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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00050011
• Collaborator: (none)
• Enrollment: 602
• Locations: 44
• Arms: 2
• Duration (Months): 76
• Patients Per Site: 13.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This protocol is designed to compare the effect on bone of Zoledronic Acid 4 mg every 6 months when given upfront versus delayed start (based on a post-baseline BMD T- Score below -2.0 SD at either the lumbar spine or total hip, or any clinical fracture unrelated to trauma, or an asymptomatic fracture discovered at the month 36 scheduled visit) in stage I-IIIb postmenopausal women with hormone receptor positive breast cancer who will receive Letrozole 2.5 mg daily as an adjuvant therapy.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms; Osteoporosis	Drug: Zoledronic Acid; Drug: Letrozole	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 602 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: An Open-Label, Randomized, Multicenter Study to Evaluate the Use of Zoledronic Acid in the Prevention of Cancer Treatment-Related Bone Loss in Postmenopausal Women With Estrogen Receptor Positive and/or Progesterone Receptor Positive Breast Cancer Receiving Letrozole as Adjuvant Therapy
• Study Start Date: Sep 1, 2002
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zoledronic Acid upfront Participants in the upfront arm received zoledronate 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.	Drug: Zoledronic Acid; Participants received Zoledronate 4 mg IV 15-minute infusion every 6 months.; Other Names: ZOL446 Zoledronate ; Drug: Letrozole; Participants received Letrozole 2.5 mg daily.; Other Names: Femara
Experimental: Zoledronate delayed-start 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 zoledronate 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.	Drug: Zoledronic Acid; Participants received Zoledronate 4 mg IV 15-minute infusion every 6 months.; Other Names: ZOL446 Zoledronate ; Drug: Letrozole; Participants received Letrozole 2.5 mg daily.; Other Names: Femara

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Lumbar Spine (L1-L4) Bone Mineral Density (BMD) [Baseline, 12 months]

   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.

Secondary Outcome Measures

1. Percent Change From Baseline in Lumbar Spine (L1-L4) BMD [Baseline, 2 years, 3 years, 5 years]

   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.

2. Percent Change From Baseline in Total Hip BMD [Baseline, 12 months, 2 years, 3 years, 5 years]

   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.

3. Percent Change From Baseline in Biochemical Markers of Bone Turnover, Serum N-Telopeptide (sNTX) and Bone-specific Alkaline Phosphatase (BSAP) [Baseline, 12 months, 2 years, 3 years, 5 years]

   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.

4. Incidence Rate of All Clinical Fractures [3 years]

   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.

5. Time to Disease Recurrence/Relapse [over 5 years]

   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.

6. Rate of Change From Baseline in Lumbar Spine (L1-L4) BMD [Baseline, 5 years]

   The rate of change from baseline in BMD was assessed.

7. Rate of Change From Baseline in Total Hip BMD [Baseline, 5 years]

   The rate of change from baseline in BMD was assessed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Signed informed consent

2. Postmenopausal status defined by one of the following :

• women equal to or greater than 55 years with cessation of menses

• spontaneous cessation of menses within the past 1 year, but amenorrheic in women less than or equal to 55 years (e.g., spontaneous or secondary to hysterectomy), and with postmenopausal gonadotrophin levels (follicle stimulating hormone levels

40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratory involved

• bilateral oophorectomy (prior to the diagnosis of breast cancer).

1. Adequately diagnosed and treated breast cancer defined as:

• Patients with breast cancer whose tumor can be removed by an appropriate surgical procedure such as mastectomy or breast conserving surgery and who receive appropriate additional local treatments such as radiotherapy according to best practice.

• Patients must be at the end of their local treatment without evidence of local residual disease.

• Patients must have no clinical or radiological evidence of distant metastasis.

1. Hormone receptor positive defined as:

• ER and/or PR greater than or equal to1 0 fmol/mg cytosol protein; or greater than or equal to 10% of the tumor cells positive by

• immunohistochemical evaluation.

