Trial Outcomes & Findings for Effects of Zoledronic Acid and Raloxifene on Bone Turnover Markers in Postmenopausal Women With Low Bone Mineral Density (NCT NCT00431444)

Results Overview

The primary efficacy variable was the change from baseline in urine NTx (corrected by creatinine). The primary analysis time point was at 6 months of treatment. The results are reported as nanomoles (nM) of bone collagen equivalents (BCE) per millimole (mM) of urine creatinine.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

110 participants

Primary outcome timeframe

Baseline and 6 months

Results posted on

2011-03-29

Participant Flow

Participant milestones

Participant milestones
Measure	Zoledronic Acid Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Overall Study STARTED	56	53
Overall Study COMPLETED	51	46
Overall Study NOT COMPLETED	5	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Overall Study Protocol Violation	1	4
Overall Study Adverse Event	2	1
Overall Study Withdrawal by Subject	1	1
Overall Study Lost to Follow-up	1	0
Overall Study Administrative Problems	0	1

Baseline Characteristics

Effects of Zoledronic Acid and Raloxifene on Bone Turnover Markers in Postmenopausal Women With Low Bone Mineral Density

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid n=56 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)	Total n=109 Participants Total of all reporting groups
Age Continuous	58.8 years STANDARD_DEVIATION 6.97 • n=5 Participants	61.5 years STANDARD_DEVIATION 8.20 • n=7 Participants	60.1 years STANDARD_DEVIATION 7.68 • n=5 Participants
Age, Customized Between 45 and 65 years	43 participants n=5 Participants	35 participants n=7 Participants	78 participants n=5 Participants
Age, Customized >=65 years	13 participants n=5 Participants	18 participants n=7 Participants	31 participants n=5 Participants
Sex: Female, Male Female	56 Participants n=5 Participants	53 Participants n=7 Participants	109 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Post-menopausal	12.5 year STANDARD_DEVIATION 8.94 • n=5 Participants	13.4 year STANDARD_DEVIATION 9.17 • n=7 Participants	13.0 year STANDARD_DEVIATION 9.03 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 6 months

Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable of urine N-telopeptide of Type 1 collagen (NTx).Observed cases were used, no imputation was performed.

The primary efficacy variable was the change from baseline in urine NTx (corrected by creatinine). The primary analysis time point was at 6 months of treatment. The results are reported as nanomoles (nM) of bone collagen equivalents (BCE) per millimole (mM) of urine creatinine.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=52 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Change From Baseline in Urine N-telopeptide of Type 1 Collagen (NTx.) Baseline (n = 52, 53)	49.054 nM BCE/mM Cr Standard Deviation 20.4515	44.460 nM BCE/mM Cr Standard Deviation 23.2789
Change From Baseline in Urine N-telopeptide of Type 1 Collagen (NTx.) 6 months (n = 49, 47)	23.676 nM BCE/mM Cr Standard Deviation 11.9152	34.183 nM BCE/mM Cr Standard Deviation 16.4667
Change From Baseline in Urine N-telopeptide of Type 1 Collagen (NTx.) Change from baseline to Month 6 (n= 48, 47)	-24.646 nM BCE/mM Cr Standard Deviation 13.9893	-8.362 nM BCE/mM Cr Standard Deviation 15.3852

SECONDARY outcome

Timeframe: Baseline and 2 months

Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable of urine N-telopeptide of Type 1 collagen (NTx).Observed cases were used, no imputation was performed.

The results are reported as nanomoles (nM) of bone collagen equivalents (BCE) per millimole (mM) of urine creatinine.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=54 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Change From Baseline in Urine NTx at 2 Months Baseline (n= 52, 53)	49.054 nM BCE/mM Cr Standard Deviation 20.4515	44.460 nM BCE/mM Cr Standard Deviation 23.2789
Change From Baseline in Urine NTx at 2 Months At Month 2 (n= 54, 50)	17.774 nM BCE/mM Cr Standard Deviation 9.1107	40.756 nM BCE/mM Cr Standard Deviation 23.3700
Change From Baseline in Urine NTx at 2 Months Change from baseline to Month 2 (n= 52, 50)	-31.065 nM BCE/mM Cr Standard Deviation 16.4960	-4.000 nM BCE/mM Cr Standard Deviation 11.2757

SECONDARY outcome

Timeframe: Baseline and 4 months

Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable of urine N-telopeptide of Type 1 collagen (NTx).Observed cases were used, no imputation was performed.

