Zoledronic Acid - Letrozole Adjuvant Synergy Trial (ZFAST) - Cancer Treatment Related Bone Loss in Postmenopausal Women With Estrogen Receptor Positive and/or Progesterone Receptor Positive Breast Cancer Receiving Adjuvant Hormonal Therapy

• ClinicalTrials.gov Identifier: NCT00050011
• Recruitment Status: Completed
• First Posted: November 20, 2002
• Results First Posted: January 28, 2014
• Last Update Posted: March 21, 2014
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Conditions: Breast Neoplasms; Osteoporosis
• Interventions: Drug: Zoledronic Acid; Drug: Letrozole
• Enrollment: 602

Participant Flow

Recruitment Details
Pre-assignment Details	Overall, 602 participants (301 in the upfront arm and 301 in the delayed-start arm) were randomized. Of these, 600 participants (300 in each arm) were treated. One participant in the upfront arm withdrew before taking any study drug and one participant in the delayed-start arm withdrew for administrative reasons prior to taking any study drug.

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed-start
Arm/Group Description	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence) or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on zoledronic acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic acid 4 mg IV 15-minute infusion every 6 months.
Period Title: Overall Study
Started	301	301
Intent-to-treat Population	300	300
Completed	180	175
Not Completed	121	126
Reason Not Completed
Adverse Event	41	46
Abnormal laboratory value(s)	1	1
Abnormal test procedure results	0	1
Lack of Efficacy	16	21
Participant condition no longer required	1	0
Protocol Violation	4	10
Withdrawal by Subject	34	26
Lost to Follow-up	7	9
Administrative problems	10	6
Death	7	4
Unknown - Reason is missing	0	2

Baseline Characteristics

Arm/Group Title		Zoledronic Acid Upfront	Zoledronic Acid Delayed-start	Total
Arm/Group Description		Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid upfront 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid upfront 4 mg IV 15-minute infusion every 6 months.	Total of all reporting groups
Overall Number of Baseline Participants		301	301	602
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	301 participants	301 participants	602 participants
		61.4 (9.28)	61.0 (8.92)	61.2 (9.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	301 participants	301 participants	602 participants
	Female	301 100.0%	301 100.0%	602 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Lumbar Spine (L1-L4) Bone Mineral Density (BMD)
Description	Bone mineral density (BMD) measurements were assessed by dual energy x-ray absorptiometry (DXA). The DXA devices of participating sites were cross-calibrated and the DXA results were compiled and analyzed by a central reader. Percent change = 100*((BMD at Month 12 - Baseline BMD)/Baseline BMD)). Missing data at month 12 were imputed by using the last observation carried forward (LOCF) method. Post-baseline non-missing data from month 6 were carried forward to month 12. Data prior to month 6 were not carried forward.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT population) was used. The ITT population contained all patients in the safety population for whom at least one post-baseline efficacy measurement was collected.

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed-start
Arm/Group Description:	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on zoledronic acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed	253	256
Mean (Standard Deviation); Unit of Measure: Percentage of BMD
	1.955 (3.3658)	-2.325 (3.9542)

2. Secondary Outcome

Title	Percent Change From Baseline in Lumbar Spine (L1-L4) BMD
Description	Bone mineral density (BMD) measurements were assessed by dual energy x-ray absorptiometry (DXA). The DXA devices of participating sites were cross-calibrated and the DXA results were compiled and analyzed by a central reader. Percent change = 100*((BMD at Time Frame - Baseline BMD)/Baseline BMD)). Missing data beyond month 12 were not imputed by LOCF.
Time Frame	Baseline, 2 years, 3 years, 5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed Start
Arm/Group Description:	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed	300	300
Mean (Standard Deviation); Unit of Measure: Percentage of BMD
2 years (n=206,202)	3.137 (4.1599)	-2.889 (5.0783)
3 years (n=189,190)	3.853 (4.5414)	-2.990 (5.7925)
5 years (n=140,132)	6.192 (5.9723)	-2.418 (7.4545)

