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Effects of PTH Replacement on Bone in Hypoparathyroidism

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00395538
Recruitment Status : Terminated (Pharmacy temporarily suspended by FDA)
First Posted : November 3, 2006
Results First Posted : January 8, 2019
Last Update Posted : August 28, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Dental and Craniofacial Research (NIDCR) )

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Hypoparathyroidism
DiGeorge Syndrome
Intervention Drug: PTH 1-34
Enrollment 46
Recruitment Details Individuals with hypoparathyroidism were enrolled at the NIH clinical center, beginning in October 2006. The protocol was redesigned and amended in February 2010. Some of the previously enrolled participants were re-enrolled in the new study. New participants were also enrolled on the new study through October 2014.
Pre-assignment Details All participants were put on conventional care therapy for 2-6 months prior to HPTH therapy. Previously enrolled participants had their baseline bone biopsy prior to the study's conventional care period. Newly enrolled participants had their baseline bone biopsy performed at the started of HPTH therapy.
Arm/Group Title Cohort 1: Received HPTH on Original Protocol Cohort 2: Received Conventional Care on Original Protocol Cohort 3: Newly Enrolled No Prior Participation
Hide Arm/Group Description Treated with HPTH therapy on original protocol Treated with conventional care (CC) throughout original protocol New participants in revised protocol
Period Title: Overall Study
Started [1] 8 15 23
Signed Consent to the New Protocol 7 5 23
Received HPTH on New Protocol [2] 7 5 19
Randomized to Bone Biopsy Year 1 0 1 5
Randomized to Bone Biopsy Year 2 0 2 6
Randomized to Bone Biospy Year 4 0 2 8
Completed Bone Biopsy Year 1 0 1 4
Completed Bone Biopsy Year 2 0 2 3
Completed Bone Biopsy Year 4 0 1 1
Completed [3] 5 2 0
Not Completed 3 13 23
Reason Not Completed
Did not re-consent to revised protocol             1             10             0
FDA partial hold on PTH             0             0             11
Failed screening             0             0             4
Switch to Natpara             0             0             3
Adverse Event             1             0             2
DXA or QCT z-score or t-score<-2             0             2             0
Non-compliance with study protocol             0             1             0
PTH resistance             0             0             1
Pregnancy             1             0             0
Partial recovery of parathyroid function             0             0             1
Participant elected to discontinue             0             0             1
[1]
Previously enrolled in original protocol or (for Cohort 3) newly enrolled in current protocol
[2]
This category identifies the subset of subjects in the Safety Population.
[3]
Completed 5 years of HPTH therapy and 6 month safety follow-up visit.
Arm/Group Title Cohort 1 (HPTH on Old Study) and Received HPTH on New Study Cohort 2 (CC on Old Study) and Treated With HPTH on New Study Cohort 3 (Newly Enrolled) and Treated With HPTH on New Study Total
Hide Arm/Group Description Cohort 1 was treated with HPTH therapy on original protocol. Cohort 1 participants who consented to the new protocol and were treated with HPTH on the new protocol were followed for safety outcomes only. The Safety population of Cohort 1 consisted of 7 participants. Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 2 participants who received at least one dose of HPTH on the new protocol were included in safety population. Cohort 2 safety population includes 5 participants. Cohort 3 consists of new participants (i.e. not previously enrolled) that consented to the revised protocol. The Cohort 3 safety population includes 19 subjects who received any HPTH on the new study. Total of all reporting groups
Overall Number of Baseline Participants 7 5 19 31
Hide Baseline Analysis Population Description
Safety Population: The Safety Population will consist of all enrolled subjects (all cohorts) who have started any study treatment including, but not limited to, conventional care. This population will be used for safety data summaries.
