The Use of Zoledronic Acid to Prevent Cancer-treatment Bone Loss in Post-menopausal Women Receiving Adjuvant Letrozole for Breast Cancer

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00171314
• Collaborator: (none)
• Enrollment: 527
• Locations: 49
• Arms: 2
• Patients Per Site: 10.8

Study Details

Study Description

Brief Summary

Post-menopausal breast cancer patients will receive letrozole 2.5 mg daily for the treatment of breast cancer and will be randomized to a treatment group to receive either upfront zoledronic acid 4 mg IV 15-minute infusion every 6 months or delayed start zoledronic acid 4 mg IV 15-minute infusion every 6 months. Delayed start zoledronic acid will be initiated when either the Bone Mineral Density T-score is below -2 Standard Deviations at either the lumbar spine or hip or any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the month 36 scheduled visit. Letrozole 2.5 mg will be given daily for 5 years.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Zoledronic acid; Drug: Letrozole	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 527 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Use of Zoledronic Acid to Prevent Cancer-treatment Bone Loss in Post-menopausal Women Receiving Adjuvant Letrozole for Breast Cancer
• Study Start Date: Mar 1, 2004
• Actual Primary Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Upfront Zoledronic Acid Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1	Drug: Zoledronic acid; Zoledronic acid 4 mg Intravenous (IV)15 minute infusion every 6 months.; Other Names: ZOL446 Zometa® ; Drug: Letrozole; Letrozole tablets 2.5 mg/day/taken orally for 5 years.; Other Names: Femara®
Experimental: Delayed Zoledronic Acid Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1	Drug: Zoledronic acid; Zoledronic acid 4 mg Intravenous (IV)15 minute infusion every 6 months.; Other Names: ZOL446 Zometa® ; Drug: Letrozole; Letrozole tablets 2.5 mg/day/taken orally for 5 years.; Other Names: Femara®

Outcome Measures

Primary Outcome Measures

1. Percent Change in Lumbar Spine (L2-L4) BMD After 12 Months of Letrozole Therapy [From Baseline - 12 months]

   Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.

Secondary Outcome Measures

1. Percent Change in Lumbar Spine (L2-L4) BMD at 2 Years, 3 Years, 4 Years and 5 Years [From Baseline to Year 2, Year 3, Year 4, Year 5]

   Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.

2. Percent Change in Lumbar Spine (L1-L4) BMD at Year 1, Year 2, Year 3, Year 4 and Year 5 [From Baseline to Year 1, Year 2, Year 3, Year 4, Year 5]

   Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.

3. Percent Change in Total Hip BMD at Year 1, Year 2, Year 3, Year 4 and Year 5 [From baseline to Year 1, Year 2, Year 3, Year 4, Year 5]

   Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.

4. Percentage of Participants With Radiological (Vertebra) Fractures Which Were Not Present at Baseline But Were Present at Year 3 [Year 3]

   Radiological Fracture at 36 months which was not present at baseline = (new fracture/number participant analyzed)*100. Evaluation of radiological fractures were based on central lab X-ray data. A subject with multiple fractures at the same time or multiple fractures with the same grade is counted only once for that treatment.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Stage I-IIIa breast cancer

• Postmenopausal

• Recent surgery for breast cancer

Exclusion Criteria:

• Metastatic disease

• Invasive bilateral disease

• Clinical or radiological evidence of existing fracture in spine or hip

Other protocol-defined inclusion / exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Buenos Aires		Argentina
2	Novartis Investigative Site	Rosario - Santa Fe		Argentina
3	Novartis Investigative Site	Aalst		Belgium
4	Novartis Investigative Site	Anderlecht		Belgium
5	Novartis Investigative Site	Bonheiden		Belgium
6	Novartis Investigative Site	Brasschaat		Belgium
7	Novartis Investigative Site	Bruxelles		Belgium
8	Novartis Investigative Site	Edegem		Belgium
9	Novartis Investigative Site	Hasselt		Belgium
10	Novartis Investigative Site	Leuven		Belgium
11	Novartis Investigative Site	Libramont-Chevigny		Belgium
12	Novartis Investigative Site	Liège		Belgium
13	Novartis Investigative Site	Mons		Belgium
14	Novartis Investigative Site	Ottignies		Belgium
15	Novartis Investigative Site	St. Niklaas		Belgium
16	Novartis Investigative Site	Wilrijk		Belgium
17	Novartis Investigative Site	Yvoir		Belgium
18	Novartis Investigative Site	Limoges		France
19	Novartis Investigative Site	Mougins		France
20	Novartis Investigative Site	Perigueux Cedex		France
21	Novartis Investigative Site	Rennes		France
22	Novartis Investigative Site	Saint Brieuc Cedex		France
23	Novartis Investigative Site	Saint-Herblain Cedex		France
24	Novartis Investigative Site	Toulon Cedex		France
25	Novartis Investigative Site	Vandoeuvre Les Nancy Cedex		France
26	Novartis Investigative Site	Genova		Italy
27	Novartis Investigative Site	Ivrea		Italy
28	Novartis Investigative Site	Lecco		Italy
29	Novartis Investigative Site	Monteforte Irpino (Av)		Italy
30	Novartis Investigative Site	Pietra Ligure		Italy
31	Novartis Investigative Site	Roma		Italy
32	Novartis Investigative Site	Sassari		Italy
33	Novartis Investigative Site	Torino		Italy
34	Novartis Investigative Site	Vicenza		Italy
35	Novartis Investigative Site	Daegu		Korea, Republic of
36	Novartis Investigative Site	Jeollanam-do		Korea, Republic of
37	Novartis Investigative Site	Seoul		Korea, Republic of
38	Novartis Investigative Site	Den Haag		Netherlands
39	Novartis Investigative Site	Eindhoven		Netherlands
40	Novartis Investigative Site	Hoogeveen		Netherlands
41	Novartis Investigative Site	Nijmegen		Netherlands
42	Novartis Investigative Site	Riyadh		Saudi Arabia
43	Novartis Investigative Site	Cape Town		South Africa
44	Novartis Investigative Site	Durban		South Africa
45	Novartis Investigative Site	Johannesburg		South Africa
46	Novartis Investigative Site	Barcelona		Spain
47	Novartis Investigative Site	Cordoba		Spain
48	Novartis Investigative Site	Madrid		Spain
49	Novartis Investigative Site	Valencia		Spain

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00171314
• Other Study ID Numbers: CFEM345D2406
• First Posted: Sep 15, 2005
• Last Update Posted: Apr 11, 2012
• Last Verified: Mar 1, 2012

• Keywords provided by Novartis Pharmaceuticals: breast cancer; letrozole; zoledronic acid; adjuvant; postmenopausal
• Additional relevant MeSH terms: Breast Neoplasms; Zoledronic Acid; Letrozole

Study Results

Participant Flow

Arm/Group Title	Upfront Zoledronic Acid	Delayed Zoledronic Acid
Arm/Group Description	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Period Title: Overall Study
STARTED	263	264
Safety Population	254	269
COMPLETED	172	186
NOT COMPLETED	91	78

Baseline Characteristics

Arm/Group Title	Upfront Zoledronic Acid	Delayed Zoledronic Acid	Total
Arm/Group Description	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Total of all reporting groups
Overall Participants	263	264	527
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.2 (8.19)	58.4 (7.73)	58.29 (7.96)
Sex: Female, Male (Count of Participants)
Female	263 100%	264 100%	527 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percent Change in Lumbar Spine (L2-L4) BMD After 12 Months of Letrozole Therapy
Description	Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.
Time Frame	From Baseline - 12 months

Outcome Measure Data

Analysis Population Description

For the analysis of safety, the safety population for treatment arms were defined by the actual treatment received, rather than the treatment arm assigned by randomization. Participants with observations at baseline and 12 months were included in this analysis.

Arm/Group Title	Upfront Zoledronic Acid	Delayed Zoledronic Acid
Arm/Group Description	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Measure Participants	254	269
Mean (Standard Deviation) [Percent Change]	2.680 (2.8451)	-3.314 (3.9632)

2. Secondary Outcome

Title	Percent Change in Lumbar Spine (L2-L4) BMD at 2 Years, 3 Years, 4 Years and 5 Years
Description	Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.
Time Frame	From Baseline to Year 2, Year 3, Year 4, Year 5

Outcome Measure Data

Analysis Population Description

Analysis of safety:safety population for treatment arms were defined by the actual treatment received, rather than the treatment arm assigned by randomization. "n" in each category indicates participants with data at baseline and each corresponding timepoint.