3. Secondary Outcome

Title	Percent Change From Baseline in Total Hip BMD
Description	Bone mineral density (BMD) measurements were assessed by dual energy x-ray absorptiometry (DXA). The DXA devices of participating sites were cross-calibrated and the DXA results were compiled and analyzed by a central reader. Percent change = 100*((BMD at Time Frame - Baseline BMD)/Baseline BMD)). Missing data at month 12 were imputed by using the LOCF method. Post-baseline non-missing data from month 6 were carried forward to month 12. Data prior to month 6 were not carried forward.
Time Frame	Baseline, 12 months, 2 years, 3 years, 5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed Start
Arm/Group Description:	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed	300	300
Mean (Standard Deviation); Unit of Measure: Percentage of BMD
12 months (n=253,256)	1.256 (2.5878)	-1.883 (3.3007)
2 years (n=208,200)	1.413 (2.9178)	-3.150 (4.0450)
3 years (n=187,189)	1.676 (3.6979)	-3.463 (5.2585)
5 years (n=141,132)	2.571 (4.8794)	-4.115 (6.1071)

4. Secondary Outcome

Title	Percent Change From Baseline in Biochemical Markers of Bone Turnover, Serum N-Telopeptide (sNTX) and Bone-specific Alkaline Phosphatase (BSAP)
Description	Blood samples from a subset of participants (231 participants in total) were collected to measure the sNTX and BSAP. Missing data at month 12 were imputed by using the LOCF method. Post-baseline non-missing data from months 6 and 9 were carried forward to month 12. Data prior to month 6 were not carried forward. Missing data beyond month 12 were not imputed by LOCF.
Time Frame	Baseline, 12 months, 2 years, 3 years, 5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed Start
Arm/Group Description:	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed	300	300
Mean (Standard Deviation); Unit of Measure: Percentage of biochemical markers
sNTX, 12 months (n=87,85)	-20.1 (42.1)	21.7 (55.2)
sNTX, 2 years	NA [1] (NA)	NA [1] (NA)
sNTX, 3 years	NA [1] (NA)	NA [1] (NA)
sNTX, 5 years	NA [1] (NA)	NA [1] (NA)
BSAP, 12 months (n=88,90)	-7.8 (28.2)	19.0 (39.2)
BSAP, 2 years (n=63,60)	-12.0 (26.3)	19.9 (48.1)
BSAP, 3 years (n=59,52)	-12.4 (23.2)	10.6 (42.2)
BSAP, 5 years (n=95,102)	-6.4 (35.4)	11.9 (41.0)

[1]

After data analysis was performed for the 24 month interim analysis, a technical problem with the sNTX assay was identified. As a result, sNTX data collected at time points after 12 months were not considered reliable for inclusion.

5. Secondary Outcome

Title	Incidence Rate of All Clinical Fractures
Description	The number of participants who experienced a clinical fracture at month 36 was assessed. Initial x-ray (both AP and lateral views) of the lumbar and thoracic spine were performed at baseline to exclude participants with evidence of fracture. In addition, repeated bone scan and/or x-ray were performed at the Principal Investigator's discretion during the course of the study to confirm evidence of clinical fracture, or at month 36 if there was no evidence of clinical fracture (lumbar and thoracic spine - lateral view). X-ray films were sent to a central reader.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed Start
Arm/Group Description:	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed	300	300
Measure Type: Number; Unit of Measure: Participants
	18	21

6. Secondary Outcome

Title	Time to Disease Recurrence/Relapse
Description	The median time to disease progression was assessed by Kaplan-Meier analysis. The Principal Investigator assessed each participant for disease recurrence at each visit. Further testing was performed at the discretion of the Principal Investigator and as clinically indicated. Disease progression was defined as chest wall and/or regional recurrence confirmed by positive cytology or biopsy, and/or distance recurrence of the 1) skin, subcutaneous tissue, and lymph nodes (other than local or regional), 2) bone marrow, 3) lung, 4) skeleton 5) liver and 6) central nervous system confirmed by positive cytology, biopsy, aspirate or radiology as appropriate.
Time Frame	over 5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed Start
Arm/Group Description:	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed	300	300
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

The median time to disease recurrence relapse was not achieved because of the small number of patients with recurrence.