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Age Number Analyzed 7 participants 5 participants 19 participants 31 participants
< 20 years
2
  28.6%
0
   0.0%
0
   0.0%
2
   6.5%
20-29 years
0
   0.0%
0
   0.0%
2
  10.5%
2
   6.5%
30-39 years
1
  14.3%
1
  20.0%
6
  31.6%
8
  25.8%
40-49 years
3
  42.9%
3
  60.0%
7
  36.8%
13
  41.9%
50-59 years
1
  14.3%
1
  20.0%
4
  21.1%
6
  19.4%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 5 participants 19 participants 31 participants
Female
6
  85.7%
3
  60.0%
16
  84.2%
25
  80.6%
Male
1
  14.3%
2
  40.0%
3
  15.8%
6
  19.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 5 participants 19 participants 31 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
7
 100.0%
5
 100.0%
19
 100.0%
31
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 5 participants 19 participants 31 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
1
   5.3%
1
   3.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
7
 100.0%
5
 100.0%
18
  94.7%
30
  96.8%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 7 participants 5 participants 19 participants 31 participants
72.2  (14.39) 74.9  (21.92) 82.6  (19.01) 79.0  (18.56)
Height   [1] 
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 3 participants 0 participants 7 participants 10 participants
160.8  (6.93) 171.1  (9.67) 168.0  (9.89)
[1]
Measure Analysis Population Description: Baseline height was missing for some participants.
BMI   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 3 participants 0 participants 7 participants 10 participants
29.71  (2.232) 29.14  (6.310) 29.31  (5.266)
[1]
Measure Analysis Population Description: Since some participants had missing height measures, the BMI could not be calculated for these participants.
1.Primary Outcome
Title Change in Bone Biopsy Cancellous Bone Volume (Cn.BV/TV)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, so the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.BV/TV is one of 8 primary endpoints measured from the bone biopsy. The changes in Cn.BV/TV outcome between two time-points are being reported. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only. )
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: z-score
Biopsy Year 1 - Baseline Number Analyzed 5 participants
3.05  (1.095)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
3.69  (0.940)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
0.64  (1.379)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.BV/TV at biopsy baseline, year 1, 2 & 4 combined as the dependent variable; biopsy year as the independent variable, covariate for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2. No bone biopsy baseline covariate was included because it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the cn.BV/TV between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.015
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.BV/TV at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2. No bone biopsy baseline covariate included because it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the cn.BV/TV between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.002
Comments No adjustments were made for multiple comparisons, because the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with: Cn.BV/TV change from baseline at biopsy year 1 or years 2 and 4 combined as the dependent variable; biopsy year, and baseline Cn.BV/TV, as model covariates; and a random effect for participant. Since Cohort 2 had a time delay of 30 to 31 months from the baseline biopsy to start of HPTH therapy, this time delay (centered to stabilize variance) was added as a covariate to the model for Cohort 2 only (using a Cohort 2 indicator variable).
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the cn.BV/TV between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.649
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
2.Primary Outcome
Title Change in Total Number of Cortical Pores Per mm^2 (Ct.Po.N)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, so the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.Po.N is a bone biopsy measure that assess the amount of holes in the cortical bone within a predetermined area of cortical bone. The changes in Cn.BV/TV outcome between two time-points are being reported. Cortical bone with a higher number of holes may be at greater risk of fracture. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: cortical pores/mm^2
Biopsy Year 1 - Baseline Number Analyzed 4 participants
1.12  (1.214)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
1.86  (1.149)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
0.74  (1.175)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ct.Po.N at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Po.N between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ct.Po.N values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.371
Comments No adjustments were made for multiple comparisons, because the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with: Ct.Po.N change from baseline at biopsy year 1 or years 2 and 4 combined as the dependent variable; biopsy year, and baseline Ct.Po.N, as model covariates; and a random effect for participant. Since Cohort 2 had a time delay of 30 to 31 months from the baseline biopsy to start of HPTH therapy, this time delay (centered to stabilize variance) was added as a covariate to the model for Cohort 2 only (using a Cohort 2 indicator variable).
