Study to Evaluate Efficacy of Odanacatib (MK-0822) on Bone Mineral Density (BMD) and Bone Micro-architecture and Overall Safety in Postmenopausal Women (MK-0822-031)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00729183
• Collaborator: (none)
• Enrollment: 214
• Arms: 2
• Actual Duration (Months): 29.6

Study Details

Study Description

Brief Summary

This study will evaluate the safety and treatment effect of 50 mg odanacatib (MK-0822) with Vitamin D versus placebo with Vitamin D in postmenopausal women with low bone density. The primary efficacy hypothesis is that odanacatib will increase aBMD at the lumbar spine compared to placebo at 12 months.

Condition or Disease	Intervention/Treatment	Phase
Osteoporosis	Drug: Odanacatib; Drug: Placebo; Drug: Vitamin D3; Drug: Calcium supplement	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 214 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized, Placebo-Controlled Study to Evaluate the Effect of Odanacatib (MK-0822) on Bone Mineral Density (BMD) and Overall Safety, and to Estimate the Effect of Odanacatib (MK-0822) on Bone Micro-architecture in Postmenopausal Women Treated With Vitamin D
• Actual Study Start Date: Oct 2, 2008
• Actual Primary Completion Date: Mar 23, 2010
• Actual Study Completion Date: Mar 21, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Odanacatib 50 mg Participants receive 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also receive 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Drug: Odanacatib; Odanacatib 50 mg tablets, taken orally once weekly for 24 months.; Other Names: MK-0822 ; Drug: Vitamin D3; Vitamin D3 tablets (5600 IU) taken orally once weekly for 24 months.; Drug: Calcium supplement; Calcium supplement 500 mg tablet taken orally once daily (up to ~1200 mg total) for 24 months.; Other Names: calcium carbonate calcium citrate
Placebo Comparator: Placebo Participants receive matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also receive 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Drug: Placebo; Matching placebo tablets to odanacatib taken orally once weekly for 24 months.; Drug: Vitamin D3; Vitamin D3 tablets (5600 IU) taken orally once weekly for 24 months.; Drug: Calcium supplement; Calcium supplement 500 mg tablet taken orally once daily (up to ~1200 mg total) for 24 months.; Other Names: calcium carbonate calcium citrate

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline to Month 12 in Lumbar Spine Areal Bone Mineral Density (aBMD) [Baseline, 12 months]

   aBMD (g/cm^2) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and mean BMD measurements from at least 3 evaluable lumbar spine vertebrae (L1-L4) were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal Analysis of Covariates (ANCOVA) model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively.

2. Percentage of Participants That Experienced an Adverse Event (AE) [Up to ~14 days post study end (up to ~24 months)]

   An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm.

3. Percentage of Participants That Discontinued Study Treatment Due to an AE [Up to ~14 days post study end (up to ~24 months)]

   An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that discontinued study treatment (different from discontinuation of the study) due to an AE was reported for each treatment arm.

Secondary Outcome Measures

1. Percent Change From Baseline to Month 24 in Lumbar Spine aBMD [Baseline, 24 months]

   aBMD (g/cm^2) was measured by DXA at the lumbar spine and mean BMD measurements from at least 3 evaluable vertebrae from L1 through L4 were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively.

2. Percent Change From Baseline in Total Hip aBMD [Baseline, 12 months, 24 months]

   aBMD (g/cm^2) data was measured by DXA at the total hip. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total hip was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.

3. Percent Change From Baseline in Femoral Neck aBMD [Baseline, 12 months, 24 months]

   aBMD (g/cm^2) data was measured by DXA at the femoral neck (hip). All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the femoral neck was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.

4. Percent Change From Baseline in Hip Trochanter aBMD [Baseline, 12 months, 24 months]

   aBMD (g/cm^2) data was measured by DXA at the hip trochanter. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the hip trochanter was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.

5. Percent Change From Baseline in Total Radius aBMD [Baseline, 12 months, 24 months]

   aBMD (g/cm^2) data was measured by DXA at the total radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.

6. Percent Change From Baseline in Ultradistal Radius aBMD [Baseline, 12 months, 24 months]

   aBMD (g/cm^2) data was measured by DXA at the ultradistal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the ultradistal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.