The results are reported as nanomoles (nM) of bone collagen equivalents (BCE) per millimole (mM) of urine creatinine.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=52 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Change From Baseline in Urine NTx at 4 Months Baseline (n= 52 , 53)	49.054 nM BCE/mM Cr Standard Deviation 20.4515	44.460 nM BCE/mM Cr Standard Deviation 23.2789
Change From Baseline in Urine NTx at 4 Months At Month 4 (n= 48, 46)	20.802 nM BCE/mM Cr Standard Deviation 13.1632	38.143 nM BCE/mM Cr Standard Deviation 24.9307
Change From Baseline in Urine NTx at 4 Months Change from baseline to Month 4 (n= 47, 46)	-27.832 nM BCE/mM Cr Standard Deviation 15.4142	-3.920 nM BCE/mM Cr Standard Deviation 17.1348

SECONDARY outcome

Timeframe: Baseline and 2 months

Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable of urine N-telopeptide of Type 1 collagen (NTx).Observed cases were used, no imputation was performed.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=51 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=51 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 2 Months Baseline (n= 50, 48)	30.104 U/L Standard Deviation 10.8868	27.094 U/L Standard Deviation 9.4039
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 2 Months At Month 2 (n= 51, 51)	20.855 U/L Standard Deviation 5.8499	26.424 U/L Standard Deviation 7.8699
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 2 Months Change from baseline to Month 2 (n= 47, 46)	-8.947 U/L Standard Deviation 6.4181	-1.085 U/L Standard Deviation 4.0969

SECONDARY outcome

Timeframe: Baseline and 4 months

Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable of urine N-telopeptide of Type 1 collagen (NTx).Observed cases were used, no imputation was performed.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=50 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=48 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 4 Months Baseline (n= 50, 48)	30.104 U/L Standard Deviation 10.8868	27.094 U/L Standard Deviation 9.4039
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 4 Months At Month 4 (n= 49, 47)	18.218 U/L Standard Deviation 5.1846	25.111 U/L Standard Deviation 8.4530
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 4 Months Change from baseline to Month 4 (n= 45, 42)	-11.442 U/L Standard Deviation 7.8097	-2.000 U/L Standard Deviation 5.0356

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable of urine N-telopeptide of Type 1 collagen (NTx).Observed cases were used, no imputation was performed.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=51 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=48 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 6 Months Baseline (n= 50, 48)	30.104 U/L Standard Deviation 10.8868	27.094 U/L Standard Deviation 9.4039
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 6 Months At Month 6 (n= 51, 47)	19.237 U/L Standard Deviation 5.5181	24.981 U/L Standard Deviation 7.9932
Change From Baseline in Serum Bone Specific Alkaline Phosphatase (BSAP) at 6 Months Change from baseline to Month 6 (n= 47, 42)	-10.572 U/L Standard Deviation 7.3263	-2.250 U/L Standard Deviation 7.1307

SECONDARY outcome

Timeframe: Immediately after infusion procedure

Population: Intention-to-treat (ITT) population.

The investigator was asked to complete satisfaction questionnaires at baseline (Visit 2/Day 1) when each patient's i.v. drug administration occurred. The questionnaire assessed overall satisfaction with the i.v. infusion procedure. The possible answers to the question were: "not at all," "a little," "somewhat," "quite," or "completely."

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=54 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Overall Principal Investigator Satisfaction Assessed by Satisfaction Questionnaire Somewhat	3 Participants	1 Participants
Overall Principal Investigator Satisfaction Assessed by Satisfaction Questionnaire Quite	2 Participants	3 Participants
Overall Principal Investigator Satisfaction Assessed by Satisfaction Questionnaire Not at all / A little	0 Participants	0 Participants
Overall Principal Investigator Satisfaction Assessed by Satisfaction Questionnaire Completely	16 Participants	11 Participants
Overall Principal Investigator Satisfaction Assessed by Satisfaction Questionnaire Missing	33 Participants	38 Participants

SECONDARY outcome

Timeframe: Immediately after infusion procedure

Population: Intention-to-treat (ITT) population.

The study coordinator (nurse) was asked to complete satisfaction questionnaires at baseline (Visit 2/Day 1) when each patient's i.v. drug administration occurred. The questionnaire assessed overall satisfaction with the i.v. infusion procedure. The possible answers to the question were: "not at all," "a little," "somewhat," "quite," or "completely."