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Po.N between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.129
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ct.Po.N at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Po.N between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.538
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
3.Primary Outcome
Title Change in Cancellous Bone Formation Rate Per Unit of Bone Surface (Cn.BFR/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.BFR/BS, measured from the bone biopsy, is the cancellous bone formation rate per unit of bone surface where cancellous refers to the spongy structure of the bone. The changes in Cn.BFR/BS between two time-points are being reported. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: z-score
Biopsy Year 1 - Baseline Number Analyzed 5 participants
4.25  (1.420)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
5.75  (1.251)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
1.50  (1.647)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.BFR/BS between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.009
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments A baseline covariate not added to model since it would over-parameterize the model.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.BFR/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.BFR/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.374
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
4.Primary Outcome
Title Change in Cancellous Mineralizing Surface (Bone Surface Based)(Cn.MS/BS)
Hide Description Following their baseline bone biopsy, 5, 5, and 2 participants were randomized to receive their second bone biopsy at years 1, 2, and 4 after the start of HPTH therapy, respectively. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced in size due to withdrawal and the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the cancellous bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Cn.MS/BS between two time-points are being reported.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 and 3 Combined
Hide Arm/Group Description:
Cohort 1 consisted of previously enrolled participants who were on HPTH therapy, were re-consented, and allowed to continue on the current study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only. Cohort 2 were previously enrolled participants on conventional care, were re-consented, re-enrolled, and randomized to a biopsy year. Cohort 3 consisted of all new participants consent, enrolled and randomized to a biopsy year. Efficacy outcomes were only analyzed for Cohorts 2 and 3 combined.
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: percentage of predefined area of bone
Biopsy Year 1 - Baseline Number Analyzed 5 participants
14.63  (3.996)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
21.47  (3.489)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
6.85  (4.774)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 and 3 Combined
Comments Mixed models analysis: Cn.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.MS/BS between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.002
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 and 3 Combined
Comments Mixed models analysis: Cn.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.MS/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 and 3 Combined
Comments Mixed models analysis: Cn.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.MS/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.168
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
5.Primary Outcome
Title Change in Endocortical Bone Formation Rate Per Unit of Bone Surface (Ec.BFR/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. However, because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.BFR/BS is measured from the bone biopsy. This measures the rate of new bone formation per day on the inner cortical (endocortical) surface in a predefined region of cortical bone. The changes in Ec.BFR/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. The randomization to a biopsy year provided the opportunity to compare the effects of PTH across-time, in a cross-sectional manner. However, because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group.
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: um^2/um/d
Biopsy Year 1 - Baseline Number Analyzed 4 participants
0.12  (0.063)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
0.22  (0.055)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
0.10  (0.072)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.BFR/BS between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ec.BFR/BS values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.083
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.BFR/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.BFR/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.164
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
6.Primary Outcome
Title Change in Endocortical Mineralizing Surface (Bone Surface Based) (Ec.MS/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the endocortical bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Ec.MS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants who completed both their baseline and randomized 1, 2, or 4 year bone biopsies. This will only include participants from cohorts 2 and 3.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: percentage of regional interest
Biopsy Year 1 - Baseline Number Analyzed 4 participants
18.39  (7.748)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
30.94  (6.757)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
12.55  (8.944)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.MS/BS between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ec.MS/BS values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.031
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.MS/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.MS/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.178
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
7.Primary Outcome
Title Change in Intracortical Bone Formation Rate Per Unit of Bone Surface (Ic.BFR/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. However, because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.BFR/BS is measured from the bone biopsy. This measures the rate of new bone formation between the two cortical surfaces (intracortical) in a predefined region of cortical bone. The changes in Ic.BFR/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: um^2/um/d
Biopsy Year 1 - Baseline Number Analyzed 4 participants
0.18  (0.045)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
0.10  (0.040)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-0.07  (0.052)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.BFR/BS between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ic.BFR/BS values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.BFR/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.022
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.BFR/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.BFR/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.172
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
8.Primary Outcome
Title Change in Intracortical Mineralizing Surface (Bone Surface Based) (Ic.MS/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the intracortical bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Ic.MS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: percentage of regional interest
Biopsy Year 1 - Baseline Number Analyzed 4 participants
24.75  (6.000)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
14.36  (5.208)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-10.4  (6.999)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.MS/BS between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ic.MS/BS values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.MS/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.018
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.MS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.MS/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.155
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
9.Secondary Outcome
Title Change in Trabecular Thickness (Tb.Th)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Tb.Th is measured from the bone biopsy. Tb.Th is the mean thickness of trabeculae, assessed using direct 3D methods. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Tb.Th between two time-points are being reported.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: z-score
Biopsy Year 1 - Baseline Number Analyzed 5 participants
-0.28  (0.779)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
0.05  (0.675)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
0.33  (0.950)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Tb.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.Th between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.720
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Tb.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.Th between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.944
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Tb.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.Th between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.730
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
10.Secondary Outcome
Title Change in Trabecular Number (Tb.N)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Tb.N is measured from the bone biopsy. Tb.N is the measure of the average number of trabeculae per unit length. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Tb.N between two time-points are being reported.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: z-score
Biopsy Year 1 - Baseline Number Analyzed 5 participants
3.62  (1.382)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
3.30  (1.221)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
-0.32  (1.586)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with: Tb.N change from baseline at biopsy year 1 or years 2 and 4 combined as the dependent variable; biopsy year, and baseline Tb.N, as model covariates; and a random effect for participant. Since Cohort 2 had a time delay of 30 to 31 months from the baseline biopsy to start of HPTH therapy, this time delay (centered to stabilize variance) was added as a covariate to the model for Cohort 2 only (using a Cohort 2 indicator variable).