7. Secondary Outcome

Title	Rate of Change From Baseline in Lumbar Spine (L1-L4) BMD
Description	The rate of change from baseline in BMD was assessed.
Time Frame	Baseline, 5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed Start
Arm/Group Description:	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed	300	300
Mean (95% Confidence Interval); Unit of Measure: g/sq cm/month
	0.01043; (0.00810 to 0.01277)	-0.00157; (-0.00396 to 0.00081)

8. Secondary Outcome

Title	Rate of Change From Baseline in Total Hip BMD
Description	The rate of change from baseline in BMD was assessed.
Time Frame	Baseline, 5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed Start
Arm/Group Description:	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed	300	300
Mean (95% Confidence Interval); Unit of Measure: g/sq. cm/month
	0.00226; (0.00071 to 0.00382)	-0.00625; (-0.00784 to -0.00466)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Overall, 602 participants (301 in the upfront arm and 301 in the delayed-start arm) were randomized. Of these, 600 participants (300 in each arm) were treated. One participant in the upfront arm withdrew before taking any study drug and one participant in the delayed-start arm withdrew for administrative reasons prior to taking any study drug.
Arm/Group Title	Zoledronic Acid Upfront	Zoledronic Acid Delayed-start
Arm/Group Description	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Femara 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on zoledronic acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic acid 4 mg IV 15-minute infusion every 6 months.
All-Cause Mortality
	Zoledronic Acid Upfront	Zoledronic Acid Delayed-start
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Zoledronic Acid Upfront	Zoledronic Acid Delayed-start
	Affected / at Risk (%)	Affected / at Risk (%)
Total	83/300 (27.67%)	71/300 (23.67%)
Blood and lymphatic system disorders
Anaemia † 1	2/300 (0.67%)	0/300 (0.00%)
Granulocytopenia † 1	1/300 (0.33%)	0/300 (0.00%)
Iron deficiency anaemia † 1	1/300 (0.33%)	1/300 (0.33%)
Thrombocytopenia † 1	0/300 (0.00%)	1/300 (0.33%)
Cardiac disorders
Acute coronary syndrome † 1	1/300 (0.33%)	0/300 (0.00%)
Acute myocardial infarction † 1	2/300 (0.67%)	1/300 (0.33%)
Angina pectoris † 1	2/300 (0.67%)	1/300 (0.33%)
Aortic valve stenosis † 1	1/300 (0.33%)	0/300 (0.00%)
Atrial fibrillation † 1	4/300 (1.33%)	4/300 (1.33%)
Cardiac failure † 1	0/300 (0.00%)	1/300 (0.33%)
Cardiac failure chronic † 1	1/300 (0.33%)	0/300 (0.00%)
Cardiac failure congestive † 1	2/300 (0.67%)	2/300 (0.67%)