1. Patients with a baseline lumbar spine and total hip BMD T-score at or above -2.0 SD are eligible.

2. Patients who will receive adjuvant chemotherapy are eligible for participation. Adjuvant chemotherapy must be completed prior to randomization.

3. The date of randomization must not be more than the following:

• 12 weeks from completion of surgery;

• 12 weeks after completion of adjuvant chemotherapy;

• 12 weeks after completion of surgery and radiation therapy; however the patient may be randomized while receiving radiation therapy - this decision is at the Investigator's discretion.

• 12 weeks after completion of chemotherapy and radiation therapy; however, the patient may be randomized while receiving radiation therapy - this decision is at the Investigator's discretion.

1. Patients who have undergone neoadjuvant chemotherapy are eligible.

2. No prior treatment with Femara.

Exclusion criteria:

1. Patients with any clinical or radiological evidence of distant spread of their disease at any point before randomization.

2. Patients with clinical or radiological evidence of existing fracture in the lumbar spine and/or total hip.

3. Patients with a history of fracture with low-intensity or no associated trauma.

4. Patients who have started adjuvant hormonal therapy or who have completed adjuvant hormonal therapy prior to randomization.

5. Patients who have received any endocrine therapy within the past 12 months (other than neoadjuvant tamoxifen or toremifene, insulin and/or oral anti-diabetic medications, and thyroid hormone replacement). Hormone replacement therapy must be discontinued prior to randomization.

6. Patients who have received prior treatment with intravenous bisphosphonates within the past 12 months.

7. Patients currently receiving oral bisphosphonates. Oral bisphosphonates must be discontinued within 3 weeks of baseline evaluations.

8. Patients who have received prior treatment with systemic corticosteroids within the past 12 months (short term corticosteroid therapy, e.g. to prevent/treat chemotherapy-induced nausea/vomiting, is acceptable).

9. Patients with prior exposure to anabolic steroids or growth hormone within the past 6 months.

10. Patients with prior use of Tibolone within the last 6 months.

11. Any prior use of PTH for more than 1 week.

12. Prior use of systemic sodium fluoride for > 3 months during the past 2 years.

13. Patients currently treated with any drugs known to affect the skeleton (e.g., calcitonin, mithramycin, or gallium nitrate) within 2 weeks prior to randomization.

14. Patients with previous or concomitant malignancy (not breast cancer) within the past 5 years EXCEPT adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix. Patients who have had a previous other malignancy must have been disease free for five years.

15. Patients with other non-malignant systemic diseases including uncontrolled infections, uncontrolled type 2 diabetes mellitus, uncontrolled thyroid dysfunction, cardiovascular, renal, hepatic, and lung diseases which would prevent prolonged follow-up. Patients with previous history of thrombosis or thromboembolism can be included only if medically suitable. Patients with a known history of HIV are excluded.

16. Uncontrolled seizure disorders associated with falls.

17. Patients with abnormal renal function as evidenced by a serum creatinine equal to or greater than 3 mg/dL (265.2 mmol/L).

18. History of diseases with influence on bone metabolism, such as Paget's disease, Osteogenesis Imperfecta, and primary or secondary hyperthyroidism within 12 months prior to study entry.

19. Patients with baseline lumber spine or total hip BMD T-score below -2.0 SD.

20. Patients treated with systemic investigational drug(s) and/or device(s) within the past 30 days or topical investigational drugs within the past 7 days.

Additional Exclusion Criteria: (for Spine DXA)

• History of surgery at the lumbosacral spine, with or without implantable devices.

• Scoliosis with a Cobb angle >15 degree at the lumbar spine.

• Immobility, hyperostosis or sclerotic changes at the lumbar spine, or evidence of sclerotic abdominal aorta sufficient to interfere with DXA scan.

• Any disease of the spine that would preclude the proper acquisition of a lumbar spine DXA.