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.N between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.019
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with: Tb.N change from baseline at biopsy year 1 or years 2 and 4 combined as the dependent variable; biopsy year, and baseline Tb.N, as model covariates; and a random effect for participant. Since Cohort 2 had a time delay of 30 to 31 months from the baseline biopsy to start of HPTH therapy, this time delay (centered to stabilize variance) was added as a covariate to the model for Cohort 2 only (using a Cohort 2 indicator variable).
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.N between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.017
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with: Tb.N change from baseline at biopsy year 1 or years 2 and 4 combined as the dependent variable; biopsy year, and baseline Tb.N, as model covariates; and a random effect for participant. Since Cohort 2 had a time delay of 30 to 31 months from the baseline biopsy to start of HPTH therapy, this time delay (centered to stabilize variance) was added as a covariate to the model for Cohort 2 only (using a Cohort 2 indicator variable).
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.N between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.843
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
11.Secondary Outcome
Title Change in Trabecular Separation (Tb.Sp)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Tb.Sp is measured from the bone biopsy. Tb.Sp is the mean distance between trabeculae, assessed using direct 3D methods. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Tb.Sp between two time-points are being reported.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: z-score
Biopsy Year 1 - Baseline Number Analyzed 5 participants
-2.28  (0.803)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
-1.76  (0.693)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
0.52  (0.997)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Tb.Sp at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.Sp between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.013
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Tb.Sp at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.Sp between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.025
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Tb.Sp at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Tb.Sp between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.608
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
12.Secondary Outcome
Title Change in Average Thickness of Inner and Outer Cortices (Ct.Th)
Hide Description Participants (Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.Th, measured from the bone biopsy, is the average thickness of the inner and outer cortices. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Ct.Th between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: z-score
Biopsy Year 1 - Baseline Number Analyzed 4 participants
2.02  (0.916)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
0.78  (0.771)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-1.25  (1.092)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ct.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Th between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ct.Th values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.043
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ct.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Th between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.334
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with: Ct.Th change from baseline at biopsy year 1 or years 2 and 4 combined as the dependent variable; biopsy year, and baseline Ct.Th, as model covariates; and a random effect for participant. Since Cohort 2 had a time delay of 30 to 31 months from the baseline biopsy to start of HPTH therapy, this time delay (centered to stabilize variance) was added as a covariate to the model for Cohort 2 only (using a Cohort 2 indicator variable).
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Th between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.269
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
13.Secondary Outcome
Title Total Area of Inner and Outer Cortices (Ct.Ar)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.AR is measured from the bone biopsy. This measure defines the area of the outer cortex and inner cortex within a predefined section of cortical bone. The changes in Ct.Ar between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: percentage of region of interest
Biopsy Year 1 - Baseline Number Analyzed 4 participants
6.56  (6.905)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
1.93  (6.128)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-4.64  (8.006)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ct.Ar at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Ar between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ct.Ar values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.358
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ct.Ar at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Ar between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.760
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ct.Ar at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Ar between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.570
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
14.Secondary Outcome
Title Change in Total Area of Cortical Porosity (Ct.Po.Ar)
Hide Description Following their baseline bone biopsy, 5, 5, and 2 participants were randomized to receive their second bone biopsy at years 1, 2, and 4 after the start of HPTH therapy, respectively. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced in size due to withdrawal and the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.Po.Ar is measured from the bone biopsy. This measure defines the area of the cortical bone with holes within a predefined section of cortical bone. The changes in Tb.Sp between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants who completed both their baseline and randomized 1, 2, or 4 year bone biopsies. This will only include participants from cohorts 2 and 3.