Cardio-respiratory arrest † 1	0/300 (0.00%)	1/300 (0.33%)
Cardiomyopathy † 1	0/300 (0.00%)	1/300 (0.33%)
Cardiomyopathy acute † 1	1/300 (0.33%)	0/300 (0.00%)
Coronary artery disease † 1	1/300 (0.33%)	4/300 (1.33%)
Coronary artery occlusion † 1	0/300 (0.00%)	4/300 (1.33%)
Coronary artery stenosis † 1	1/300 (0.33%)	2/300 (0.67%)
Dilatation ventricular † 1	1/300 (0.33%)	0/300 (0.00%)
Ischaemic cardiomyopathy † 1	1/300 (0.33%)	0/300 (0.00%)
Left ventricular dysfunction † 1	0/300 (0.00%)	1/300 (0.33%)
Myocardial infarction † 1	2/300 (0.67%)	1/300 (0.33%)
Myocardial ischaemia † 1	0/300 (0.00%)	1/300 (0.33%)
Sinus bradycardia † 1	1/300 (0.33%)	0/300 (0.00%)
Eye disorders
Blindness unilateral † 1	1/300 (0.33%)	0/300 (0.00%)
Retinal artery occlusion † 1	1/300 (0.33%)	0/300 (0.00%)
Visual acuity reduced † 1	1/300 (0.33%)	0/300 (0.00%)
Gastrointestinal disorders
Abdominal distension † 1	0/300 (0.00%)	1/300 (0.33%)
Abdominal pain † 1	1/300 (0.33%)	2/300 (0.67%)
Abdominal pain upper † 1	0/300 (0.00%)	1/300 (0.33%)
Aphthous stomatitis † 1	1/300 (0.33%)	0/300 (0.00%)
Colitis ulcerative † 1	2/300 (0.67%)	0/300 (0.00%)
Crohn's disease † 1	0/300 (0.00%)	1/300 (0.33%)
Duodenal ulcer perforation † 1	1/300 (0.33%)	0/300 (0.00%)
Enterovesical fistula † 1	1/300 (0.33%)	0/300 (0.00%)
Gastrointestinal haemorrhage † 1	1/300 (0.33%)	0/300 (0.00%)
Intestinal obstruction † 1	0/300 (0.00%)	1/300 (0.33%)
Large intestine perforation † 1	1/300 (0.33%)	0/300 (0.00%)
Nausea † 1	2/300 (0.67%)	0/300 (0.00%)
Oesophageal mass † 1	0/300 (0.00%)	1/300 (0.33%)
Oesophageal spasm † 1	0/300 (0.00%)	1/300 (0.33%)
Peritonitis † 1	1/300 (0.33%)	0/300 (0.00%)
Rectal haemorrhage † 1	1/300 (0.33%)	0/300 (0.00%)
Small intestinal obstruction † 1	1/300 (0.33%)	0/300 (0.00%)
Vomiting † 1	1/300 (0.33%)	0/300 (0.00%)
General disorders
Adverse drug reaction † 1	1/300 (0.33%)	0/300 (0.00%)
Asthenia † 1	1/300 (0.33%)	1/300 (0.33%)
Chest discomfort † 1	0/300 (0.00%)	1/300 (0.33%)
Chest pain † 1	3/300 (1.00%)	1/300 (0.33%)
Non-cardiac chest pain † 1	2/300 (0.67%)	0/300 (0.00%)
Pain † 1	0/300 (0.00%)	1/300 (0.33%)
Pyrexia † 1	1/300 (0.33%)	0/300 (0.00%)
Hepatobiliary disorders
Cholecystitis † 1	4/300 (1.33%)	2/300 (0.67%)
Cholelithiasis † 1	2/300 (0.67%)	1/300 (0.33%)
Cholelithiasis obstructive † 1	1/300 (0.33%)	0/300 (0.00%)
Ischaemic hepatitis † 1	0/300 (0.00%)	1/300 (0.33%)
Immune system disorders
Drug hypersensitivity † 1	0/300 (0.00%)	1/300 (0.33%)
Infections and infestations
Abdominal wall abscess † 1	0/300 (0.00%)	1/300 (0.33%)
Abscess limb † 1	0/300 (0.00%)	1/300 (0.33%)