7. Percent Change From Baseline in Distal Radius aBMD [Baseline, 12 months, 24 months]

   aBMD (g/cm^2) data was measured by DXA at the one-third distal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the distal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.

8. Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1) [Baseline, 12 months, 24 months]

   Trabecular vBMD at the lumbar spine (L1) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L1) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.

9. Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2) [Baseline, 12 months, 24 months]

   Trabecular vBMD at the lumbar spine (L2) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L2) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.

10. Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level [Baseline, 12 months, 24 months]

    s-CTx is a biochemical marker index of bone resorption. s-CTx was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. S-CTx was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI.

11. Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level [Baseline, 12 months, 24 months]

    s-P1NP is a biochemical marker index of bone formation. s-P1NP was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. s-P1NP was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 85 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant has been postmenopausal for 3 years

• Participant has BMD t-score at the total hip, hip trochanter, femoral neck, or lumbar spine ≥ -1.5 but > -3.5

• Participant has 2 hips that are evaluable by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), e.g. contain no hardware from orthopedic procedures

• Participant is ambulatory

Exclusion Criteria:

• Participant has had a previous hip fracture

• Participant has had >1 prior clinical vertebral fracture AND is a candidate for osteoporosis therapy

• Participant has been treated with oral bisphosphonates, strontium, parathyroid hormone (PTH) or other agents with an effect on bone

• Participant has had metabolic bone disorder other than osteoporosis

• Participant has renal stones, Parkinson's disease, multiple sclerosis (MS) or active parathyroid disease.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Monitor, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00729183
• Other Study ID Numbers: 0822-031; 2008_539
• First Posted: Aug 7, 2008
• Last Update Posted: Aug 27, 2018
• Last Verified: Jul 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Osteoporosis; Calcium, Dietary; Vitamin D; Cholecalciferol; Calcium Carbonate; Calcium

Study Results

Participant Flow

Pre-assignment Detail	214 participants who met inclusion criteria were randomized into either the Odanacatib 50 mg arm (N=109) or the Placebo arm (N=105).

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Period Title: Overall Study
STARTED	109	105
COMPLETED	84	90
NOT COMPLETED	25	15

Baseline Characteristics

Arm/Group Title	Odanacatib 50 mg	Placebo	Total
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Total of all reporting groups
Overall Participants	109	105	214
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.9 (7.3)	64.0 (6.2)	64.0 (6.8)
Sex: Female, Male (Count of Participants)
Female	109 100%	105 100%	214 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline to Month 12 in Lumbar Spine Areal Bone Mineral Density (aBMD)
Description	aBMD (g/cm^2) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and mean BMD measurements from at least 3 evaluable lumbar spine vertebrae (L1-L4) were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal Analysis of Covariates (ANCOVA) model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

Full-Analysis-Set (FAS) population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having Month 12 post-randomization lumbar spine aBMD endpoint data subsequent to at least one dose of study treatment, and having lumbar spine aBMD baseline (BL) data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	96	97
Least Squares Mean (95% Confidence Interval) [percent change]	3.63	0.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	A longitudinal ANCOVA was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% confidence interval (CI). The model, applied on all time points during treatment (Screening Visit [BL], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and BL value as covariate. The weighted Least Squares (LS) mean is based on the described model. Difference in LS Means = Odancatib 50 mg minus Placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Longitudinal Data Analysis (LDA) Model
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	3.49
	Confidence Interval	(2-Sided) 95%; 2.66 to 4.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Percentage of Participants That Experienced an Adverse Event (AE)
Description	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm.
Time Frame	Up to ~14 days post study end (up to ~24 months)

Outcome Measure Data

Analysis Population Description

All-Participants-as-Treated (APaT) population: all participants who took at least one dose of study medication, counted in the treatment group corresponding to the study treatment they actually received.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	109	105
Number [percentage of participants]	82.6 75.8%	84.8 80.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	Estimated difference (versus Placebo) and CI were based on the Miettinen & Nurminen method.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -12.3 to 7.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Percentage of Participants That Discontinued Study Treatment Due to an AE
Description	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that discontinued study treatment (different from discontinuation of the study) due to an AE was reported for each treatment arm.
Time Frame	Up to ~14 days post study end (up to ~24 months)

