A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804 (ASTEROID)

• ClinicalTrials.gov Identifier: NCT03118570
• Recruitment Status: Completed
• First Posted: April 18, 2017
• Results First Posted: March 2, 2022
• Last Update Posted: March 2, 2022
• Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborator: Mereo BioPharma
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Conditions: Osteogenesis Imperfecta, Type I; Osteogenesis Imperfecta Type III; Osteogenesis Imperfecta Type IV
• Interventions: Drug: setrusumab; Dietary Supplement: Calcium; Dietary Supplement: Vitamin D; Drug: zoledronic acid (optional)
• Enrollment: 112

Participant Flow

Recruitment Details

Pre-assignment Details

Participants were randomized 1:1:1:1 to 3 doses of setrusumab (20 mg/kg, 8 mg/kg and 2 mg/kg) and placebo for a 12-month Treatment Period. Per Protocol Amendment 4, participants originally randomized to the placebo group were reassigned to receive 20 mg/kg open-label setrusumab (1 discontinued study prior to the transition). Two participants in the setrusumab 20 mg/kg open-label group were randomized into this group after Amendment 4 and did not receive placebo.

Arm/Group Title	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)	Setrusumab 20 mg/kg (Open-Label)	Placebo
Arm/Group Description	Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Participants were randomized to this group after amendment 4.	Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Due to a protocol amendment, placebo was actually received for an average of 5 months. Participants originally randomized to the placebo group were reassigned to receive 20 mg/kg open-label setrusumab after amendment 4.
Period Title: Overall Study
Started	31	29	30	2	20
Reassigned From Placebo to 20 mg/kg Open-Label Setrusumab	0	0	0	0	19
Completed	26	22	25	2	15
Not Completed	5	7	5	0	5
Reason Not Completed
Adverse Event	2	0	0	0	3
Withdrawal by Subject	0	1	4	0	1
Lost to Follow-up	2	3	1	0	1
Other, Not Specified	1	3	0	0	0

Baseline Characteristics

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)	Setrusumab 20 mg/kg (Open-Label)	Placebo	Total
Arm/Group Description		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Due to a protocol amendment, placebo was actually received for an average of 5 months.	Total of all reporting groups
Overall Number of Baseline Participants		31	29	30	2	20	112
Baseline Analysis Population Description		The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are NOT "double-counted" for this analysis.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	31 participants	29 participants	30 participants	2 participants	20 participants	112 participants
		40.6 (13.73)	40.4 (14.34)	47.2 (12.42)	43.5 (14.85)	40.9 (14.68)	42.4 (13.80)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants	29 participants	30 participants	2 participants	20 participants	112 participants
	Female	17 54.8%	20 69.0%	21 70.0%	1 50.0%	14 70.0%	73 65.2%
	Male	14 45.2%	9 31.0%	9 30.0%	1 50.0%	6 30.0%	39 34.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants	29 participants	30 participants	2 participants	20 participants	112 participants
	Hispanic or Latino	3 9.7%	1 3.4%	2 6.7%	0 0.0%	1 5.0%	7 6.3%
	Not Hispanic or Latino	27 87.1%	27 93.1%	28 93.3%	2 100.0%	19 95.0%	103 92.0%
	Unknown or Not Reported	1 3.2%	1 3.4%	0 0.0%	0 0.0%	0 0.0%	2 1.8%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	31 participants	29 participants	30 participants	2 participants	20 participants	112 participants
Black or African American		2 6.5%	1 3.4%	1 3.3%	0 0.0%	0 0.0%	4 3.6%
White		29 93.5%	27 93.1%	29 96.7%	2 100.0%	20 100.0%	107 95.5%
Not Collected or Not Reported		0 0.0%	1 3.4%	0 0.0%	0 0.0%	0 0.0%	1 0.9%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12
Description	Assessed by high resolution peripheral quantitative computed tomography (HRpQCT). HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presents the ratio of the means between the visit and Baseline from analysis of covariance (ANCOVA).
Time Frame	Baseline, Month 12 (end of treatment [EOT])

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment (per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms). Participants with an assessment at given time point.

Arm/Group Title	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:	Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed	31	29	30
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: ratio
	1.004; (0.987 to 1.021)	0.993; (0.975 to 1.012)	0.992; (0.974 to 1.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.644
	Comments	Analysis is based on a log transformed analysis of covariance (ANCOVA) model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.485
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.404
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

2. Primary Outcome

Title	Change From Baseline in Radial Bone Strength (Failure Load) at Month 12
Description	Assessed by finite element analysis (FEA) of models generated from HRpQCT images of the distal radius.
Time Frame	Baseline, Month 12 (EOT)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.