Appendicitis † 1	1/300 (0.33%)	3/300 (1.00%)
Arthritis bacterial † 1	0/300 (0.00%)	1/300 (0.33%)
Breast abscess † 1	1/300 (0.33%)	0/300 (0.00%)
Breast cellulitis † 1	1/300 (0.33%)	0/300 (0.00%)
Bronchitis † 1	0/300 (0.00%)	2/300 (0.67%)
Cellulitis † 1	2/300 (0.67%)	2/300 (0.67%)
Gastroenteritis † 1	0/300 (0.00%)	1/300 (0.33%)
Helicobacter infection † 1	1/300 (0.33%)	0/300 (0.00%)
Incision site infection † 1	1/300 (0.33%)	0/300 (0.00%)
Liver abscess † 1	0/300 (0.00%)	1/300 (0.33%)
Mastitis † 1	1/300 (0.33%)	1/300 (0.33%)
Osteomyelitis chronic † 1	1/300 (0.33%)	0/300 (0.00%)
Pneumonia † 1	4/300 (1.33%)	3/300 (1.00%)
Postoperative wound infection † 1	1/300 (0.33%)	0/300 (0.00%)
Pyelonephritis † 1	1/300 (0.33%)	0/300 (0.00%)
Septic shock † 1	1/300 (0.33%)	0/300 (0.00%)
Skin bacterial infection † 1	0/300 (0.00%)	1/300 (0.33%)
Staphylococcal infection † 1	0/300 (0.00%)	2/300 (0.67%)
Upper respiratory tract infection † 1	1/300 (0.33%)	0/300 (0.00%)
Urinary tract infection † 1	1/300 (0.33%)	2/300 (0.67%)
Urosepsis † 1	1/300 (0.33%)	0/300 (0.00%)
Viral infection † 1	2/300 (0.67%)	0/300 (0.00%)
Viral upper respiratory tract infection † 1	1/300 (0.33%)	0/300 (0.00%)
Injury, poisoning and procedural complications
Accident † 1	1/300 (0.33%)	0/300 (0.00%)
Accidental overdose † 1	0/300 (0.00%)	1/300 (0.33%)
Ankle fracture † 1	1/300 (0.33%)	0/300 (0.00%)
Arthropod bite † 1	0/300 (0.00%)	1/300 (0.33%)
Brain contusion † 1	1/300 (0.33%)	0/300 (0.00%)
Breast injury † 1	1/300 (0.33%)	0/300 (0.00%)
Contusion † 1	1/300 (0.33%)	2/300 (0.67%)
Device breakage † 1	0/300 (0.00%)	1/300 (0.33%)
Fall † 1	10/300 (3.33%)	7/300 (2.33%)
Femoral neck fracture † 1	0/300 (0.00%)	1/300 (0.33%)
Fibula fracture † 1	1/300 (0.33%)	0/300 (0.00%)
Foot fracture † 1	1/300 (0.33%)	0/300 (0.00%)
Hand fracture † 1	1/300 (0.33%)	0/300 (0.00%)
Head injury † 1	0/300 (0.00%)	1/300 (0.33%)
Humerus fracture † 1	1/300 (0.33%)	0/300 (0.00%)
Intentional overdose † 1	1/300 (0.33%)	0/300 (0.00%)
Joint dislocation † 1	1/300 (0.33%)	1/300 (0.33%)
Joint sprain † 1	1/300 (0.33%)	0/300 (0.00%)
Meniscus lesion † 1	1/300 (0.33%)	0/300 (0.00%)
Multiple fractures † 1	0/300 (0.00%)	1/300 (0.33%)
Post procedural complication † 1	1/300 (0.33%)	0/300 (0.00%)
Post procedural haematoma † 1	1/300 (0.33%)	0/300 (0.00%)
Postoperative ileus † 1	0/300 (0.00%)	1/300 (0.33%)
Procedural nausea † 1	0/300 (0.00%)	1/300 (0.33%)
Procedural vomiting † 1	0/300 (0.00%)	1/300 (0.33%)
Radius fracture † 1	1/300 (0.33%)	1/300 (0.33%)
Rib fracture † 1	0/300 (0.00%)	1/300 (0.33%)
Road traffic accident † 1	0/300 (0.00%)	2/300 (0.67%)