Arm/Group Title Cohorts 2 and 3 Combined
Hide Arm/Group Description:
Cohort 1 consisted of previously enrolled participants who were on HPTH therapy, were re-consented, and allowed to continue on the current study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only. Cohort 2 were previously enrolled participants on conventional care, were re-consented, re-enrolled, and randomized to a biopsy year. Cohort 3 consisted of all new participants consent, enrolled and randomized to a biopsy year. Efficacy outcomes were only analyzed for Cohorts 2 and 3 combined.
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: percentage of region of interest
Biopsy Year 1 - Baseline Number Analyzed 4 participants
3.41  (2.337)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
0.26  (1.911)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-3.15  (2.837)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 and 3 Combined
Comments Mixed models analysis: Ct.Po.Ar at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Po.Ar between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ct.Po.Ar values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.166
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 and 3 Combined
Comments Mixed models analysis: Ct.Po.Ar at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Po.Ar between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.895
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 and 3 Combined
Comments Mixed models analysis: Ct.Po.Ar at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ct.Po.Ar between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.282
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
15.Secondary Outcome
Title Change in Cancellous Osteoid Thickness (Cn.O.Th)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.O.Th measured from the bone biopsy. This measures the thickness of the unmineralized bone (osteoid) in a predefined region of cancellous bone. The changes in Cn.O.Th between two time-points are being reported.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: um
Biopsy Year 1 - Baseline Number Analyzed 5 participants
1.99  (0.553)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
2.29  (0.472)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
0.30  (0.704)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.O.Th between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.003
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.O.Th between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.O.Th between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.680
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
16.Secondary Outcome
Title Change in Cancellous Bone Mineral Apposition Rate (Cn.MAR)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.MAR is measured from the bone biopsy. This measures the rate mineral is being laid down per day in a predefined region of the cancellous bone. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Cn.MAR between two time-points are being reported.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: z-score
Biopsy Year 1 - Baseline Number Analyzed 5 participants
3.21  (1.002)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
3.07  (0.885)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
-0.14  (1.151)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.MAR between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.006
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.MAR between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.004
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.MAR between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.904
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
17.Secondary Outcome
Title Change in Cancellous Osteoid Surface / Bone Surface (Cn.OS/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.OS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the cancellous bone surface that contains unmineralized bone (osteoid). The region of interest is the predefined area of total bone that is being measured. The changes in Cn.OS/BS between two time-points are being reported.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: percentage of region of interest
Biopsy Year 1 - Baseline Number Analyzed 5 participants
12.70  (3.407)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
24.34  (2.971)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
11.64  (4.084)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.OS/BS between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.002
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.OS/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.OS/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.010
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
18.Secondary Outcome
Title Change in Cancellous Eroded Surface / Bone Surface (Cn.ES/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.ES/BS is measured from the bone biopsy. This measure demonstrates the percentage of the cancellous bone surface that contains unmineralized bone (osteoid). The region of interest is the predefined area of total bone that is being measured. The changes in Cn.ES/BS between two time-points are being reported.