Arm/Group Title	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:	Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed	28	22	25
Least Squares Mean (Standard Error); Unit of Measure: newton (N)
	61.25 (21.669)	32.25 (24.342)	8.86 (23.200)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.006
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.190
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.704
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

3. Primary Outcome

Title	Change From Baseline in Radial Bone Strength (Stiffness) at Month 12
Description	Assessed by FEA of models generated from HRpQCT images of the distal radius.
Time Frame	Baseline, Month 12 (EOT)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.

Arm/Group Title	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:	Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed	28	22	25
Least Squares Mean (Standard Error); Unit of Measure: N/mm
	1638.70 (625.808)	1422.00 (703.275)	209.89 (671.777)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.011
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.047
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.756
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

4. Secondary Outcome

Title	Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set
Description	Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA.
Time Frame	Baseline, Months 6, 12 (EOT), 18, 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		31	29	30
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: ratio
Radial: Month 6	Number Analyzed	26 participants	25 participants	25 participants
		1.007; (0.993 to 1.021)	1.000; (0.986 to 1.015)	0.998; (0.984 to 1.013)
Radial: Month 12	Number Analyzed	28 participants	22 participants	24 participants
		1.004; (0.987 to 1.021)	0.993; (0.975 to 1.012)	0.992; (0.974 to 1.011)
Radial: Month 18	Number Analyzed	23 participants	17 participants	23 participants
		1.002; (0.984 to 1.020)	0.992; (0.973 to 1.013)	0.979; (0.962 to 0.997)
Radial: Month 24	Number Analyzed	21 participants	16 participants	16 participants
		0.997; (0.972 to 1.023)	0.998; (0.970 to 1.027)	0.979; (0.951 to 1.008)
Tibial: Month 6	Number Analyzed	23 participants	20 participants	17 participants
		1.004; (0.986 to 1.022)	1.016; (0.996 to 1.036)	0.990; (0.969 to 1.012)
Tibial: Month 12	Number Analyzed	24 participants	17 participants	15 participants
		0.991; (0.940 to 1.046)	1.018; (0.955 to 1.086)	0.973; (0.909 to 1.042)
Tibial: Month 18	Number Analyzed	20 participants	13 participants	16 participants
		0.989; (0.945 to 1.035)	1.042; (0.985 to 1.102)	0.983; (0.933 to 1.036)
Tibial: Month 24	Number Analyzed	19 participants	12 participants	11 participants
		1.000; (0.949 to 1.054)	1.062; (0.995 to 1.133)	1.017; (0.949 to 1.090)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.329
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.953
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.795
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.644
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.485
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.404
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.827
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.459
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.022
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.821
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.911
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.152
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.668
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.109
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.358
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.742
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.567
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.430
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.634
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.146
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.521
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.991
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.069
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.625
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

5. Secondary Outcome

Title	Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm
Description	Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA.
Time Frame	Baseline, Months 6, 12 (EOT)

Outcome Measure Data

Analysis Population Description

All participants in the open-label arm who took at least 1 dose of study treatment. Participants with an assessment at given time point.

Arm/Group Title		Setrusumab 20 mg/kg (Open-Label)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		21
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: ratio
Radial: Month 6	Number Analyzed	17 participants
		0.994; (0.972 to 1.017)
Radial: Month 12	Number Analyzed	16 participants
		1.011; (0.986 to 1.036)
Tibial: Month 6	Number Analyzed	15 participants
		1.013; (0.991 to 1.035)
Tibial: Month 12	Number Analyzed	15 participants
		1.035; (0.975 to 1.099)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.615
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.376
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.259
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.253
	Comments	Analysis is based on a log transformed ANCOVA model with change from baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

