Trial Outcomes & Findings for Double-blind Extension of HORIZON Pivotal Fracture Trial (Zoledronic Acid in the Treatment of Postmenopausal Osteoporosis) (NCT NCT00145327)

Last Updated: 2011-06-28

Results Overview

The primary efficacy variable was the percentage change in BMD of the femoral neck as measured by dual x-ray absorptiometry (DXA) at Year 6 relative to Year 3. It was derived as 100 \*(femoral neck BMD at Year 6 - femoral neck BMD at Year 3) / (femoral neck BMD at Year 3).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2456 participants

Primary outcome timeframe

Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72; end of extension study)

Results posted on

2011-06-28

Participant Flow

This was an international, multicenter, randomized, double-blind 3-year extension study in postmenopausal women with osteoporosis who had completed participation in the CZOL446H2301 (NCT00049829) core study. The extension study started 17 May 2005 (First patient enrolled) and ended 24 Nov 2009 (Last patient completed).

Patients who were receiving zoledronic acid in the core study were randomized in a 1:1 fashion to receive either zoledronic acid or placebo in the extension study. Patients who were receiving placebo in the core study were assigned to zoledronic acid in the extension study in order to retain the core study blind.

Participant milestones

Participant milestones
Measure	Zoledronic Acid 6 Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Overall Study STARTED	616	617	1223
Overall Study COMPLETED	474	493	975
Overall Study NOT COMPLETED	142	124	248

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid 6 Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Overall Study Withdrawal by Subject	77	72	164
Overall Study Death	26	18	30
Overall Study Adverse Event	14	11	22
Overall Study Lost to Follow-up	9	14	14
Overall Study Administrative problems	12	9	13
Overall Study Protocol Violation	2	0	2
Overall Study Abnormal laboratory value(s)	1	0	2
Overall Study Missing - not stated	1	0	1

Baseline Characteristics

Double-blind Extension of HORIZON Pivotal Fracture Trial (Zoledronic Acid in the Treatment of Postmenopausal Osteoporosis)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid 6 n=616 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=617 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=1223 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.	Total n=2456 Participants Total of all reporting groups
Age Continuous	75.5 Years STANDARD_DEVIATION 4.88 • n=5 Participants	75.5 Years STANDARD_DEVIATION 4.89 • n=7 Participants	75.6 Years STANDARD_DEVIATION 4.95 • n=5 Participants	75.5 Years STANDARD_DEVIATION 4.92 • n=4 Participants
Sex: Female, Male Female	616 Participants n=5 Participants	617 Participants n=7 Participants	1223 Participants n=5 Participants	2456 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72; end of extension study)

Population: Modified intent-to-treat (MITT) population. The MITT population included all patients in the ITT population who had DXA measurements of the femoral neck at Year 3 and Year 6. This was the primary population for primary efficacy parameter.

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=451 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=470 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=507 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3	0.557 Percentage Change in BMD Standard Error 0.2154 • Interval 0.43 to 1.65	-0.493 Percentage Change in BMD Standard Error 0.2249	3.337 Percentage Change in BMD Standard Error 0.2329

SECONDARY outcome

Timeframe: Year 4.5

Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 4.5 as determined by the analysis window.

The amount of serum n-terminal propeptide of type I collagen (P1NP) as determined by the central laboratory.

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=433 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=460 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=870 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP	18.842 ng/mL Standard Error 0.4325 • Interval 0.59 to 0.65	29.677 ng/mL Standard Error 0.6977	17.256 ng/mL Standard Error 0.3743

SECONDARY outcome

Timeframe: Year 6

Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The Number of patients analyzed = the number of patients with measurements in Year 6 as determined by the analysis window.

The amount of serum P1NP as determined by the central laboratory

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=392 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=414 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=426 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Bone Resorption and Formation Biochemical Markers at Year 6: P1NP	27.356 ng/mL Standard Error 0.6340	30.344 ng/mL Standard Error 0.6050	25.926 ng/mL Standard Error 0.7765

SECONDARY outcome

Timeframe: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)

The percentage change in BMD as measured by DXA at Year 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=101 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=102 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=195 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3	2.618 Percentage Change in BMD Standard Error 0.384 • Interval 0.38 to 2.42	1.196 Percentage Change in BMD Standard Error 0.3510	6.551 Percentage Change in BMD Standard Error 0.3035

SECONDARY outcome

Timeframe: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6

The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3).

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=100 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=84 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=128 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3	3.473 Percentage change in BMD Standard Error 0.4653	1.606 Percentage change in BMD Standard Error 0.4550	8.875 Percentage change in BMD Standard Error 0.5398

SECONDARY outcome

Timeframe: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)

The percentage change in BMD as measured by DXA at Year 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=100 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=99 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=188 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3	0.378 Percentage change in BMD Standard Error 0.3615	-0.924 Percentage change in BMD Standard Error 0.3158	0.386 Percentage change in BMD Standard Error 0.3071

SECONDARY outcome

Timeframe: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72)

The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3).