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=54 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Overall Nurse Satisfaction Assessed by Satisfaction Questionnaire Not at all / A little / Somewhat	0 Participants	0 Participants
Overall Nurse Satisfaction Assessed by Satisfaction Questionnaire Quite	4 Participants	3 Participants
Overall Nurse Satisfaction Assessed by Satisfaction Questionnaire Completely	29 Participants	35 Participants
Overall Nurse Satisfaction Assessed by Satisfaction Questionnaire Missing	21 Participants	15 Participants

SECONDARY outcome

Timeframe: Immediately after infusion procedure

Population: Intention-to-treat (ITT) population.

Patients were asked to complete the satisfaction questionnaire at baseline. The questionnaire assessed overall satisfaction with the i.v. infusion procedure. The possible answers to the question were: "not at all," "a little," "somewhat," "quite," or "completely."

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=54 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Overall Patient Satisfaction Assessed by Satisfaction Questionnaire Quite	9 Participants	7 Participants
Overall Patient Satisfaction Assessed by Satisfaction Questionnaire Completely	43 Participants	42 Participants
Overall Patient Satisfaction Assessed by Satisfaction Questionnaire Not at all	1 Participants	1 Participants
Overall Patient Satisfaction Assessed by Satisfaction Questionnaire A little	0 Participants	1 Participants
Overall Patient Satisfaction Assessed by Satisfaction Questionnaire Somewhat	1 Participants	1 Participants
Overall Patient Satisfaction Assessed by Satisfaction Questionnaire Missing	0 Participants	1 Participants

SECONDARY outcome

Timeframe: At 6 month visit

Population: Intention-to-treat (ITT) population.

At the end-of-study visit, Month 6, patients were asked to complete a questionnaire to assess preference for the different treatment modalities (annual i.v. infusion vs. daily oral capsule). The possible answers to question were: "once a year i.v. infusion," "once daily pill," or "both are equal."

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=54 Participants Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 Participants Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Patient Preference at 6 Months for Annual i.v Therapy or Daily Oral Regimens Once a year intravenous infusion	47 Participants	46 Participants
Patient Preference at 6 Months for Annual i.v Therapy or Daily Oral Regimens Once daily pill	3 Participants	4 Participants
Patient Preference at 6 Months for Annual i.v Therapy or Daily Oral Regimens Both are equal	3 Participants	3 Participants
Patient Preference at 6 Months for Annual i.v Therapy or Daily Oral Regimens Missing	1 Participants	0 Participants

Adverse Events

Zoledronic Acid

Serious events: 1 serious events

Other events: 31 other events

Deaths: 0 deaths

Raloxifene

Serious events: 1 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Zoledronic Acid n=56 participants at risk Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 participants at risk Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Gastrointestinal disorders Gastric ulcer haemorrhage	0.00% 0/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	1.9% 1/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Infections and infestations Herpes zoster	1.8% 1/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	0.00% 0/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.

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 n=56 participants at risk Zoledronic acid 5 mg (single intravenous (i.v.) infusion) + daily oral placebo for 6 months (zoledronic acid group)	Raloxifene n=53 participants at risk Placebo (single i.v. infusion) + oral raloxifene 60 mg/day for 6 months (raloxifene group)
Gastrointestinal disorders Constipation	1.8% 1/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	5.7% 3/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	8.9% 5/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	1.9% 1/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Gastrointestinal disorders Nausea	12.5% 7/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	1.9% 1/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
General disorders Chills	5.4% 3/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	1.9% 1/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
General disorders Fatigue	5.4% 3/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	1.9% 1/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
General disorders Influenza like illness	5.4% 3/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	0.00% 0/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
General disorders Pain	7.1% 4/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	0.00% 0/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
General disorders Pyrexia	10.7% 6/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	0.00% 0/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Infections and infestations Sinusitis	7.1% 4/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	7.5% 4/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Infections and infestations Urinary tract infection	7.1% 4/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	3.8% 2/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	7.1% 4/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	3.8% 2/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	5.4% 3/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	0.00% 0/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Myalgia	7.1% 4/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	5.7% 3/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Nervous system disorders Headache	5.4% 3/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	0.00% 0/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.
Vascular disorders Hypertension	5.4% 3/56 • 6 months The safety population included all randomized patients who received at least one dose of study drug.	0.00% 0/53 • 6 months The safety population included all randomized patients who received at least one dose of study drug.