6. Secondary Outcome

Title	Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set
Description	Assessed by FEA of models generated from HRpQCT images of the distal radius.
Time Frame	Baseline, Months 6, 12 (EOT), 18, 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		31	29	30
Least Squares Mean (95% Confidence Interval); Unit of Measure: N
Radial: Month 6	Number Analyzed	26 participants	25 participants	26 participants
		31.22; (-1.80 to 64.23)	39.95; (6.63 to 73.27)	-3.28; (-36.57 to 30.00)
Radial: Month 12	Number Analyzed	28 participants	22 participants	25 participants
		61.25; (18.03 to 104.46)	32.25; (-16.30 to 80.80)	8.86; (-37.41 to 55.13)
Radial: Month 18	Number Analyzed	23 participants	17 participants	24 participants
		50.39; (19.11 to 81.68)	43.11; (6.79 to 79.42)	-10.53; (-41.86 to 20.80)
Radial: Month 24	Number Analyzed	21 participants	16 participants	17 participants
		-19.59; (-72.66 to 33.47)	45.03; (-14.40 to 104.47)	-50.65; (-108.69 to 7.39)
Tibial: Month 6	Number Analyzed	23 participants	20 participants	17 participants
		46.00; (-24.91 to 116.92)	45.91; (-28.16 to 119.98)	-65.33; (-146.39 to 15.72)
Tibial: Month 12	Number Analyzed	24 participants	17 participants	15 participants
		76.15; (-11.23 to 163.54)	60.20; (-42.63 to 163.04)	-65.96; (-175.43 to 43.51)
Tibial: Month 18	Number Analyzed	20 participants	13 participants	16 participants
		50.69; (-34.55 to 135.93)	88.33; (-13.67 to 190.32)	-49.50; (-144.93 to 45.94)
Tibial: Month 24	Number Analyzed	19 participants	12 participants	11 participants
		-24.75; (-126.76 to 77.27)	41.37; (-86.68 to 169.43)	-74.94; (-208.22 to 58.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.064
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.019
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.845
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.006
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.190
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.704
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.002
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.021
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.504
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.462
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.134
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.086
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.199
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 8
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.219
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.112
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.086
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.245
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.232
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.237
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.088
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.302
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.626
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 8
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.517
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.262
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

7. Secondary Outcome

Title	Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm
Description	Assessed by FEA of models generated from HRpQCT images of the distal radius.
Time Frame	Baseline, Months 6, 12 (EOT)

Outcome Measure Data

Analysis Population Description

All participants in the open-label arm who took at least 1 dose of study treatment. Participants with an assessment at given time point.

Arm/Group Title		Setrusumab 20 mg/kg (Open-Label)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		21
Least Squares Mean (95% Confidence Interval); Unit of Measure: N
Radial: Month 6	Number Analyzed	16 participants
		110.16; (61.30 to 159.01)
Radial: Month 12	Number Analyzed	15 participants
		88.32; (28.55 to 148.09)
Tibial: Month 6	Number Analyzed	15 participants
		69.78; (-8.61 to 148.18)
Tibial: Month 12	Number Analyzed	15 participants
		112.92; (10.76 to 215.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.004
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.080
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.031
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

8. Secondary Outcome

Title	Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set
Description	Assessed by FEA of models generated from HRpQCT images of the distal radius.
Time Frame	Baseline, Months 6, 12 (EOT), 18, 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		31	29	30
Least Squares Mean (95% Confidence Interval); Unit of Measure: N/mm
Radial: Month 6	Number Analyzed	26 participants	25 participants	26 participants
		795.67; (-34.71 to 1626.04)	1048.61; (209.47 to 1887.75)	109.65; (-728.52 to 947.82)
Radial: Month 12	Number Analyzed	28 participants	22 participants	25 participants
		1638.70; (390.57 to 2886.83)	1422.00; (19.37 to 2824.64)	209.89; (-1129.93 to 1549.71)
Radial: Month 18	Number Analyzed	23 participants	17 participants	24 participants
		1295.98; (390.54 to 2201.42)	803.50; (-263.21 to 1870.21)	-215.92; (-1132.78 to 700.94)
Radial: Month 24	Number Analyzed	21 participants	16 participants	17 participants
		-625.46; (-1888.53 to 637.60)	1172.45; (-265.87 to 2610.76)	-1258.55; (-2663.69 to 146.60)
Tibial: Month 6	Number Analyzed	23 participants	20 participants	17 participants
		1344.84; (-296.83 to 2986.52)	1051.40; (-708.46 to 2811.25)	-1356.71; (-3284.14 to 570.73)
Tibial: Month 12	Number Analyzed	24 participants	17 participants	15 participants
		2326.63; (221.71 to 4431.55)	1543.85; (-973.70 to 4061.40)	-1428.87; (-4118.78 to 1261.03)
Tibial: Month 18	Number Analyzed	20 participants	13 participants	16 participants
		1047.16; (-1070.79 to 3165.11)	1697.21; (-861.80 to 4256.23)	-815.38; (-3247.85 to 1617.09)
Tibial: Month 24	Number Analyzed	19 participants	12 participants	11 participants
		-1250.69; (-4131.64 to 1630.26)	622.77; (-2966.46 to 4212.01)	-1844.84; (-5695.04 to 2005.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.060
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.015
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.795
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.011
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.047
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.756
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.006
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.137
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.639
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.325
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.108
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.078
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.106
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.236
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.164
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.031
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.224
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.291
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.324
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.188
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.503
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.385
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.727
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.338
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