Skull fracture † 1	0/300 (0.00%)	1/300 (0.33%)
Subdural haematoma † 1	1/300 (0.33%)	1/300 (0.33%)
Thoracic vertebral fracture † 1	0/300 (0.00%)	1/300 (0.33%)
Tibia fracture † 1	1/300 (0.33%)	0/300 (0.00%)
Traumatic brain injury † 1	0/300 (0.00%)	1/300 (0.33%)
Traumatic intracranial haemorrhage † 1	0/300 (0.00%)	1/300 (0.33%)
Ulna fracture † 1	1/300 (0.33%)	1/300 (0.33%)
Upper limb fracture † 1	1/300 (0.33%)	1/300 (0.33%)
Wrist fracture † 1	1/300 (0.33%)	0/300 (0.00%)
Investigations
Bone density decreased † 1	1/300 (0.33%)	0/300 (0.00%)
Electrocardiogram T wave inversion † 1	1/300 (0.33%)	0/300 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/300 (0.00%)	1/300 (0.33%)
Diabetes mellitus inadequate control † 1	1/300 (0.33%)	0/300 (0.00%)
Hyponatraemia † 1	0/300 (0.00%)	1/300 (0.33%)
Musculoskeletal and connective tissue disorders
Back pain † 1	1/300 (0.33%)	1/300 (0.33%)
Foot deformity † 1	1/300 (0.33%)	0/300 (0.00%)
Intervertebral disc protrusion † 1	1/300 (0.33%)	0/300 (0.00%)
Musculoskeletal chest pain † 1	1/300 (0.33%)	0/300 (0.00%)
Musculoskeletal pain † 1	0/300 (0.00%)	1/300 (0.33%)
Neck pain † 1	1/300 (0.33%)	1/300 (0.33%)
Osteoarthritis † 1	9/300 (3.00%)	9/300 (3.00%)
Osteonecrosis † 1	2/300 (0.67%)	2/300 (0.67%)
Osteoporosis † 1	0/300 (0.00%)	1/300 (0.33%)
Pain in jaw † 1	0/300 (0.00%)	1/300 (0.33%)
Rhabdomyolysis † 1	0/300 (0.00%)	1/300 (0.33%)
Rotator cuff syndrome † 1	1/300 (0.33%)	0/300 (0.00%)
Scoliosis † 1	1/300 (0.33%)	0/300 (0.00%)
Spinal column stenosis † 1	1/300 (0.33%)	0/300 (0.00%)
Spondylolisthesis † 1	0/300 (0.00%)	1/300 (0.33%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia † 1	1/300 (0.33%)	0/300 (0.00%)
Acute myelomonocytic leukaemia † 1	1/300 (0.33%)	0/300 (0.00%)
Benign lung neoplasm † 1	0/300 (0.00%)	1/300 (0.33%)
Bladder cancer † 1	1/300 (0.33%)	0/300 (0.00%)
Bladder neoplasm † 1	1/300 (0.33%)	0/300 (0.00%)
Bladder transitional cell carcinoma † 1	1/300 (0.33%)	0/300 (0.00%)
Breast cancer † 1	0/300 (0.00%)	1/300 (0.33%)
Degeneration of uterine fibroid † 1	1/300 (0.33%)	0/300 (0.00%)
Lung carcinoma cell type unspecified stage I † 1	1/300 (0.33%)	0/300 (0.00%)
Meningioma † 1	1/300 (0.33%)	0/300 (0.00%)
Ovarian cancer † 1	1/300 (0.33%)	1/300 (0.33%)
Pancreatic carcinoma † 1	0/300 (0.00%)	1/300 (0.33%)
Spindle cell sarcoma † 1	0/300 (0.00%)	1/300 (0.33%)
Ureteric cancer † 1	1/300 (0.33%)	0/300 (0.00%)
Nervous system disorders
Altered state of consciousness † 1	0/300 (0.00%)	1/300 (0.33%)
Amyotrophic lateral sclerosis † 1	0/300 (0.00%)	1/300 (0.33%)
Ataxia † 1	1/300 (0.33%)	0/300 (0.00%)