Outcome Measure Data

Analysis Population Description

APaT population: all participants who took at least one dose of study medication, counted in the treatment group corresponding to the study treatment they actually received.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	109	105
Number [percentage of participants]	10.1 9.3%	5.7 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	Estimated difference (versus Placebo) and CI were based on the Miettinen & Nurminen method.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; -3.2 to 12.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Change From Baseline to Month 24 in Lumbar Spine aBMD
Description	aBMD (g/cm^2) was measured by DXA at the lumbar spine and mean BMD measurements from at least 3 evaluable vertebrae from L1 through L4 were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively.
Time Frame	Baseline, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having Month 24 post-randomization lumbar spine aBMD endpoint data subsequent to at least one dose of study treatment, and having lumbar spine aBMD baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	83	90
Least Squares Mean (95% Confidence Interval) [percent change]	5.02	-0.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and BL value as covariate. The weighted LS mean is based on the described model. Difference in LS Means = Odancatib 50 mg minus Placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	5.39
	Confidence Interval	(2-Sided) 95%; 4.36 to 6.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percent Change From Baseline in Total Hip aBMD
Description	aBMD (g/cm^2) data was measured by DXA at the total hip. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total hip was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization total hip aBMD endpoint data subsequent to at least one dose of study treatment, and having total hip aBMD baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	96	97
Month 12 (n=96, n=97)	1.41	-0.16
Month 24 (n=82, n=90)	2.43	-0.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 95%; 0.88 to 2.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	3.32
	Confidence Interval	(2-Sided) 95%; 2.39 to 4.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percent Change From Baseline in Femoral Neck aBMD
Description	aBMD (g/cm^2) data was measured by DXA at the femoral neck (hip). All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the femoral neck was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization femoral neck aBMD endpoint data subsequent to at least one dose of study treatment, and having femoral neck aBMD baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	96	97
Month 12 (n=96, n=97)	1.03	-0.45
Month 24 (n=82, n=90)	2.47	-1.33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	1.48
	Confidence Interval	(2-Sided) 95%; 0.60 to 2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	3.81
	Confidence Interval	(2-Sided) 95%; 2.69 to 4.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percent Change From Baseline in Hip Trochanter aBMD
Description	aBMD (g/cm^2) data was measured by DXA at the hip trochanter. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the hip trochanter was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization hip trochanter aBMD endpoint data subsequent to at least one dose of study treatment, and having hip trochanter aBMD baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	96	97
Month 12 (n=96, n=97)	2.37	0.18
Month 24 (n=82, n=90)	4.75	-0.73

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	2.19
	Confidence Interval	(2-Sided) 95%; 1.09 to 3.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	5.48
	Confidence Interval	(2-Sided) 95%; 4.08 to 6.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percent Change From Baseline in Total Radius aBMD
Description	aBMD (g/cm^2) data was measured by DXA at the total radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization total radius aBMD endpoint data subsequent to at least one dose of study treatment, and having total radius aBMD baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	96	96
Month 12 (n=96, n=96)	0.01	-0.70
Month 24 (n=82, n=90)	-0.19	-1.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.07 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	1.70
	Confidence Interval	(2-Sided) 95%; 0.97 to 2.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percent Change From Baseline in Ultradistal Radius aBMD
Description	aBMD (g/cm^2) data was measured by DXA at the ultradistal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the ultradistal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization ultradistal radius aBMD endpoint data subsequent to at least one dose of study treatment, and having ultradistal radius aBMD baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	96	96
Month 12 (n=96, n=96)	0.98	-0.73
Month 24 (n=82, n=90)	1.25	-1.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	1.71
	Confidence Interval	(2-Sided) 95%; 0.69 to 2.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	2.70
	Confidence Interval	(2-Sided) 95%; 1.62 to 3.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percent Change From Baseline in Distal Radius aBMD
Description	aBMD (g/cm^2) data was measured by DXA at the one-third distal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the distal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization distal radius aBMD endpoint data subsequent to at least one dose of study treatment, and having distal radius aBMD baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	96	96
Month 12 (n=96, n=96)	-0.21	-0.37
Month 24 (n=82, n=90)	-0.57	-1.79