Additional protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Highlands Oncology Group	Springdale	Arkansas	United States	72764
2	East Valley Hematology & Oncology	Burbank	California	United States	91505
3	Louisiana Oncology Associates	Lafayette	California	United States	70506
4	Wilshire Oncology Medical Group	LaVerne	California	United States	91750
5	Pacific Shores Medical Group	Long Beach	California	United States	90813
6	Clinical Trials & Research Associates, Inc.	Montebello	California	United States	90640
7	Redwood Regional Medical Group	Santa Rosa	California	United States	95403
8	Cancer and Blood Institute of the Desert	Rancho Mirage	Colorado	United States	92270
9	Eastern Connecticut Hematology/Oncology Associates	Norwich	Connecticut	United States	06360
10	FL Community Cancer Center	Brooksville	Florida	United States	34613
11	Robert R. Carroll, MD, PA	Gainesville	Florida	United States	32605
12	Oncology Hematology Group of South Florida	Miami	Florida	United States	33176
13	Pasco Pinellas Cancer Center	New Port Richey	Florida	United States	34652
14	Ocala Oncology Center	Ocala	Florida	United States	33479
15	Cancer Research Network, Inc.	Plantation	Florida	United States	33324
16	Bay Area Oncology	Tampa	Florida	United States	33607
17	Space Coast Medical	Titusville	Florida	United States	32796
18	Elmhurst Memorial Hospital	Elhurst	Illinois	United States	60126
19	Kentuckiana Cancer Institute	Louisville	Kentucky	United States	40202
20	Frederick Memorial Hospital Regional Cancer Therapy Center	Frederick	Maryland	United States	21701
21	New England Hematology/Oncology Associates	Wellesley	Massachusetts	United States	02481
22	Cook Research Department at Spectrum Health	Grand Rapids	Michigan	United States	49503
23	Metro Minnesota CCOP	St. Louis Park	Minnesota	United States	55416
24	Hematology-Oncology Centers of the Northern Rockies, PC	Billings	Montana	United States	59101
25	Methodist Cancer Center	Omaha	Nebraska	United States	68114
26	Hematology-Oncology Associates of Northern NJ	Morristown	New Jersey	United States	07962
27	New Mexico Oncology Hematology, Ltd.	Albuquerque	New Mexico	United States	87109
28	Hemoncare PC	Brooklyn	New York	United States	11235
29	Odyssey Research Services	Bismarck	North Dakota	United States	58501
30	Nashat Y. Gabrail MD Inc.	Canton	Ohio	United States	44718
31	Oncology Partners Network	Cincinnati	Ohio	United States	45238
32	Physician Associates, Inc.	Cincinnati	Ohio	United States	45238
33	Dayton Clinical Oncology Program	Dayton	Ohio	United States	45420
34	University of Pittsburgh Cancer Institute/Magee Womens Hospital	Pittsburgh	Pennsylvania	United States	15213
35	Charleston Hematology Oncology	Charleston	South Carolina	United States	29403
36	The Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203
37	St. Joseph Regional Cancer Center	Bryan	Texas	United States	77802
38	Cancer Specialists of South Texas	Corpus Christi	Texas	United States	78412
39	Center for Oncology Research & Tx. PA	Dallas	Texas	United States	75230
40	Northern Virginia Oncology Group	Fairfax	Virginia	United States	22031
41	Virginia Physicians, Inc.- Oncology	Richmond	Virginia	United States	23294
42	Swedish Cancer Institute	Seattle	Washington	United States	98122
43	Rockwood Clinic, PS	Spokane	Washington	United States	99220
44	VA Medical Center	San Juan		Puerto Rico	00927

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, MD, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00050011
• Other Study ID Numbers: CZOL446EUS32
• First Posted: Nov 20, 2002
• Last Update Posted: Mar 21, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by Novartis Pharmaceuticals: cancer-treatment related bone loss; postmenopausal women; breast cancer; hormone receptor positive breast cancer; adjuvant therapy; hormonal therapy; bone loss; bisphosphonates; ZFAST; Letrozole; Zoledronic Acid; US32
• Additional relevant MeSH terms: Breast Neoplasms; Osteoporosis; Zoledronic Acid; Letrozole