Cerebral haemorrhage † 1	1/300 (0.33%)	0/300 (0.00%)
Cerebrovascular accident † 1	2/300 (0.67%)	3/300 (1.00%)
Dementia † 1	0/300 (0.00%)	1/300 (0.33%)
Dizziness † 1	1/300 (0.33%)	0/300 (0.00%)
Haemorrhage intracranial † 1	1/300 (0.33%)	0/300 (0.00%)
Hepatic encephalopathy † 1	1/300 (0.33%)	0/300 (0.00%)
Loss of consciousness † 1	0/300 (0.00%)	1/300 (0.33%)
Lumbar radiculopathy † 1	1/300 (0.33%)	0/300 (0.00%)
Multiple sclerosis † 1	1/300 (0.33%)	0/300 (0.00%)
Subdural hygroma † 1	0/300 (0.00%)	1/300 (0.33%)
Syncope † 1	2/300 (0.67%)	1/300 (0.33%)
Transient ischaemic attack † 1	1/300 (0.33%)	0/300 (0.00%)
Psychiatric disorders
Alcoholism † 1	1/300 (0.33%)	0/300 (0.00%)
Confusional state † 1	1/300 (0.33%)	0/300 (0.00%)
Depression † 1	1/300 (0.33%)	0/300 (0.00%)
Suicide attempt † 1	1/300 (0.33%)	0/300 (0.00%)
Renal and urinary disorders
Calculus ureteric † 1	1/300 (0.33%)	0/300 (0.00%)
Cystitis haemorrhagic † 1	1/300 (0.33%)	0/300 (0.00%)
Renal failure † 1	1/300 (0.33%)	0/300 (0.00%)
Reproductive system and breast disorders
Breast cyst † 1	1/300 (0.33%)	0/300 (0.00%)
Cystocele † 1	0/300 (0.00%)	2/300 (0.67%)
Ovarian cyst † 1	1/300 (0.33%)	2/300 (0.67%)
Rectocele † 1	0/300 (0.00%)	1/300 (0.33%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	0/300 (0.00%)	1/300 (0.33%)
Acute respiratory failure † 1	1/300 (0.33%)	0/300 (0.00%)
Bronchospasm † 1	0/300 (0.00%)	1/300 (0.33%)
Chronic obstructive pulmonary disease † 1	1/300 (0.33%)	2/300 (0.67%)
Dyspnoea † 1	2/300 (0.67%)	1/300 (0.33%)
Mediastinal mass † 1	0/300 (0.00%)	1/300 (0.33%)
Pleural effusion † 1	0/300 (0.00%)	1/300 (0.33%)
Pleurisy † 1	1/300 (0.33%)	0/300 (0.00%)
Pneumothorax † 1	0/300 (0.00%)	3/300 (1.00%)
Pulmonary embolism † 1	1/300 (0.33%)	2/300 (0.67%)
Pulmonary mass † 1	0/300 (0.00%)	1/300 (0.33%)
Respiratory failure † 1	1/300 (0.33%)	0/300 (0.00%)
Skin and subcutaneous tissue disorders
Subcutaneous emphysema † 1	0/300 (0.00%)	1/300 (0.33%)
Urticaria † 1	0/300 (0.00%)	1/300 (0.33%)
Vascular disorders
Deep vein thrombosis † 1	3/300 (1.00%)	4/300 (1.33%)
Haemorrhage † 1	1/300 (0.33%)	0/300 (0.00%)
Hypertension † 1	1/300 (0.33%)	0/300 (0.00%)
Jugular vein distension † 1	1/300 (0.33%)	0/300 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Zoledronic Acid Upfront	Zoledronic Acid Delayed-start
	Affected / at Risk (%)	Affected / at Risk (%)
Total	283/300 (94.33%)	275/300 (91.67%)
Blood and lymphatic system disorders
Anaemia † 1	13/300 (4.33%)	20/300 (6.67%)
Gastrointestinal disorders
Constipation † 1	29/300 (9.67%)	28/300 (9.33%)
Diarrhoea † 1	25/300 (8.33%)	31/300 (10.33%)