Arm/Group Title	Upfront Zoledronic Acid	Delayed Zoledronic Acid
Arm/Group Description	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Measure Participants	254	269
Year 2 (n=122,142)	4.136 (3.8182)	-3.924 (4.7442)
Year 3 (n=119,133)	4.777 (4.8959)	-4.297 (5.3583)
Year 4 (n=104, 122)	5.462 (5.2922)	-4.746 (5.6588)
Year 5 (n=86, 102)	6.013 (5.4366)	-4.572 (6.1617)

3. Secondary Outcome

Title	Percent Change in Lumbar Spine (L1-L4) BMD at Year 1, Year 2, Year 3, Year 4 and Year 5
Description	Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.
Time Frame	From Baseline to Year 1, Year 2, Year 3, Year 4, Year 5

Outcome Measure Data

Analysis Population Description

For the analysis of safety, the safety population for treatment arms were defined by the actual treatment received, rather than the treatment arm assigned by randomization.

Arm/Group Title	Upfront Zoledronic Acid	Delayed Zoledronic Acid
Arm/Group Description	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Measure Participants	254	269
Year 1 (n=123, 156)	2.330 (2.7465)	-3.532 (3.7830)
Year 2 (n=122, 142)	3.994 (3.6344)	-3.934 (4.7162)
Year 3 (n=199, 133)	4.523 (4.5197)	-4.292 (5.2317)
Year 4 (n=104, 122)	5.051 (4.9739)	-4.713 (5.4101)
Year 5 (n=86, 102)	5.476 (5.0395)	-4.692 (6.0242)

4. Secondary Outcome

Title	Percent Change in Total Hip BMD at Year 1, Year 2, Year 3, Year 4 and Year 5
Description	Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.
Time Frame	From baseline to Year 1, Year 2, Year 3, Year 4, Year 5

Outcome Measure Data

Analysis Population Description

For the analysis of safety, the safety population for treatment arms were defined by the actual treatment received, rather than the treatment arm assigned by randomization. During different time points, participants with observations at that time point were included in the analysis.

Arm/Group Title	Upfront Zoledronic Acid	Delayed Zoledronic Acid
Arm/Group Description	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Measure Participants	254	269
Year 1 (n=173, 187)	1.637 (2.4371)	-1.644 (2.9994)
Year 2 (n=169, 168)	2.119 (2.9435)	-2.628 (3.5659)
Year 3 (n=163, 162)	1.991 (3.4207)	-3.011 (4.7684)
Year 4 (n=145, 152)	2.439 (3.5236)	-3.074 (5.4515)
Year 5 (n=119, 121)	2.788 (3.8386)	-4.012 (5.1321)

5. Secondary Outcome

Title	Percentage of Participants With Radiological (Vertebra) Fractures Which Were Not Present at Baseline But Were Present at Year 3
Description	Radiological Fracture at 36 months which was not present at baseline = (new fracture/number participant analyzed)*100. Evaluation of radiological fractures were based on central lab X-ray data. A subject with multiple fractures at the same time or multiple fractures with the same grade is counted only once for that treatment.
Time Frame	Year 3

Outcome Measure Data

Analysis Population Description

For the analysis of safety, the safety population for treatment arms were defined by the actual treatment received, rather than the treatment arm assigned by randomization. Participants with observations at Year 3 were included in this analysis.

Arm/Group Title	Upfront Zoledronic Acid	Delayed Zoledronic Acid
Arm/Group Description	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Measure Participants	254	269
Number [Percentage of Participants]	2.8 1.1%	3.3 1.3%