9. Secondary Outcome

Title	Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm
Description	Assessed by FEA of models generated from HRpQCT images of the distal radius.
Time Frame	Baseline, Months 6, 12 (EOT)

Outcome Measure Data

Analysis Population Description

All participants in the open-label arm who took at least 1 dose of study treatment. Participants with an assessment at given time point.

Arm/Group Title		Setrusumab 20 mg/kg (Open-Label)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		21
Least Squares Mean (95% Confidence Interval); Unit of Measure: N/mm
Radial: Month 6	Number Analyzed	16 participants
		5056.51; (3404.58 to 6708.45)
Radial: Month 12	Number Analyzed	15 participants
		4992.82; (3056.80 to 6928.84)
Tibial: Month 6	Number Analyzed	15 participants
		4225.92; (1840.16 to 6611.68)
Tibial: Month 12	Number Analyzed	15 participants
		5827.81; (2601.54 to 9054.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Open-Label)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

10. Secondary Outcome

Title	Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12
Description	Fracture assessment, confirmed by central radiographic reading, was carried out for peripheral including all major long bones, minor bone (digits, ribs) and vertebral fractures. Fractures without clinical symptoms, detected only by means of radiographic investigations, were not included in the analysis.
Time Frame	Month 12 (EOT)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment.

Arm/Group Title	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:	Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed	31	29	30
Measure Type: Number; Unit of Measure: percentage of participants
Peripheral	6.5	17.2	13.3
Vertebral	0	0	0
Long-Bone	3.2	13.8	3.3
Any	16.1	34.5	23.3

11. Secondary Outcome

Title	Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6
Description	BMD was evaluated by dual-energy x-ray absorptiometry (DXA). T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given timepoint.

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		31	29	30
Least Squares Mean (95% Confidence Interval); Unit of Measure: T-score
Lumbar	Number Analyzed	24 participants	25 participants	26 participants
		0.273; (0.142 to 0.405)	0.338; (0.213 to 0.464)	0.110; (-0.014 to 0.233)
Total Body	Number Analyzed	23 participants	24 participants	27 participants
		0.072; (-0.049 to 0.194)	0.071; (-0.048 to 0.189)	0.122; (0.009 to 0.235)
Femoral Neck	Number Analyzed	21 participants	19 participants	24 participants
		-0.024; (-0.143 to 0.095)	0.102; (-0.023 to 0.226)	0.087; (-0.026 to 0.199)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.080
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.238
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.238
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.035
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.687
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.107
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.128
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

12. Secondary Outcome

Title	Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6
Description	BMD was evaluated by DXA.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given timepoint.

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		31	29	30
Least Squares Mean (95% Confidence Interval); Unit of Measure: g/cm^2
Lumbar	Number Analyzed	24 participants	25 participants	26 participants
		4.06; (2.12 to 6.00)	4.70; (2.86 to 6.55)	1.58; (-0.24 to 3.40)
Total Body	Number Analyzed	23 participants	24 participants	27 participants
		0.77; (-0.38 to 1.92)	0.83; (-0.29 to 1.94)	1.21; (0.14 to 2.28)
Femoral Neck	Number Analyzed	21 participants	19 participants	24 participants
		-0.42; (-2.51 to 1.68)	1.64; (-0.57 to 3.84)	1.61; (-0.38 to 3.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.088
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.184
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.144
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.028
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.694
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.143
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.111
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12
Description	BMD was evaluated by DXA. T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD.
Time Frame	Baseline, Month 12 (EOT)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given timepoint.