Gastrooesophageal reflux disease † 1	16/300 (5.33%)	15/300 (5.00%)
Nausea † 1	39/300 (13.00%)	40/300 (13.33%)
General disorders
Chest pain † 1	18/300 (6.00%)	9/300 (3.00%)
Fatigue † 1	101/300 (33.67%)	88/300 (29.33%)
Oedema peripheral † 1	36/300 (12.00%)	30/300 (10.00%)
Pain † 1	16/300 (5.33%)	14/300 (4.67%)
Pyrexia † 1	28/300 (9.33%)	14/300 (4.67%)
Infections and infestations
Bronchitis † 1	17/300 (5.67%)	6/300 (2.00%)
Sinusitis † 1	19/300 (6.33%)	15/300 (5.00%)
Upper respiratory tract infection † 1	26/300 (8.67%)	26/300 (8.67%)
Urinary tract infection † 1	37/300 (12.33%)	26/300 (8.67%)
Metabolism and nutrition disorders
Hypercholesterolaemia † 1	21/300 (7.00%)	17/300 (5.67%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	141/300 (47.00%)	136/300 (45.33%)
Arthritis † 1	22/300 (7.33%)	19/300 (6.33%)
Back pain † 1	44/300 (14.67%)	52/300 (17.33%)
Bone pain † 1	48/300 (16.00%)	24/300 (8.00%)
Muscle spasms † 1	15/300 (5.00%)	17/300 (5.67%)
Musculoskeletal chest pain † 1	17/300 (5.67%)	8/300 (2.67%)
Musculoskeletal pain † 1	33/300 (11.00%)	22/300 (7.33%)
Myalgia † 1	61/300 (20.33%)	47/300 (15.67%)
Neck pain † 1	16/300 (5.33%)	8/300 (2.67%)
Pain in extremity † 1	45/300 (15.00%)	40/300 (13.33%)
Nervous system disorders
Dizziness † 1	29/300 (9.67%)	22/300 (7.33%)
Headache † 1	39/300 (13.00%)	37/300 (12.33%)
Hypoaesthesia † 1	17/300 (5.67%)	17/300 (5.67%)
Paraesthesia † 1	17/300 (5.67%)	6/300 (2.00%)
Psychiatric disorders
Anxiety † 1	24/300 (8.00%)	25/300 (8.33%)
Depression † 1	35/300 (11.67%)	42/300 (14.00%)
Insomnia † 1	41/300 (13.67%)	29/300 (9.67%)
Reproductive system and breast disorders
Breast pain † 1	19/300 (6.33%)	18/300 (6.00%)
Vulvovaginal dryness † 1	24/300 (8.00%)	22/300 (7.33%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	30/300 (10.00%)	38/300 (12.67%)
Dyspnoea † 1	26/300 (8.67%)	25/300 (8.33%)
Skin and subcutaneous tissue disorders
Alopecia † 1	24/300 (8.00%)	18/300 (6.00%)
Rash † 1	19/300 (6.33%)	17/300 (5.67%)
Vascular disorders
Hot flush † 1	122/300 (40.67%)	118/300 (39.33%)
Hypertension † 1	30/300 (10.00%)	24/300 (8.00%)
Lymphoedema † 1	19/300 (6.33%)	20/300 (6.67%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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 or disclosure of trial results in their entirety.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT00050011
• Other Study ID Numbers: CZOL446EUS32
• First Submitted: November 18, 2002
• First Posted: November 20, 2002
• Results First Submitted: December 4, 2013
• Results First Posted: January 28, 2014
• Last Update Posted: March 21, 2014