Adverse Events

Arm/Group Title	Upfront Zoledronic Acid		Delayed Zoledronic Acid
Arm/Group Description	Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1		Zoledronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score <= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
All Cause Mortality
	Upfront Zoledronic Acid		Delayed Zoledronic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Upfront Zoledronic Acid		Delayed Zoledronic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/254 (18.5%)		56/269 (20.8%)
Blood and lymphatic system disorders
Anaemia	1/254 (0.4%)		1/269 (0.4%)
Febrile neutropenia	1/254 (0.4%)		0/269 (0%)
Lymphadenopathy	1/254 (0.4%)		0/269 (0%)
Cardiac disorders
Acute myocardial infarction	1/254 (0.4%)		0/269 (0%)
Angina pectoris	0/254 (0%)		3/269 (1.1%)
Angina unstable	0/254 (0%)		1/269 (0.4%)
Bundle branch block left	0/254 (0%)		1/269 (0.4%)
Cardiac failure	4/254 (1.6%)		1/269 (0.4%)
Coronary artery disease	0/254 (0%)		1/269 (0.4%)
Coronary artery stenosis	1/254 (0.4%)		0/269 (0%)
Cytotoxic cardiomyopathy	1/254 (0.4%)		0/269 (0%)
Mitral valve incompetence	1/254 (0.4%)		0/269 (0%)
Myocardial infarction	2/254 (0.8%)		0/269 (0%)
Myocardial ischaemia	1/254 (0.4%)		0/269 (0%)
Palpitations	1/254 (0.4%)		0/269 (0%)
Pericardial effusion	1/254 (0.4%)		0/269 (0%)
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula	1/254 (0.4%)		0/269 (0%)
Endocrine disorders
Goitre	1/254 (0.4%)		0/269 (0%)
Eye disorders
Cataract	1/254 (0.4%)		0/269 (0%)
Cataract cortical	0/254 (0%)		1/269 (0.4%)
Conjunctival hyperaemia	1/254 (0.4%)		0/269 (0%)
Corneal oedema	1/254 (0.4%)		0/269 (0%)
Gastrointestinal disorders
Abdominal pain	1/254 (0.4%)		0/269 (0%)
Abdominal strangulated hernia	0/254 (0%)		1/269 (0.4%)
Constipation	1/254 (0.4%)		0/269 (0%)
Diverticulum	0/254 (0%)		1/269 (0.4%)
Duodenal ulcer haemorrhage	0/254 (0%)		1/269 (0.4%)
Dyspepsia	1/254 (0.4%)		0/269 (0%)
Gingival erosion	0/254 (0%)		1/269 (0.4%)
Gingivitis	0/254 (0%)		1/269 (0.4%)
Large intestine perforation	0/254 (0%)		1/269 (0.4%)
Loose tooth	0/254 (0%)		1/269 (0.4%)
Oesophagitis	0/254 (0%)		1/269 (0.4%)
Pancreatitis acute	1/254 (0.4%)		0/269 (0%)
Peritonitis	1/254 (0.4%)		2/269 (0.7%)
Splenic artery aneurysm	0/254 (0%)		1/269 (0.4%)
Vomiting	0/254 (0%)		1/269 (0.4%)
General disorders
Chest pain	1/254 (0.4%)		0/269 (0%)
Gait disturbance	0/254 (0%)		1/269 (0.4%)
General physical health deterioration	1/254 (0.4%)		0/269 (0%)
Impaired healing	0/254 (0%)		1/269 (0.4%)
Non-cardiac chest pain	1/254 (0.4%)		0/269 (0%)
Sudden death	0/254 (0%)		1/269 (0.4%)
Hepatobiliary disorders
Bile duct stone	1/254 (0.4%)		0/269 (0%)
Cholecystitis	1/254 (0.4%)		0/269 (0%)
Cholecystitis acute	1/254 (0.4%)		1/269 (0.4%)
Cholelithiasis	0/254 (0%)		2/269 (0.7%)
Immune system disorders
Corneal graft rejection	1/254 (0.4%)		0/269 (0%)
Infections and infestations
Abscess jaw	1/254 (0.4%)		0/269 (0%)
Acanthamoeba keratitis	1/254 (0.4%)		0/269 (0%)
Appendicitis	1/254 (0.4%)		1/269 (0.4%)
Breast cellulitis	0/254 (0%)		2/269 (0.7%)
Cellulitis	0/254 (0%)		1/269 (0.4%)
Device related infection	0/254 (0%)		1/269 (0.4%)
Diverticulitis	1/254 (0.4%)		2/269 (0.7%)