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 12
Least Squares Mean (Standard Error)
Unit of Measure: percentage of region of interest
Biopsy Year 1 - Baseline Number Analyzed 5 participants
6.55  (1.648)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
10.30  (1.543)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 12 participants
3.75  (1.415)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.ES/BS between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.ES/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.ES/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.020
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
19.Secondary Outcome
Title Change in Cancellous Adjusted Apposition Rate (Cn.AjAR)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.AjAR is measured from the bone biopsy. Cn.AjAR represents the Cn.MAR averaged over the entire osteoid surface.The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Cn.AjAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: z-score
Biopsy Year 1 - Baseline Number Analyzed 5 participants
3.10  (0.824)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 6 participants
1.89  (0.722)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-1.21  (0.972)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.AjAR between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.002
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.AjAR between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.022
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Cn.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cn.AjAR between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.228
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
20.Secondary Outcome
Title Change in Endocortical Osteoid Thickness (Ec.O.Th)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.O.Th is measured from the bone biopsy. This measures the thickness of the unmineralized bone (osteoid) on the inner side of the cortex(endocortical). The changes in Cn.AjAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: um
Biopsy Year 1 - Baseline Number Analyzed 4 participants
2.15  (0.628)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
1.84  (0.552)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-0.31  (0.718)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.O.Th between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ec.O.Th values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.004
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.O.Th between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.006
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.O.Th between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.670
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
21.Secondary Outcome
Title Change in Endocortical Bone Mineral Apposition Rate (Ec.MAR)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose.Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.MAR is measured from the bone biopsy. This measures the rate mineral is being laid down per day on the inner cortical (endocortical) surface in a predefined region of cortical bone. The changes in Ec.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: um/d
Biopsy Year 1 - Baseline Number Analyzed 4 participants
0.41  (0.115)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
0.46  (0.104)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
0.05  (0.126)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.MAR between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ec.MAR values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.003
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.MAR between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.MAR between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.712
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
22.Secondary Outcome
Title Change in Endocortical Osteoid Surface / Bone Surface (Ec.OS/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.OS/BS is measured from the bone biopsy. This measures the rate mineral is being laid down per day on the inner cortical (endocortical) surface in a predefined region of cortical bone. The changes in Ec.OS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: percentage of region of interest
Biopsy Year 1 - Baseline Number Analyzed 4 participants
13.43  (5.606)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
24.56  (4.872)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
11.13  (6.491)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.OS/BS between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ec.OS/BS values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.029
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.OS/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.OS/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.104
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
23.Secondary Outcome
Title Change in Endocortical Eroded Surface / Bone Surface (Ec.ES/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4- year biopsies were collapsed into one biopsy year group. Ec.ES/BS is measured from the bone biopsy. This measure demonstrates the percentage of the endocortical bone surface that is resorbed (eroded). The region of interest is the predefined area of total bone that is being measured. The changes in Ec.ES/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: percentage of region of interest
Biopsy Year 1 - Baseline Number Analyzed 4 participants
5.95  (3.270)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
9.29  (3.063)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
3.34  (3.288)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.ES/BS between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ec.ES/BS values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.088
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.ES/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.009
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.ES/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.325
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
24.Secondary Outcome
Title Change in Endocortical Adjusted Apposition Rate (Ec.AjAR)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.AjAR is measured from the bone biopsy. Ec.AjAR represents the endocortical mineral apposition rate (Ec.MAR) averaged over the entire osteoid surface. This is another histomorphometric way to evaluate the rate at which bone is laid down on the inner cortical surface per day. The changes in Ec.AjAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 8
Least Squares Mean (Standard Error)
Unit of Measure: um/d
Biopsy Year 1 - Baseline Number Analyzed 3 participants
0.50  (0.109)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 5 participants
0.49  (0.088)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 8 participants
-0.00  (0.135)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.AjAR between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 3 participants with non-missing Ec.AjAR values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.AjAR between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ec.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ec.AjAR between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.974