Study Results

Participant Flow

Pre-assignment Detail	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

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 Participants	301	301	602
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.4 (9.28)	61.0 (8.92)	61.2 (9.1)
Sex: Female, Male (Count of Participants)
Female	301 100%	301 100%	602 100%
Male	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.
Measure Participants	253	256
Mean (Standard Deviation) [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.
Measure Participants	300	300
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.
Measure Participants	300	300
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.
Measure Participants	300	300
sNTX, 12 months (n=87,85)	-20.1 (42.1)	21.7 (55.2)
sNTX, 2 years	NA (NA)	NA (NA)
sNTX, 3 years	NA (NA)	NA (NA)
sNTX, 5 years	NA (NA)	NA (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)

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.
Measure Participants	300	300
Number [Participants]	18 6%	21 7%

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.
Measure Participants	300	300
Median (95% Confidence Interval) [months]	NA	NA

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.
Measure Participants	300	300
Mean (95% Confidence Interval) [g/sq cm/month]	0.01043	-0.00157

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.
Measure Participants	300	300
Mean (95% Confidence Interval) [g/sq. cm/month]	0.00226	-0.00625

Adverse Events

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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zoledronic Acid Upfront		Zoledronic Acid Delayed-start
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/300 (27.7%)		71/300 (23.7%)
Blood and lymphatic system disorders
Anaemia	2/300 (0.7%)		0/300 (0%)
Granulocytopenia	1/300 (0.3%)		0/300 (0%)
Iron deficiency anaemia	1/300 (0.3%)		1/300 (0.3%)
Thrombocytopenia	0/300 (0%)		1/300 (0.3%)
Cardiac disorders
Acute coronary syndrome	1/300 (0.3%)		0/300 (0%)
Acute myocardial infarction	2/300 (0.7%)		1/300 (0.3%)
Angina pectoris	2/300 (0.7%)		1/300 (0.3%)
Aortic valve stenosis	1/300 (0.3%)		0/300 (0%)
Atrial fibrillation	4/300 (1.3%)		4/300 (1.3%)
Cardiac failure	0/300 (0%)		1/300 (0.3%)
Cardiac failure chronic	1/300 (0.3%)		0/300 (0%)
Cardiac failure congestive	2/300 (0.7%)		2/300 (0.7%)
Cardio-respiratory arrest	0/300 (0%)		1/300 (0.3%)
Cardiomyopathy	0/300 (0%)		1/300 (0.3%)
Cardiomyopathy acute	1/300 (0.3%)		0/300 (0%)
Coronary artery disease	1/300 (0.3%)		4/300 (1.3%)
Coronary artery occlusion	0/300 (0%)		4/300 (1.3%)
Coronary artery stenosis	1/300 (0.3%)		2/300 (0.7%)
Dilatation ventricular	1/300 (0.3%)		0/300 (0%)