Erysipelas	1/254 (0.4%)		0/269 (0%)
Escherichia sepsis	0/254 (0%)		1/269 (0.4%)
Escherichia urinary tract infection	0/254 (0%)		1/269 (0.4%)
Gastroenteritis	1/254 (0.4%)		0/269 (0%)
Influenza	1/254 (0.4%)		0/269 (0%)
Lung infection	0/254 (0%)		1/269 (0.4%)
Osteomyelitis	0/254 (0%)		1/269 (0.4%)
Pleural infection	1/254 (0.4%)		0/269 (0%)
Soft tissue infection	0/254 (0%)		1/269 (0.4%)
Tooth abscess	1/254 (0.4%)		1/269 (0.4%)
Tooth infection	1/254 (0.4%)		0/269 (0%)
Tuberculosis	0/254 (0%)		1/269 (0.4%)
Urogenital infection bacterial	1/254 (0.4%)		0/269 (0%)
Injury, poisoning and procedural complications
Ankle fracture	2/254 (0.8%)		0/269 (0%)
Brain contusion	0/254 (0%)		1/269 (0.4%)
Drug toxicity	0/254 (0%)		2/269 (0.7%)
Fall	2/254 (0.8%)		3/269 (1.1%)
Fracture	0/254 (0%)		1/269 (0.4%)
Hip fracture	0/254 (0%)		2/269 (0.7%)
Intentional overdose	1/254 (0.4%)		0/269 (0%)
Meniscus lesion	1/254 (0.4%)		0/269 (0%)
Muscle rupture	0/254 (0%)		1/269 (0.4%)
Post procedural discomfort	1/254 (0.4%)		0/269 (0%)
Radius fracture	1/254 (0.4%)		0/269 (0%)
Tibia fracture	1/254 (0.4%)		0/269 (0%)
Investigations
Computerised tomogram thorax abnormal	1/254 (0.4%)		0/269 (0%)
Weight increased	0/254 (0%)		1/269 (0.4%)
Metabolism and nutrition disorders
Dehydration	0/254 (0%)		1/269 (0.4%)
Metabolic alkalosis	0/254 (0%)		1/269 (0.4%)
Obesity	0/254 (0%)		1/269 (0.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/254 (0.8%)		2/269 (0.7%)
Back pain	0/254 (0%)		2/269 (0.7%)
Bone fistula	1/254 (0.4%)		0/269 (0%)
Bone pain	0/254 (0%)		1/269 (0.4%)
Foot deformity	0/254 (0%)		1/269 (0.4%)
Intervertebral disc protrusion	1/254 (0.4%)		3/269 (1.1%)
Lumbar spinal stenosis	1/254 (0.4%)		0/269 (0%)
Myositis	0/254 (0%)		1/269 (0.4%)
Osteoarthritis	2/254 (0.8%)		5/269 (1.9%)
Osteonecrosis of jaw	3/254 (1.2%)		1/269 (0.4%)
Pain in jaw	1/254 (0.4%)		0/269 (0%)
Primary sequestrum	1/254 (0.4%)		0/269 (0%)
Synovial cyst	0/254 (0%)		1/269 (0.4%)
Trigger finger	1/254 (0.4%)		0/269 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/254 (0%)		1/269 (0.4%)
Benign gastric neoplasm	1/254 (0.4%)		0/269 (0%)
Breast cancer	1/254 (0.4%)		0/269 (0%)
Colon adenoma	1/254 (0.4%)		0/269 (0%)
Fibroadenoma of breast	0/254 (0%)		1/269 (0.4%)
Laryngeal cancer	1/254 (0.4%)		0/269 (0%)
Malignant melanoma	1/254 (0.4%)		0/269 (0%)
Metastases to spine	0/254 (0%)		1/269 (0.4%)
Renal cancer	0/254 (0%)		1/269 (0.4%)
Thyroid cancer	0/254 (0%)		1/269 (0.4%)
Uterine leiomyoma	1/254 (0.4%)		0/269 (0%)
Nervous system disorders
Amnestic disorder	0/254 (0%)		1/269 (0.4%)
Carpal tunnel syndrome	1/254 (0.4%)		0/269 (0%)
Cerebral haemorrhage	0/254 (0%)		1/269 (0.4%)
Chronic inflammatory demyelinating polyradiculoneuropathy	0/254 (0%)		1/269 (0.4%)
Hypoaesthesia	0/254 (0%)		1/269 (0.4%)
Ischaemic stroke	1/254 (0.4%)		0/269 (0%)
Monoplegia	0/254 (0%)		1/269 (0.4%)
Paraesthesia	0/254 (0%)		1/269 (0.4%)
Parkinson's disease	0/254 (0%)		1/269 (0.4%)
Sciatica	1/254 (0.4%)		2/269 (0.7%)
Psychiatric disorders
Apathy	0/254 (0%)		1/269 (0.4%)
Depression	0/254 (0%)		3/269 (1.1%)
Mental disorder	1/254 (0.4%)		1/269 (0.4%)
Mutism	0/254 (0%)		1/269 (0.4%)