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
25.Secondary Outcome
Title Change in Intracortical Osteoid Thickness (Ic.O.Th)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.O.Th is one of 21 secondary endpoints measured from the bone biopsy. This measures the thickness of the unmineralized bone (osteoid) within the middle of the cortex (intracortical). The changes in Ic.O.Th between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: um
Biopsy Year 1 - Baseline Number Analyzed 4 participants
2.39  (0.687)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
1.48  (0.564)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-0.91  (0.833)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.O.Th between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ic.O.Th values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.004
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.O.Th between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.023
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.O.Th at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.O.Th between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.288
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
26.Secondary Outcome
Title Change in Intracortical Bone Mineral Apposition Rate (Ic.MAR)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.MAR is measured from the bone biopsy. This measures the rate mineral is being laid down per day within the middle of the cortex (intracortical) surface in a predefined region of cortical bone. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: um/d
Biopsy Year 1 - Baseline Number Analyzed 4 participants
0.23  (0.174)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
0.12  (0.161)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
-0.12  (0.185)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.MAR between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ic.MAR values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.202
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.MAR between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.486
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.MAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.MAR between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.535
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
27.Secondary Outcome
Title Change in Intracortical Osteoid Surface / Bone Surface (Ic.OS/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.OS/BS measured from the bone biopsy. This measure demonstrates the percentage of the intracortical bone surface that is not mineralized (osteoid). The region of interest is the predefined area of total bone that is being measured. The changes in OS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: percentage of region of interest
Biopsy Year 1 - Baseline Number Analyzed 4 participants
18.39  (4.284)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
13.17  (3.540)
Years 2 and 4 (combined) - Year 1 Biopsy Number Analyzed 11 participants
-5.22  (5.181)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.OS/BS between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ic.OS/BS values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.OS/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.003
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.OS/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.OS/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.328
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
28.Secondary Outcome
Title Change in Intracortical Eroded Surface / Bone Surface (Ic.ES/BS)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.ES/BS is measured from the bone biopsy. This measure demonstrates the percentage of bone surface within the middle of the cortex that is resorbed (eroded). The region of interest is the predefined area of total bone that is being measured. The changes in Ic.ES/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: percentage of region of interest
Biopsy Year 1 - Baseline Number Analyzed 4 participants
6.79  (1.840)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 7 participants
7.40  (1.500)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 11 participants
0.61  (2.239)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.ES/BS between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ic.ES/BS values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.002
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.ES/BS between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value <0.001
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.ES/BS at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Equivalence
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.ES/BS between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.789
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
29.Secondary Outcome
Title Change in Intracortical Adjusted Apposition Rate (Ic.AjAR)
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.AjAR is one of 21 secondary endpoints measured from the bone biopsy. Ic.AjAR represents the intracortical mineral apposition rate (Ic.MAR) averaged over the the entire osteoid surface. This is another histomorphometric way to evaluate the rate at which bone is laid down within the middle of the cortex per day. The changes in Ic.AjAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline values)
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 10
Least Squares Mean (Standard Error)
Unit of Measure: um/d
Biopsy Year 1 - Baseline Number Analyzed 4 participants
0.16  (0.349)
Biopsy Years 2 and 4 (combined) - Baseline Number Analyzed 6 participants
-0.18  (0.318)
Biopsy Years 2 and 4 (combined) - Year 1 Number Analyzed 10 participants
-0.34  (0.345)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.AjAR between the baseline and the year 1 biopsy. P-value interpretation is questionable since there were only 4 participants with non-missing Ic.AjAR values for both their baseline and year 1 biopsies.
Statistical Test of Hypothesis P-Value 0.651
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.AjAR between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.580
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis: Ic.AjAR at biopsy baseline, year 1, and years 2 and 4 combined as the dependent variable; biopsy year as the independent variable, model covariates for Cohort; and a random effect for participant. Since Cohort 2 had a time delay from the baseline biopsy to start of HPTH therapy, this time delay (centered) was added as a covariate for Cohort 2 (using a Cohort 2 indicator variable). No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Ic.AjAR between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.338
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
30.Secondary Outcome
Title Change in Cortex 1 Spectral Calcium Mean From the Back-Scattered Electron Imaging of Bone-Biopsies
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium Mean is a measure of mean bone calcium content of the bone cortex 1 based on the mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of the region of interest
Year 1 - Baseline Biopsy Number Analyzed 5 participants