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.697
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.27 to 2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1)
Description	Trabecular vBMD at the lumbar spine (L1) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L1) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization QCT spine (L1) endpoint data subsequent to at least one dose of study treatment, and having QCT spine (L1) baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	82	86
Month 12 (n=82, n=86)	6.58	-1.43
Month 24 (n=72, n=79)	6.44	-5.02

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	8.01
	Confidence Interval	(2-Sided) 95%; 6.03 to 9.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	11.46
	Confidence Interval	(2-Sided) 95%; 8.96 to 13.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2)
Description	Trabecular vBMD at the lumbar spine (L2) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L2) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization QCT spine (L2) endpoint data subsequent to at least one dose of study treatment, and having QCT spine (L2) baseline data.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	84	86
Month 12 (n=84, n=86)	5.67	-0.00
Month 24 (n=73, n=79)	5.97	-3.41

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	5.68
	Confidence Interval	(2-Sided) 95%; 3.77 to 7.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit [Baseline], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	9.38
	Confidence Interval	(2-Sided) 95%; 6.98 to 11.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level
Description	s-CTx is a biochemical marker index of bone resorption. s-CTx was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. S-CTx was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

Per-Protocol (PP) population: All participants receiving at least one dose of study treatment and with available s-CTx data, excluding participants with important deviations from the protocol that may have substantially affected the results.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	89	87
Month 12 (n=89, n=87)	-53.33	0.70
Month 24 (n=74, n=78)	-42.56	3.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain geometric LS mean percent change from BL in s-CTx (back-transformation of the log-transformed fraction from BL) and its 95% CI. The model, applied on all time points during treatment (Baseline [Randomization], Month 6, Month 12, Month 18, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-54.03
	Confidence Interval	(2-Sided) 95%; -64.81 to -43.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain geometric LS mean percent change from BL in s-CTx (back-transformation of the log-transformed fraction from BL) and its 95% CI. The model, applied on all time points during treatment (Baseline [Randomization], Month 6, Month 12, Month 18, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-45.59
	Confidence Interval	(2-Sided) 95%; -62.22 to -28.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level
Description	s-P1NP is a biochemical marker index of bone formation. s-P1NP was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. s-P1NP was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI.
Time Frame	Baseline, 12 months, 24 months

Outcome Measure Data

Analysis Population Description

PP population: All participants receiving at least one dose of study treatment and with available s-P1NP data, excluding participants with important deviations from the protocol that may have substantially affected the results.

Arm/Group Title	Odanacatib 50 mg	Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.	Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
Measure Participants	90	88
Month 12 (n=90, n=88)	-28.32	-2.97
Month 24 (n=76, n=80)	-11.06	-1.99