Ischaemic cardiomyopathy	1/300 (0.3%)		0/300 (0%)
Left ventricular dysfunction	0/300 (0%)		1/300 (0.3%)
Myocardial infarction	2/300 (0.7%)		1/300 (0.3%)
Myocardial ischaemia	0/300 (0%)		1/300 (0.3%)
Sinus bradycardia	1/300 (0.3%)		0/300 (0%)
Eye disorders
Blindness unilateral	1/300 (0.3%)		0/300 (0%)
Retinal artery occlusion	1/300 (0.3%)		0/300 (0%)
Visual acuity reduced	1/300 (0.3%)		0/300 (0%)
Gastrointestinal disorders
Abdominal distension	0/300 (0%)		1/300 (0.3%)
Abdominal pain	1/300 (0.3%)		2/300 (0.7%)
Abdominal pain upper	0/300 (0%)		1/300 (0.3%)
Aphthous stomatitis	1/300 (0.3%)		0/300 (0%)
Colitis ulcerative	2/300 (0.7%)		0/300 (0%)
Crohn's disease	0/300 (0%)		1/300 (0.3%)
Duodenal ulcer perforation	1/300 (0.3%)		0/300 (0%)
Enterovesical fistula	1/300 (0.3%)		0/300 (0%)
Gastrointestinal haemorrhage	1/300 (0.3%)		0/300 (0%)
Intestinal obstruction	0/300 (0%)		1/300 (0.3%)
Large intestine perforation	1/300 (0.3%)		0/300 (0%)
Nausea	2/300 (0.7%)		0/300 (0%)
Oesophageal mass	0/300 (0%)		1/300 (0.3%)
Oesophageal spasm	0/300 (0%)		1/300 (0.3%)
Peritonitis	1/300 (0.3%)		0/300 (0%)
Rectal haemorrhage	1/300 (0.3%)		0/300 (0%)
Small intestinal obstruction	1/300 (0.3%)		0/300 (0%)
Vomiting	1/300 (0.3%)		0/300 (0%)
General disorders
Adverse drug reaction	1/300 (0.3%)		0/300 (0%)
Asthenia	1/300 (0.3%)		1/300 (0.3%)
Chest discomfort	0/300 (0%)		1/300 (0.3%)
Chest pain	3/300 (1%)		1/300 (0.3%)
Non-cardiac chest pain	2/300 (0.7%)		0/300 (0%)
Pain	0/300 (0%)		1/300 (0.3%)
Pyrexia	1/300 (0.3%)		0/300 (0%)
Hepatobiliary disorders
Cholecystitis	4/300 (1.3%)		2/300 (0.7%)
Cholelithiasis	2/300 (0.7%)		1/300 (0.3%)
Cholelithiasis obstructive	1/300 (0.3%)		0/300 (0%)
Ischaemic hepatitis	0/300 (0%)		1/300 (0.3%)
Immune system disorders
Drug hypersensitivity	0/300 (0%)		1/300 (0.3%)
Infections and infestations
Abdominal wall abscess	0/300 (0%)		1/300 (0.3%)
Abscess limb	0/300 (0%)		1/300 (0.3%)
Appendicitis	1/300 (0.3%)		3/300 (1%)
Arthritis bacterial	0/300 (0%)		1/300 (0.3%)
Breast abscess	1/300 (0.3%)		0/300 (0%)
Breast cellulitis	1/300 (0.3%)		0/300 (0%)
Bronchitis	0/300 (0%)		2/300 (0.7%)
Cellulitis	2/300 (0.7%)		2/300 (0.7%)
Gastroenteritis	0/300 (0%)		1/300 (0.3%)
Helicobacter infection	1/300 (0.3%)		0/300 (0%)
Incision site infection	1/300 (0.3%)		0/300 (0%)
Liver abscess	0/300 (0%)		1/300 (0.3%)
Mastitis	1/300 (0.3%)		1/300 (0.3%)
Osteomyelitis chronic	1/300 (0.3%)		0/300 (0%)
Pneumonia	4/300 (1.3%)		3/300 (1%)
Postoperative wound infection	1/300 (0.3%)		0/300 (0%)
Pyelonephritis	1/300 (0.3%)		0/300 (0%)
Septic shock	1/300 (0.3%)		0/300 (0%)
Skin bacterial infection	0/300 (0%)		1/300 (0.3%)
Staphylococcal infection	0/300 (0%)		2/300 (0.7%)