-0.98  (0.357)
Years 2 and 4 (combined) - Baseline Biopsy Number Analyzed 6 participants
-1.15  (0.633)
Years 2 and 4 (combined) - Year 1 Biopsy Number Analyzed 11 participants
-0.16  (0.525)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Mean as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Mean between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.020
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Mean as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Mean between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.110
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Mean as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Mean between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.764
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
31.Secondary Outcome
Title Change in Cortex 1 Spectral Calcium Peak From the Back-Scattered Electron Imaging of Bone-Biopsies
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium Peak is a measure of the most frequent calcium content of the bone cortex 1 based on the bone mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of the region of interest
Year 1 Biopsy - Baseline Biopsy Number Analyzed 5 participants
-0.47  (0.365)
Years 2 and 4 (combined) - Baseline Biopsy Number Analyzed 6 participants
-0.96  (0.673)
Years 2 and 4 (combined) - Year 1 Biopsy Number Analyzed 11 participants
-0.49  (0.588)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Peak as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Peak between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.227
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Peak as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Peak between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.194
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Peak as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Peak between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.434
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
32.Secondary Outcome
Title Change in Cortex 1 Spectral Calcium Width From the Back-Scattered Electron Imaging of Bone-Biopsies
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium Low is a measure of the area of low bone cortex 1 mineralization based on the mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of the region of interest
Year 1 - Baseline Biopsy Number Analyzed 5 participants
1.24  (0.343)
Years 2 and 4 (combined) - Baseline Biopsy Number Analyzed 6 participants
1.13  (0.302)
Years 2 and 4 (combined) - Year 1 Biopsy Number Analyzed 11 participants
-0.11  (0.415)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Width as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Width between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.003
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Width as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Width between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.002
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Width as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Width between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.787
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
33.Secondary Outcome
Title Change in Cortex 1 Spectral Calcium Low From the Back-Scattered Electron Imaging of Bone-Biopsies
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium Low is a measure of the area of low bone cortex 1 mineralization based on the mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of the region of interest
Year 1 - Baseline Biopsy Number Analyzed 5 participants
4.95  (2.172)
Years 2 and 4 (combined) - Baseline Biopsy Number Analyzed 6 participants
7.51  (3.245)
Years 2 and 4 (combined) - Year 1 Biopsy Number Analyzed 11 participants
2.55  (4.088)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Low as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Low between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.082
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Low as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Low between the baseline and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.057
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium Low as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium Low between the year 1 biopsy and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.547
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
34.Secondary Outcome
Title Change in Cortex 1 Spectral Calcium High From the Back-Scattered Electron Imaging of Bone-Biopsies
Hide Description Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium High is a measure of the area of high bone cortex 1 mineralization based on the mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).
Time Frame Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Hide Outcome Measure Data
Hide Analysis Population Description
The Bone Biopsy Analysis Population was used for the primary bone biopsy biomarkers. The Bone Biopsy Population consisted of all participants in Cohorts 2 and 3 who completed both their baseline and randomized 1, 2, or 4 year bone biopsies.
Arm/Group Title Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Hide Arm/Group Description:
Cohort 2 consists of participants previously treated with conventional care (CC) throughout the original protocol. Cohort 3 consisted of all new participants. Efficacy outcomes were only analyzed for Cohorts 2 and 3. (Cohort 1 consisted of previously enrolled participants who were on HPTH therapy on the original protocol and continued on HPTH on the new study as a separate group. These participants were not randomized to a bone biopsy year, nor did they have additional biopsies performed. Cohort 1 participants were followed for safety outcomes only.)
Overall Number of Participants Analyzed 11
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of the region of interest
Year 1 - Baseline Biopsy Number Analyzed 5 participants
-0.40  (4.052)
Years 2 and 4 (combined) - Baseline Biopsy Number Analyzed 6 participants
-3.54  (3.592)
Years 2 and 4 (combined) - Year 1 Biopsy Number Analyzed 11 participants
-3.14  (4.049)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium High as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium High between the baseline and the year 1 biopsy.
Statistical Test of Hypothesis P-Value 0.922
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohorts 2 (CC on Old Study) and 3 (Newly Enrolled) Combined
Comments Mixed models analysis was performed with Cortex 1 Spectral Calcium High as the dependent variable; biopsy year (baseline, year 1, and years 2 and 4 combined) as the independent variable; study cohort as a covariate; and a random effect for participant. No bone biopsy baseline covariate included since it would over-parameterize the model.
Type of Statistical Test Other
Comments A contrast statement within the mixed models analysis tested for differences in the Cortex 1 Spectral Calcium High between the year 1 and the years 2 and 4 (combined) biopsy.
Statistical Test of Hypothesis P-Value 0.342
Comments No adjustments were made for multiple comparisons, since the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively.
Method Mixed Models Analysis
Comments [Not Specified]