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		31	29	30
Least Squares Mean (95% Confidence Interval); Unit of Measure: T-score
Lumbar	Number Analyzed	24 participants	22 participants	25 participants
		0.587; (0.427 to 0.746)	0.486; (0.324 to 0.648)	0.174; (0.022 to 0.327)
Total Body	Number Analyzed	23 participants	22 participants	26 participants
		0.181; (0.051 to 0.310)	0.199; (0.068 to 0.330)	0.108; (-0.015 to 0.231)
Femoral Neck	Number Analyzed	21 participants	18 participants	22 participants
		0.163; (0.008 to 0.319)	0.159; (-0.007 to 0.326)	0.104; (-0.053 to 0.260)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.026
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.007
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.004
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.085
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.040
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.061
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.189
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

14. Secondary Outcome

Title	Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12
Description	BMD was evaluated by DXA.
Time Frame	Baseline, Month 12 (EOT)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given timepoint.

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		31	29	30
Least Squares Mean (95% Confidence Interval); Unit of Measure: g/cm^2
Lumbar	Number Analyzed	24 participants	22 participants	25 participants
		8.55; (6.13 to 10.97)	6.79; (4.34 to 9.25)	2.50; (0.19 to 4.81)
Total Body	Number Analyzed	23 participants	22 participants	26 participants
		1.98; (0.70 to 3.25)	2.03; (0.73 to 3.33)	1.06; (-0.16 to 2.27)
Femoral Neck	Number Analyzed	21 participants	18 participants	22 participants
		3.30; (0.64 to 5.96)	2.65; (-0.20 to 5.51)	1.90; (-0.77 to 4.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.035
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.003
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.003
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Total body
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.088
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.016
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.068
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Femoral neck
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.160
	Comments	Analysis is based on an ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

15. Secondary Outcome

Title	Change From Baseline in Total vBMD (Radial and Tibial) Over Time
Description	Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA.
Time Frame	Baseline, Months 6, 12 (EOT), 18, and 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given timepoint.

Arm/Group Title		Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Arm/Group Description:		Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.	Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Overall Number of Participants Analyzed		31	29	30
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: ratio
Radial, Month 6	Number Analyzed	26 participants	25 participants	26 participants
		1.011; (0.999 to 1.022)	0.995; (0.984 to 1.007)	1.000; (0.989 to 1.012)
Radial, Month 12	Number Analyzed	28 participants	22 participants	25 participants
		1.017; (1.006 to 1.029)	1.008; (0.995 to 1.021)	0.999; (0.986 to 1.011)
Radial, Month 18	Number Analyzed	23 participants	17 participants	24 participants
		1.013; (1.000 to 1.026)	0.992; (0.978 to 1.007)	0.996; (0.983 to 1.009)
Radial, Month 24	Number Analyzed	21 participants	16 participants	17 participants
		0.998; (0.984 to 1.012)	1.009; (0.994 to 1.025)	0.985; (0.969 to 1.000)
Tibial, Month 6	Number Analyzed	23 participants	20 participants	17 participants
		1.017; (1.001 to 1.033)	1.011; (0.995 to 1.028)	0.995; (0.977 to 1.031)
Tibial, Month 12	Number Analyzed	24 participants	17 participants	15 participants
		1.024; (1.004 to 1.045)	1.011; (0.988 to 1.035)	0.989; (0.965 to 1.014)
Tibial, Month 18	Number Analyzed	20 participants	13 participants	16 participants
		1.020; (0.997 to 1.045)	1.021; (0.992 to 1.050)	0.987; (0.961 to 1.014)
Tibial, Month 24	Number Analyzed	19 participants	12 participants	11 participants
		1.001; (0.982 to 1.021)	1.025; (1.001 to 1.050)	0.994; (0.970 to 1.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.065
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.405
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.966
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.003
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.229
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.807
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.042
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.283
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.536
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.765
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.247
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Radial, Month 24
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.050
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.037
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.174
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 6
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.558
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.020
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.346
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 2 mg/kg (Blinded)
	Comments	Tibial, Month 12
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.387
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 20 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority
	Comments	Comparison is between the Visit and Baseline
Statistical Test of Hypothesis	P-Value	0.093
	Comments	Analysis is based on a log transformed ANCOVA model with Change from Baseline as outcome parameter; including categorical effects of treatment and randomization stratum as well as the associated baseline value as a covariate.
	Method	ANCOVA
	Comments	[Not Specified]

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Setrusumab 8 mg/kg (Blinded)
	Comments	Tibial, Month 18
	Type of Statistical Test	Superiority