Upper respiratory tract infection	1/300 (0.3%)		0/300 (0%)
Urinary tract infection	1/300 (0.3%)		2/300 (0.7%)
Urosepsis	1/300 (0.3%)		0/300 (0%)
Viral infection	2/300 (0.7%)		0/300 (0%)
Viral upper respiratory tract infection	1/300 (0.3%)		0/300 (0%)
Injury, poisoning and procedural complications
Accident	1/300 (0.3%)		0/300 (0%)
Accidental overdose	0/300 (0%)		1/300 (0.3%)
Ankle fracture	1/300 (0.3%)		0/300 (0%)
Arthropod bite	0/300 (0%)		1/300 (0.3%)
Brain contusion	1/300 (0.3%)		0/300 (0%)
Breast injury	1/300 (0.3%)		0/300 (0%)
Contusion	1/300 (0.3%)		2/300 (0.7%)
Device breakage	0/300 (0%)		1/300 (0.3%)
Fall	10/300 (3.3%)		7/300 (2.3%)
Femoral neck fracture	0/300 (0%)		1/300 (0.3%)
Fibula fracture	1/300 (0.3%)		0/300 (0%)
Foot fracture	1/300 (0.3%)		0/300 (0%)
Hand fracture	1/300 (0.3%)		0/300 (0%)
Head injury	0/300 (0%)		1/300 (0.3%)
Humerus fracture	1/300 (0.3%)		0/300 (0%)
Intentional overdose	1/300 (0.3%)		0/300 (0%)
Joint dislocation	1/300 (0.3%)		1/300 (0.3%)
Joint sprain	1/300 (0.3%)		0/300 (0%)
Meniscus lesion	1/300 (0.3%)		0/300 (0%)
Multiple fractures	0/300 (0%)		1/300 (0.3%)
Post procedural complication	1/300 (0.3%)		0/300 (0%)
Post procedural haematoma	1/300 (0.3%)		0/300 (0%)
Postoperative ileus	0/300 (0%)		1/300 (0.3%)
Procedural nausea	0/300 (0%)		1/300 (0.3%)
Procedural vomiting	0/300 (0%)		1/300 (0.3%)
Radius fracture	1/300 (0.3%)		1/300 (0.3%)
Rib fracture	0/300 (0%)		1/300 (0.3%)
Road traffic accident	0/300 (0%)		2/300 (0.7%)
Skull fracture	0/300 (0%)		1/300 (0.3%)
Subdural haematoma	1/300 (0.3%)		1/300 (0.3%)
Thoracic vertebral fracture	0/300 (0%)		1/300 (0.3%)
Tibia fracture	1/300 (0.3%)		0/300 (0%)
Traumatic brain injury	0/300 (0%)		1/300 (0.3%)
Traumatic intracranial haemorrhage	0/300 (0%)		1/300 (0.3%)
Ulna fracture	1/300 (0.3%)		1/300 (0.3%)
Upper limb fracture	1/300 (0.3%)		1/300 (0.3%)
Wrist fracture	1/300 (0.3%)		0/300 (0%)
Investigations
Bone density decreased	1/300 (0.3%)		0/300 (0%)
Electrocardiogram T wave inversion	1/300 (0.3%)		0/300 (0%)
Metabolism and nutrition disorders
Dehydration	0/300 (0%)		1/300 (0.3%)
Diabetes mellitus inadequate control	1/300 (0.3%)		0/300 (0%)
Hyponatraemia	0/300 (0%)		1/300 (0.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/300 (0.3%)		1/300 (0.3%)
Foot deformity	1/300 (0.3%)		0/300 (0%)
Intervertebral disc protrusion	1/300 (0.3%)		0/300 (0%)
Musculoskeletal chest pain	1/300 (0.3%)		0/300 (0%)
Musculoskeletal pain	0/300 (0%)		1/300 (0.3%)
Neck pain	1/300 (0.3%)		1/300 (0.3%)
Osteoarthritis	9/300 (3%)		9/300 (3%)
Osteonecrosis	2/300 (0.7%)		2/300 (0.7%)
Osteoporosis	0/300 (0%)		1/300 (0.3%)
Pain in jaw	0/300 (0%)		1/300 (0.3%)