Suicide attempt	1/254 (0.4%)		2/269 (0.7%)
Renal and urinary disorders
Nephrolithiasis	1/254 (0.4%)		0/269 (0%)
Renal failure acute	1/254 (0.4%)		0/269 (0%)
Stress urinary incontinence	0/254 (0%)		1/269 (0.4%)
Urinary incontinence	0/254 (0%)		1/269 (0.4%)
Reproductive system and breast disorders
Cervical dysplasia	1/254 (0.4%)		0/269 (0%)
Ovarian cyst	3/254 (1.2%)		1/269 (0.4%)
Postmenopausal haemorrhage	1/254 (0.4%)		0/269 (0%)
Uterine prolapse	0/254 (0%)		1/269 (0.4%)
Vaginal discharge	0/254 (0%)		1/269 (0.4%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/254 (0.4%)		0/269 (0%)
Dyspnoea exertional	0/254 (0%)		2/269 (0.7%)
Lung infiltration	0/254 (0%)		1/269 (0.4%)
Pulmonary embolism	2/254 (0.8%)		1/269 (0.4%)
Pulmonary infarction	0/254 (0%)		1/269 (0.4%)
Pulmonary oedema	1/254 (0.4%)		0/269 (0%)
Respiratory failure	1/254 (0.4%)		0/269 (0%)
Vocal cord polyp	1/254 (0.4%)		0/269 (0%)
Skin and subcutaneous tissue disorders
Erythema	1/254 (0.4%)		0/269 (0%)
Hyperhidrosis	1/254 (0.4%)		0/269 (0%)
Vascular disorders
Circulatory collapse	0/254 (0%)		1/269 (0.4%)
Lymphoedema	0/254 (0%)		1/269 (0.4%)
Vasoconstriction	0/254 (0%)		1/269 (0.4%)
Venous insufficiency	1/254 (0.4%)		0/269 (0%)
Other (Not Including Serious) Adverse Events
	Upfront Zoledronic Acid		Delayed Zoledronic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	225/254 (88.6%)		240/269 (89.2%)
Gastrointestinal disorders
Constipation	20/254 (7.9%)		16/269 (5.9%)
Nausea	24/254 (9.4%)		21/269 (7.8%)
General disorders
Asthenia	26/254 (10.2%)		36/269 (13.4%)
Fatigue	46/254 (18.1%)		57/269 (21.2%)
Influenza like illness	18/254 (7.1%)		5/269 (1.9%)
Oedema peripheral	20/254 (7.9%)		26/269 (9.7%)
Pyrexia	21/254 (8.3%)		3/269 (1.1%)
Infections and infestations
Bronchitis	10/254 (3.9%)		16/269 (5.9%)
Influenza	14/254 (5.5%)		9/269 (3.3%)
Nasopharyngitis	12/254 (4.7%)		14/269 (5.2%)
Investigations
Weight increased	33/254 (13%)		23/269 (8.6%)
Metabolism and nutrition disorders
Hypercholesterolaemia	24/254 (9.4%)		33/269 (12.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	123/254 (48.4%)		136/269 (50.6%)
Back pain	41/254 (16.1%)		36/269 (13.4%)
Bone pain	27/254 (10.6%)		21/269 (7.8%)
Muscle spasms	7/254 (2.8%)		15/269 (5.6%)
Musculoskeletal pain	26/254 (10.2%)		34/269 (12.6%)
Musculoskeletal stiffness	10/254 (3.9%)		16/269 (5.9%)
Myalgia	33/254 (13%)		35/269 (13%)
Osteoarthritis	11/254 (4.3%)		18/269 (6.7%)
Pain in extremity	26/254 (10.2%)		46/269 (17.1%)
Nervous system disorders
Headache	24/254 (9.4%)		28/269 (10.4%)
Paraesthesia	7/254 (2.8%)		15/269 (5.6%)
Psychiatric disorders
Anxiety	17/254 (6.7%)		22/269 (8.2%)
Depression	13/254 (5.1%)		24/269 (8.9%)
Insomnia	20/254 (7.9%)		11/269 (4.1%)
Reproductive system and breast disorders
Vulvovaginal dryness	13/254 (5.1%)		11/269 (4.1%)
Respiratory, thoracic and mediastinal disorders
Cough	15/254 (5.9%)		17/269 (6.3%)
Skin and subcutaneous tissue disorders
Alopecia	9/254 (3.5%)		21/269 (7.8%)
Vascular disorders
Hot flush	66/254 (26%)		101/269 (37.5%)
Hypertension	32/254 (12.6%)		25/269 (9.3%)
Lymphoedema	20/254 (7.9%)		19/269 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.