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 12: A longitudinal ANCOVA model was used to obtain geometric LS mean percent change from BL in s-P1NP (back-transformation of the log-transformed fraction from BL) and its 95% CI. The model, applied on all time points during treatment (Baseline [Randomization], Month 6, Month 12, Month 18, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and BL value as covariate. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-25.34
	Confidence Interval	(2-Sided) 95%; -37.77 to -12.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg, Placebo
	Comments	MONTH 24: A longitudinal ANCOVA model was used to obtain geometric LS mean percent change from BL in s-P1NP (back-transformation of the log-transformed fraction from BL) and its 95% CI. The model, applied on all time points during treatment (Baseline [Randomization], Month 6, Month 12, Month 18, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and BL value as covariate. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.225
	Comments
	Method	LDA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-9.07
	Confidence Interval	(2-Sided) 95%; -23.69 to 5.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	~14 days post study end (up to ~24 months)
Adverse Event Reporting Description	APaT population: all participants who took at least one dose of study medication, counted in the treatment group corresponding to the study treatment they actually received.
Arm/Group Title	Odanacatib 50 mg		Placebo
Arm/Group Description	Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.		Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg.
All Cause Mortality
	Odanacatib 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Odanacatib 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/109 (11.9%)		16/105 (15.2%)
Cardiac disorders
Cardiomyopathy	0/109 (0%)	0	1/105 (1%)	1
Coronary artery disease	1/109 (0.9%)	1	1/105 (1%)	1
Myocardial infarction	0/109 (0%)	0	1/105 (1%)	1
Sick sinus syndrome	0/109 (0%)	0	1/105 (1%)	1
Supraventricular tachycardia	0/109 (0%)	0	1/105 (1%)	1
Gastrointestinal disorders
Abdominal pain upper	0/109 (0%)	0	1/105 (1%)	1
General disorders
Chest pain	1/109 (0.9%)	1	1/105 (1%)	1
Pyrexia	0/109 (0%)	0	1/105 (1%)	1
Immune system disorders
Sarcoidosis	1/109 (0.9%)	1	0/105 (0%)	0
Infections and infestations
Gastroenteritis	1/109 (0.9%)	1	0/105 (0%)	0
Herpes zoster	0/109 (0%)	0	1/105 (1%)	1
Injury, poisoning and procedural complications
Lumbar vertebral fracture	0/109 (0%)	0	1/105 (1%)	1
Thoracic vertebral fracture	0/109 (0%)	0	1/105 (1%)	1
Metabolism and nutrition disorders
Diabetes mellitus	0/109 (0%)	0	1/105 (1%)	1
Hypercalcaemia	1/109 (0.9%)	1	0/105 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/109 (0%)	0	2/105 (1.9%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	3/109 (2.8%)	4	1/105 (1%)	1
Breast cancer	2/109 (1.8%)	2	0/105 (0%)	0
Breast cancer recurrent	1/109 (0.9%)	1	0/105 (0%)	0
Ovarian cancer	1/109 (0.9%)	1	0/105 (0%)	0
Ovarian epithelial cancer	1/109 (0.9%)	1	0/105 (0%)	0
Nervous system disorders
Sciatica	0/109 (0%)	0	1/105 (1%)	1
Transient ischaemic attack	2/109 (1.8%)	2	0/105 (0%)	0
Reproductive system and breast disorders
Vaginal prolapse	0/109 (0%)	0	1/105 (1%)	1
Skin and subcutaneous tissue disorders
Granuloma annulare	1/109 (0.9%)	1	0/105 (0%)	0
Other (Not Including Serious) Adverse Events
	Odanacatib 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	67/109 (61.5%)		68/105 (64.8%)
Gastrointestinal disorders
Constipation	6/109 (5.5%)	6	1/105 (1%)	1
Nausea	2/109 (1.8%)	3	6/105 (5.7%)	6
Infections and infestations
Bronchitis	2/109 (1.8%)	2	7/105 (6.7%)	9
Cystitis	5/109 (4.6%)	6	6/105 (5.7%)	9
Influenza	10/109 (9.2%)	10	6/105 (5.7%)	6
Nasopharyngitis	15/109 (13.8%)	18	8/105 (7.6%)	10
Urinary tract infection	8/109 (7.3%)	11	10/105 (9.5%)	10
Injury, poisoning and procedural complications
Fall	2/109 (1.8%)	2	8/105 (7.6%)	10
Musculoskeletal and connective tissue disorders
Arthralgia	18/109 (16.5%)	19	14/105 (13.3%)	15
Back pain	12/109 (11%)	14	16/105 (15.2%)	19
Muscle spasms	6/109 (5.5%)	8	3/105 (2.9%)	3
Musculoskeletal pain	6/109 (5.5%)	6	3/105 (2.9%)	3
Pain in extremity	5/109 (4.6%)	9	8/105 (7.6%)	10
Nervous system disorders
Headache	6/109 (5.5%)	7	1/105 (1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/109 (2.8%)	3	9/105 (8.6%)	10
Skin and subcutaneous tissue disorders
Pruritus	1/109 (0.9%)	2	6/105 (5.7%)	6
Rash	5/109 (4.6%)	6	9/105 (8.6%)	12
Vascular disorders
Hypertension	7/109 (6.4%)	7	4/105 (3.8%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission. SPONSOR review can be expedited to meet publication guidelines.