Rhabdomyolysis	0/300 (0%)		1/300 (0.3%)
Rotator cuff syndrome	1/300 (0.3%)		0/300 (0%)
Scoliosis	1/300 (0.3%)		0/300 (0%)
Spinal column stenosis	1/300 (0.3%)		0/300 (0%)
Spondylolisthesis	0/300 (0%)		1/300 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	1/300 (0.3%)		0/300 (0%)
Acute myelomonocytic leukaemia	1/300 (0.3%)		0/300 (0%)
Benign lung neoplasm	0/300 (0%)		1/300 (0.3%)
Bladder cancer	1/300 (0.3%)		0/300 (0%)
Bladder neoplasm	1/300 (0.3%)		0/300 (0%)
Bladder transitional cell carcinoma	1/300 (0.3%)		0/300 (0%)
Breast cancer	0/300 (0%)		1/300 (0.3%)
Degeneration of uterine fibroid	1/300 (0.3%)		0/300 (0%)
Lung carcinoma cell type unspecified stage I	1/300 (0.3%)		0/300 (0%)
Meningioma	1/300 (0.3%)		0/300 (0%)
Ovarian cancer	1/300 (0.3%)		1/300 (0.3%)
Pancreatic carcinoma	0/300 (0%)		1/300 (0.3%)
Spindle cell sarcoma	0/300 (0%)		1/300 (0.3%)
Ureteric cancer	1/300 (0.3%)		0/300 (0%)
Nervous system disorders
Altered state of consciousness	0/300 (0%)		1/300 (0.3%)
Amyotrophic lateral sclerosis	0/300 (0%)		1/300 (0.3%)
Ataxia	1/300 (0.3%)		0/300 (0%)
Cerebral haemorrhage	1/300 (0.3%)		0/300 (0%)
Cerebrovascular accident	2/300 (0.7%)		3/300 (1%)
Dementia	0/300 (0%)		1/300 (0.3%)
Dizziness	1/300 (0.3%)		0/300 (0%)
Haemorrhage intracranial	1/300 (0.3%)		0/300 (0%)
Hepatic encephalopathy	1/300 (0.3%)		0/300 (0%)
Loss of consciousness	0/300 (0%)		1/300 (0.3%)
Lumbar radiculopathy	1/300 (0.3%)		0/300 (0%)
Multiple sclerosis	1/300 (0.3%)		0/300 (0%)
Subdural hygroma	0/300 (0%)		1/300 (0.3%)
Syncope	2/300 (0.7%)		1/300 (0.3%)
Transient ischaemic attack	1/300 (0.3%)		0/300 (0%)
Psychiatric disorders
Alcoholism	1/300 (0.3%)		0/300 (0%)
Confusional state	1/300 (0.3%)		0/300 (0%)
Depression	1/300 (0.3%)		0/300 (0%)
Suicide attempt	1/300 (0.3%)		0/300 (0%)
Renal and urinary disorders
Calculus ureteric	1/300 (0.3%)		0/300 (0%)
Cystitis haemorrhagic	1/300 (0.3%)		0/300 (0%)
Renal failure	1/300 (0.3%)		0/300 (0%)
Reproductive system and breast disorders
Breast cyst	1/300 (0.3%)		0/300 (0%)
Cystocele	0/300 (0%)		2/300 (0.7%)
Ovarian cyst	1/300 (0.3%)		2/300 (0.7%)
Rectocele	0/300 (0%)		1/300 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/300 (0%)		1/300 (0.3%)
Acute respiratory failure	1/300 (0.3%)		0/300 (0%)
Bronchospasm	0/300 (0%)		1/300 (0.3%)
Chronic obstructive pulmonary disease	1/300 (0.3%)		2/300 (0.7%)
Dyspnoea	2/300 (0.7%)		1/300 (0.3%)
Mediastinal mass	0/300 (0%)		1/300 (0.3%)
Pleural effusion	0/300 (0%)		1/300 (0.3%)
Pleurisy	1/300 (0.3%)		0/300 (0%)
Pneumothorax	0/300 (0%)		3/300 (1%)
Pulmonary embolism	1/300 (0.3%)		2/300 (0.7%)
Pulmonary mass	0/300 (0%)		1/300 (0.3%)
Respiratory failure	1/300 (0.3%)		0/300 (0%)