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=96 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=82 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=125 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3	0.178 Percentage change in BMD Standard Error 0.3661	-0.567 Percentage change in BMD Standard Error 0.4025	0.299 Percentage change in BMD Standard Error 0.3473

SECONDARY outcome

Timeframe: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)

The percentage change in BMD as measured by DXA at 4.5 relative to Year 3. It was derived as 100 \* (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=525 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=544 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=1047 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 Femoral Neck	0.738 Percentage change in BMD Standard Error 0.1874	0.210 Percentage change in BMD Standard Error 0.2058	2.697 Percentage change in BMD Standard Error 0.1516
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 Total Hip	0.479 Percentage change in BMD Standard Error 0.1337	-0.070 Percentage change in BMD Standard Error 0.1354	3.228 Percentage change in BMD Standard Error 0.1244
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 Trochanter	0.813 Percentage change in BMD Standard Error 0.1919	0.041 Percentage change in BMD Standard Error 0.1936	4.611 Percentage change in BMD Standard Error 0.2050

SECONDARY outcome

Timeframe: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72)

The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 \* (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3).

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=451 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=470 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=570 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 Femoral Neck	0.577 Percentage change in BMD Standard Error 0.2154 • Interval 0.58 to 2.15	-0.493 Percentage change in BMD Standard Error 0.2249	3.337 Percentage change in BMD Standard Error 0.2329
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 Total Hip	0.083 Percentage change in BMD Standard Error 0.1647 • Interval 0.8 to 2.14	-1.151 Percentage change in BMD Standard Error 0.1817	3.815 Percentage change in BMD Standard Error 0.1877
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 Trochanter	0.628 Percentage change in BMD Standard Error 0.2275 • Interval 1.56 to 3.44	-0.903 Percentage change in BMD Standard Error 0.2462	6.072 Percentage change in BMD Standard Error 0.2894

SECONDARY outcome

Timeframe: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6

Lateral vertebral x-rays were performed at the final core study visit and at Year 6 and read by a central expert reader at a central imaging laboratory to assess for new or new/worsening morphometric vertebral fracture. The percentage of patients with new morphometric vertebral fractures (observed for the first time) and patients with either new or worsening morphometric vertebral fractures was calculated.

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=469 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=486 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=585 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures New morphometric vertebral fracture	3.0 Percentage of patients Interval 0.26 to 0.9	6.2 Percentage of patients	2.9 Percentage of patients
Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures New/Worsening morphometric vertebral fracture	3.4 Percentage of patients	7.0 Percentage of patients	3.1 Percentage of patients

SECONDARY outcome

Timeframe: Extension Baseline (Year 3; Month 36) to Year 6

Population: Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. n = the number of patients with measurements at Year 6 as determined by the analysis window.

Clinical fracture excludes finger, toe, and facial bone fractures. Clinical vertebral fracture includes thoracic spine fracture and lumbar spine fracture. Non-vertebral fracture excludes clinical vertebral, finger, toe, and facial bone fractures.

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=616 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=617 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=1223 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Number of Participants With Incidence of Clinical Fracture Clinical fracture	51 Participants 8.15	51 Participants 8.52	91 Participants
Number of Participants With Incidence of Clinical Fracture Clinical vertebral fractures	7 Participants	4 Participants	7 Participants
Number of Participants With Incidence of Clinical Fracture Non-vertebral fractures	45 Participants	47 Participants	85 Participants
Number of Participants With Incidence of Clinical Fracture Hip fracture	7 Participants	8 Participants	10 Participants

SECONDARY outcome

Timeframe: End of Study Visit at Year 6

Population: Bone Biopsy sub-population.

Unpaired transiliac crest bone biopsy was performed for histomorphometry, which was obtained after double tetracycline labeling. No data were collected for Patients who received Placebo for the first 3 years of the study (Placebo 3 Zoledronic Acid 3).

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=3 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=2 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Qualitative Bone Biopsy Parameters Osteomalacia	0 Participants	0 Participants	—
Qualitative Bone Biopsy Parameters Woven bone	0 Participants	0 Participants	—
Qualitative Bone Biopsy Parameters Cortical trabeculation	0 Participants	0 Participants	—
Qualitative Bone Biopsy Parameters Marrow fibrosis	0 Participants	0 Participants	—
Qualitative Bone Biopsy Parameters Normal mineralization and normal osteoid	3 Participants	2 Participants	—
Qualitative Bone Biopsy Parameters Contained double labeling	3 Participants	2 Participants	—

SECONDARY outcome

Timeframe: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 3 infusion

Population: Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.

Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after study drug infusion in Z6 patients compared to Z3P3 patients and in P3Z3 patients.

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=613 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=616 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=1221 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion	1.96 μmol/L Standard Deviation 9.364	1.28 μmol/L Standard Deviation 8.757	0.21 μmol/L Standard Deviation 12.360

SECONDARY outcome

Timeframe: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 4 infusion

Population: Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.

Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after Year 4 study drug infusion.

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=613 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=616 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=1221 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion	3.35 μmol/L Standard Deviation 23.580	2.23 μmol/L Standard Deviation 9.891	2.47 μmol/L Standard Deviation 13.042

SECONDARY outcome

Timeframe: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 5 infusion

Population: Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.

Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after Year 5 study drug infusion.

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=613 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=616 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=1221 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion	3.46 μmol/L Standard Deviation 21.735	0.71 μmol/L Standard Deviation 10.278	1.04 μmol/L Standard Deviation 11.882

SECONDARY outcome

Timeframe: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to Year 6

Population: Safety Population included all patients in the ITT population who received at least one dose of study drug during the extension study.

Evaluate the laboratory key profile such as Calcium, Creatinine and Urea. The number of patients with clinically significant calcium, creatinine and urea were reported.

Outcome measures

Outcome measures
Measure	Zoledronic Acid 6 n=612 Participants Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=615 Participants Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=1210 Participants Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
The Number of Participants With Clinically Significant Laboratory Parameters Creatinine <18 μmol/L	1 Participants	0 Participants	1 Participants
The Number of Participants With Clinically Significant Laboratory Parameters Creatinine >221 μmol/L	3 Participants	0 Participants	2 Participants
The Number of Participants With Clinically Significant Laboratory Parameters Calcium <1.87 mmol/L	0 Participants	0 Participants	1 Participants
The Number of Participants With Clinically Significant Laboratory Parameters Calcium >2.89 mmol/L	4 Participants	0 Participants	4 Participants
The Number of Participants With Clinically Significant Laboratory Parameters Urea < 0.7 mmol/L	0 Participants	0 Participants	0 Participants
The Number of Participants With Clinically Significant Laboratory Parameters Urea >14.3 mmol/L	9 Participants	10 Participants	17 Participants

Adverse Events

Zoledronic Acid 6

Serious events: 191 serious events

Other events: 421 other events

Deaths: 0 deaths

Zoledronic Acid 3 Placebo 3

Serious events: 168 serious events

Other events: 427 other events

Deaths: 0 deaths

Placebo 3 Zoledronic Acid 3

Serious events: 297 serious events

Other events: 908 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

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

Restriction type: OTHER

Measure	Zoledronic Acid 6 n=613 participants at risk Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.	Zoledronic Acid 3 Placebo 3 n=616 participants at risk Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.	Placebo 3 Zoledronic Acid 3 n=1221 participants at risk Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Eye disorders Cataract	5.7% 35/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	7.0% 43/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	5.9% 72/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Gastrointestinal disorders Diarrhoea	5.1% 31/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	5.2% 32/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	4.7% 57/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Gastrointestinal disorders Nausea	3.3% 20/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	4.2% 26/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	7.7% 94/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
General disorders Fatigue	3.9% 24/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	3.2% 20/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	5.2% 64/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
General disorders Pyrexia	4.9% 30/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	3.1% 19/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	14.8% 181/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Infections and infestations Bronchitis	7.8% 48/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	8.0% 49/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	6.6% 80/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Infections and infestations Influenza	5.2% 32/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	5.0% 31/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	5.2% 63/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Infections and infestations Nasopharyngitis	10.0% 61/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	9.9% 61/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	7.8% 95/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Infections and infestations Urinary tract infection	12.6% 77/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	15.3% 94/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	11.7% 143/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Injury, poisoning and procedural complications Fall	8.2% 50/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	9.7% 60/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	9.0% 110/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Musculoskeletal and connective tissue disorders Arthralgia	19.4% 119/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	17.2% 106/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	20.7% 253/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Musculoskeletal and connective tissue disorders Back pain	18.4% 113/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	18.0% 111/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	16.9% 206/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Musculoskeletal and connective tissue disorders Bone pain	4.9% 30/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	2.6% 16/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	7.2% 88/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.5% 34/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	5.0% 31/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	6.2% 76/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Musculoskeletal and connective tissue disorders Myalgia	4.6% 28/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	4.1% 25/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	12.0% 147/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Musculoskeletal and connective tissue disorders Osteoarthritis	9.0% 55/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	8.0% 49/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	7.1% 87/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Musculoskeletal and connective tissue disorders Pain in extremity	8.3% 51/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	8.8% 54/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	9.9% 121/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Nervous system disorders Dizziness	4.2% 26/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	5.0% 31/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	5.7% 69/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Nervous system disorders Headache	6.0% 37/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	6.5% 40/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	10.2% 125/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.
Vascular disorders Hypertension	7.5% 46/613 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	14.9% 92/616 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.	11.1% 136/1221 • Extension Baseline (Year 3; Month 36) to Year 6 Adverse events and serious adverse events were based on the safety population which includes all patients in the ITT population who received at least one dose of study drug during the extension study.