalgia	7.1% 16/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.6% 12/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Musculoskeletal and connective tissue disorders Pain in extremity	4.9% 11/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.2% 11/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Nervous system disorders Dizziness	6.7% 15/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	6.1% 13/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Nervous system disorders Headache	8.5% 19/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	10.8% 23/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Psychiatric disorders Insomnia	9.4% 21/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	7.5% 16/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Respiratory, thoracic and mediastinal disorders Cough	26.8% 60/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	25.4% 54/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Respiratory, thoracic and mediastinal disorders Dyspnoea	20.5% 46/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	23.0% 49/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Respiratory, thoracic and mediastinal disorders Haemoptysis	8.9% 20/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.2% 11/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Respiratory, thoracic and mediastinal disorders Productive cough	4.9% 11/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	5.2% 11/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.
Skin and subcutaneous tissue disorders Rash	7.6% 17/224 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.	2.8% 6/213 Safety results are subsequently presented according to treatment actually received at the start of the study (224 in zoledronic acid arm, 213 in control arm); two patients were randomized to the zoledronic acid arm but did not receive study drug at the start of the study hence included into control arm for safety analysis.