Skin and subcutaneous tissue disorders
Subcutaneous emphysema	0/300 (0%)		1/300 (0.3%)
Urticaria	0/300 (0%)		1/300 (0.3%)
Vascular disorders
Deep vein thrombosis	3/300 (1%)		4/300 (1.3%)
Haemorrhage	1/300 (0.3%)		0/300 (0%)
Hypertension	1/300 (0.3%)		0/300 (0%)
Jugular vein distension	1/300 (0.3%)		0/300 (0%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid Upfront		Zoledronic Acid Delayed-start
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	283/300 (94.3%)		275/300 (91.7%)
Blood and lymphatic system disorders
Anaemia	13/300 (4.3%)		20/300 (6.7%)
Gastrointestinal disorders
Constipation	29/300 (9.7%)		28/300 (9.3%)
Diarrhoea	25/300 (8.3%)		31/300 (10.3%)
Gastrooesophageal reflux disease	16/300 (5.3%)		15/300 (5%)
Nausea	39/300 (13%)		40/300 (13.3%)
General disorders
Chest pain	18/300 (6%)		9/300 (3%)
Fatigue	101/300 (33.7%)		88/300 (29.3%)
Oedema peripheral	36/300 (12%)		30/300 (10%)
Pain	16/300 (5.3%)		14/300 (4.7%)
Pyrexia	28/300 (9.3%)		14/300 (4.7%)
Infections and infestations
Bronchitis	17/300 (5.7%)		6/300 (2%)
Sinusitis	19/300 (6.3%)		15/300 (5%)
Upper respiratory tract infection	26/300 (8.7%)		26/300 (8.7%)
Urinary tract infection	37/300 (12.3%)		26/300 (8.7%)
Metabolism and nutrition disorders
Hypercholesterolaemia	21/300 (7%)		17/300 (5.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	141/300 (47%)		136/300 (45.3%)
Arthritis	22/300 (7.3%)		19/300 (6.3%)
Back pain	44/300 (14.7%)		52/300 (17.3%)
Bone pain	48/300 (16%)		24/300 (8%)
Muscle spasms	15/300 (5%)		17/300 (5.7%)
Musculoskeletal chest pain	17/300 (5.7%)		8/300 (2.7%)
Musculoskeletal pain	33/300 (11%)		22/300 (7.3%)
Myalgia	61/300 (20.3%)		47/300 (15.7%)
Neck pain	16/300 (5.3%)		8/300 (2.7%)
Pain in extremity	45/300 (15%)		40/300 (13.3%)
Nervous system disorders
Dizziness	29/300 (9.7%)		22/300 (7.3%)
Headache	39/300 (13%)		37/300 (12.3%)
Hypoaesthesia	17/300 (5.7%)		17/300 (5.7%)
Paraesthesia	17/300 (5.7%)		6/300 (2%)
Psychiatric disorders
Anxiety	24/300 (8%)		25/300 (8.3%)
Depression	35/300 (11.7%)		42/300 (14%)
Insomnia	41/300 (13.7%)		29/300 (9.7%)
Reproductive system and breast disorders
Breast pain	19/300 (6.3%)		18/300 (6%)
Vulvovaginal dryness	24/300 (8%)		22/300 (7.3%)
Respiratory, thoracic and mediastinal disorders
Cough	30/300 (10%)		38/300 (12.7%)
Dyspnoea	26/300 (8.7%)		25/300 (8.3%)
Skin and subcutaneous tissue disorders
Alopecia	24/300 (8%)		18/300 (6%)
Rash	19/300 (6.3%)		17/300 (5.7%)
Vascular disorders
Hot flush	122/300 (40.7%)		118/300 (39.3%)
Hypertension	30/300 (10%)		24/300 (8%)
Lymphoedema	19/300 (6.3%)		20/300 (6.7%)

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 or disclosure of trial results in their entirety.